REGULATORY NUCLEIC ACID SEQUENCES
20230233710 · 2023-07-27
Assignee
Inventors
- Jorge Omar Yanez-Cuna (Edinburgh, GB)
- Juan Manuel Iglesias (Edinburgh, GB)
- Sinclair Cooper (Edinburgh, GB)
- Katie Baker (Edinburgh, GB)
- Polyxeni Katsoupi (Edinburgh, GB)
- Rinku Rajan (Edinburgh, GB)
- Ileana Guerrini (Edinburgh, GB)
- Antonia Evripioti (Edinburgh, GB)
- Kira Mourao (Edinburgh, GB)
- Michael L. Roberts (Edinburgh, GB)
Cpc classification
A61K48/0058
HUMAN NECESSITIES
C12N2830/008
CHEMISTRY; METALLURGY
C12N2750/14143
CHEMISTRY; METALLURGY
A61K48/005
HUMAN NECESSITIES
International classification
A61K48/00
HUMAN NECESSITIES
Abstract
The present invention relates to regulatory nucleic acid sequences, in particular muscle-specific promoters, elements thereof, and other such nucleic acid sequences, that are capable of enhancing muscle-specific expression of genes. The invention also relates to expression constructs, vectors and cells comprising such muscle-specific regulatory nucleic acid sequences, and to methods of their use. The regulatory nucleic acid sequences are of particular utility for gene therapy applications, but also find utility in other areas such as bioprocessing and biotechnology.
Claims
1-49. (canceled)
50. A synthetic cardiac muscle-specific CRM comprising two or more operably linked CREs selected from the group consisting of: CRE0035 (SEQ ID NO: 310) or a functional variant thereof; CRE0029 (SEQ ID NO: 307) or a functional variant thereof; CRE0069 (SEQ ID NO: 320) or a functional variant thereof; CRE0071 (SEQ ID NO: 321) or a functional variant thereof; CRE0036 (SEQ ID NO: 311) or a functional variant thereof; CRE0096 (SEQ ID NO: 417) or a functional variant thereof; CRE0079 (SEQ ID NO: 329) or a functional variant thereof; CRE0051 (SEQ ID NO: 314) or a functional variant thereof; CRE0031 (SEQ ID NO: 308) or a functional variant thereof; and CRE0020 (SEQ ID NO: 303) or a functional variant thereof.
51. The synthetic cardiac muscle-specific CRM of claim 50, comprising a combination of CREs, or functional variants thereof, selected from the groups of: CRE0020, CRE0029 and CRE0071; CRE0020, CRE0069 and CRE0071; CRE0029, CRE0035 and CRE0071; CRE0020, CRE0020 and CRE0071; CRE0020 and CRE0071; CRE0079 and CRE0071; CRE0035 and CRE0071; CRE0029 and CRE0071; CRE0035 and CRE0036; CRE0069 and CRE0051; CRE0069 and CRE0071; CRE0035 and CRE0031; CRE0035 and CRE0035; CRE0079 and CRE0035; CRE0020 and CRE0036; CRE0069 and CRE0035; CRE0029 and CRE0071; CRE0071 and CRE0035; CRE0035 and CRE0020; CRE0029 and CRE0035; CRE0035 and CRE0036; CRE0020 and CRE0035; and CRE0071 and CRE0020.
52. The synthetic cardiac muscle-specific CRM of claim 51, wherein the CREs are present in the CRM in the recited order and preferably adjacent to one another.
53. The synthetic cardiac muscle-specific CRM of claim 50, wherein the CRM is selected from the group consisting of: CRM_SP0229 (SEQ ID NO: 185), CRM_SP0228 (SEQ ID NO: 184), CRM_SP0328 (SEQ ID NO: 217), CRM_SP0229A (SEQ ID NO: 549), CRM_SP0349 (SEQ ID NO: 236), CRM_SP0230 (SEQ ID NO: 186), CRM_SP0279 (SEQ ID NO: 198), CRM_SP0366 (SEQ ID NO: 251), CRM_SP0467 (SEQ ID NO: 527), CRM_SP0332 (SEQ ID NO: 221), CRM_SP0057 (SEQ ID NO: 145), CRM_SP0159 (SEQ ID NO: 172), CRM_SP0134 (SEQ ID NO: 161), CRM_SP0322 (SEQ ID NO: 211), CRM_SP0327 (SEQ ID NO: 216), CRM_SP0345 (SEQ ID NO: 232), CRM_SP0160 (SEQ ID NO: 173), CRM_SP0350 (SEQ ID NO: 237), CRM_SP0346 (SEQ ID NO: 233), CRM_SP0231 (SEQ ID NO: 187), CRM_SP0309 (SEQ ID NO: 202), CRM_SP0368 (SEQ ID NO: 253), CRM_SP0158 (SEQ ID NO: 171), CRM_SP0338 (SEQ ID NO: 226), CRM_SP0364 (SEQ ID NO: 249), CRM_SP0468 (SEQ ID NO: 528), CRM_SP0232 (SEQ ID NO: 188), CRM_SP0156 (SEQ ID NO: 169), CRM_SP0306 (SEQ ID NO: 200), CRM_SP0453 (SEQ ID NO: 514), CRM_SP0459 (SEQ ID NO: 520), CRM_SP0163 (SEQ ID NO: 176), CRM_SP0162 (SEQ ID NO: 175), CRM_SP0307 (SEQ ID NO: 201), CRM_SP0471 (SEQ ID NO: 530), CRM_SP0458 (SEQ ID NO: 519), CRM_SP0161 (SEQ ID NO: 174), CRM_SP0464 (SEQ ID NO: 524), CRM_SP0463 (SEQ ID NO: 523), and CRM_SP0465 (SEQ ID NO: 525), or a functional variant of any thereof.
54. A synthetic cardiac muscle-specific promoter comprising: a) at least one CRM of claim 50 or b) at least one of the following CREs: CRE0035 (SEQ ID NO: 310) or a functional variant thereof; CRE0029 (SEQ ID NO: 307) or a functional variant thereof; CRE0069 (SEQ ID NO: 320) or a functional variant thereof; CRE0071 (SEQ ID NO: 321) or a functional variant thereof; CRE0036 (SEQ ID NO: 311) or a functional variant thereof; CRE0096 (SEQ ID NO: 417) or a functional variant thereof; CRE0079 (SEQ ID NO: 329) or a functional variant thereof; CRE0051 (SEQ ID NO: 314) or a functional variant thereof; CRE0031 (SEQ ID NO: 308) or a functional variant thereof; and CRE0020 (SEQ ID NO: 303) or a functional variant thereof, operably linked to a promoter element selected from: SKM_18 (SEQ ID NO: 135) or a functional variant thereof; CRE0070 (SEQ ID NO: 284) or a functional variant thereof; CRE0010 ITGB1BP2 (SEQ ID NO: 272) or a functional variant thereof; CRE0037 (SEQ ID NO: 275) or a functional variant thereof; CRE0046 (SEQ ID NO: 276) or a functional variant thereof; and Des_mp_V1 (SEQ ID NO: 292) or a functional variant thereof.
55. The synthetic cardiac muscle-specific promoter of claim 54, wherein the promoter is selected from the group consisting of SP0229, SP0228, SP0328, SP0229A, SP0349, SP0230, SP0279, SP0366, SP0467, SP0332, 20 SP0057, SP0159, SP0134, SP0322, SP0327, SP0345, SP0160, SP0350, SP0346, SP0231, SP0309, SP0368, SP0158, SP0338, SP0364, SP0468, SP0232, SP0156, SP0306, SP0453, SP0459, SP0163, SP0162, SP0307, SP0471, SP0458, SP0161, SP0464, SP0463, SP0465, or selected from the group consisting of: SP0326, SP0286, SP0451, SP0042, SP0362, SP0334, SP0343, SP0066, SP0440, SP0170, SP0347, SP0469, SP0068, SP0267, SP0132, SP0310, SP0365, SP0379, SP0339, SP0136, SP0325, SP0337, SP0270, SP0457, SP0268, SP0341, SP0378, SP0380, SP0262, SP0359, SP0455, SP0381, SP0441, SP0153, SP0442, SP0154, SP0155, SP0454, SP0456, SP0305, SP0382, SP0279, SP0320, SP0366, SP0467, SP0332, SP0057, SP0159, SP0134, SP0322, SP0257, SP0327, SP0345, SP0173, SP0160, SP0350, SP0346, SP0231, SP0309, SP0368, SP0158, SP0338, SP0364, SP0468, SP0232, SP0453, SP0340, SP0471, SP0229, SP0228, SP0328, SP0349, and SP0230, or a functional variant of any thereof.
56. An expression cassette comprising a synthetic cardiac muscle-specific promoter of claim 54 operably linked to a sequence encoding an expression product.
57. A vector comprising a synthetic cardiac muscle-specific promoter of claim 54.
58. A vector comprising an expression cassette according to claim 56.
59. The vector of claim 57, which is an AAV vector, an adenoviral vector, a retroviral vector or a lentiviral vector.
60. The vector of claim 58, which is an AAV vector, an adenoviral vector, a retroviral vector or a lentiviral vector.
61. A virion comprising a vector according to claim 57.
62. A pharmaceutical composition comprising a synthetic cardiac muscle-specific promoter of claim 54.
63. A cell comprising a synthetic cardiac muscle-specific promoter of claim 54.
64. A method for producing an expression product, the method comprising providing a synthetic muscle-specific expression cassette of claim 56 in a muscle cell and expressing the gene present in the synthetic muscle-specific expression cassette.
65. A method of expressing a therapeutic transgene in a muscle cell, the method comprising introducing into the muscle cell a synthetic muscle-specific expression cassette of claim 56.
66. A method of therapy of a subject in need thereof, the method comprising: administering to the subject an expression cassette comprising a sequence encoding a therapeutic product operably linked to a promoter of claim 54, and expressing a therapeutic amount of the therapeutic product in the muscle of said subject.
67. A method of therapy of a subject in need thereof, the method comprising: administering to the subject an expression cassette of claim 56, and expressing a therapeutic amount of the therapeutic product in the muscle of said subject.
68. A method of therapy of a subject in need thereof, the method comprising: administering to the subject a vector of claim 57, and expressing a therapeutic amount of the therapeutic product in the muscle of said subject.
69. The method of therapy of a subject of claim 66, wherein the therapeutic amount of the therapeutic product is expressed in the skeletal and/or cardiac muscle.
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF EMBODIMENTS THE INVENTION AND EXAMPLES
[0844] CREs and Functional Variants Thereof:
[0845] Disclosed herein are various CREs that can be used in the construction of muscle-specific promoters. These CREs are generally derived from genomic promoter and enhancer sequences, but they are used herein in contexts quite different from their native genomic environment. Generally, the CREs constitute small parts of much larger genomic regulatory domains, which control expression of the genes with which they are normally associated. It has been surprisingly found that these CREs, many of which are very small, can be isolated form their normal environment and retain muscle-specific regulatory activity when used to construct various synthetic promoters. This is surprising because the removal of a regulatory sequence from the complex and “three dimensional” natural context in the genome often results in a significant loss of activity, so there is no reason to expect a given CRE to retain the levels of activity observed once removed from their natural environment. Many combinations of these CREs have been tested and found to be highly effective at enhancing muscle-specific promoter activity when combined with minimal and proximal promoters. It should be noted that the sequences of the CREs of the present invention can be altered without causing a substantial loss of activity. Functional variants of the CREs can be prepared by modifying the sequence of the CREs, provided that modifications which are significantly detrimental to activity of the CRE are avoided. In view of the information provided in the present disclosure, modification of CREs to provide functional variants is straightforward. Moreover, the present disclosure provides methodologies for simply assessing the functionality of any given CRE variant. Functional variants for each CRE are discussed below.
[0846] Functional variants of some of the CREs according to the present invention are shown in Table 11. CRE0020.2 (SEQ ID NO: 411), CRE0093 (SEQ ID NO: 412), CRE0094 (SEQ ID NO: 413), CRE0093.2 (SEQ ID NO: 545) and CRE0094.2 (SEQ ID NO: 546) are functional variants of CRE0020 (SEQ ID NO: 303) and vice versa. CRE0117 (SEQ ID NO: 469) is a functional variant of CRE0028 (SEQ ID NO: 306) and vice versa. CRE0029.2 (SEQ ID NO: 395) is a functional variant of CRE0029 (SEQ ID NO: 307) and vice versa. CRE0108 (SEQ ID NO: 465) is a functional variant of CRE0033 (SEQ ID NO: 309) and vice versa. CRE0050 (SEQ ID NO: 313) and CRE0099 (SEQ ID NO: 300) are functional variants of CRE0035 (SEQ ID NO: 310). DES_MT_enhancer_48 bp (SEQ ID NO: 547), DES_MT_enhancer_48 bp_v2 (SEQ ID NO: 335), DES_MT_enhancer_48 bp_v3 (SEQ ID NO: 336), DES_MT_enhancer_72 bp (SEQ ID NO: 400), DES_MT_enhancer_72 bp_v2 (SEQ ID NO: 337), DES_MT_enhancer_72 bp_v3 (SEQ ID NO: 338), DES_MT_enhancer_72 bp_v4 (SEQ ID NO: 339), DES_MT_enhancer_72 bp_v5 (SEQ ID NO: 340), DES_MT_enhancer_72 bp_v6 (SEQ ID NO: 341), CRE0059 (SEQ ID NO: 317) and CRE0060 (SEQ ID NO: 318) are functional variants of CRE0047 (SEQ ID NO: 312). CRE0084 (SEQ ID NO: 404) is a functional variant of CRE0052 (SEQ ID NO: 315) and vice versa. CRE0069.2 (SEQ ID NO: 396) is a functional variant of CRE0069 (SEQ ID NO: 320) and vice versa. CRE0051 (SEQ ID NO: 314), CRE0071.2 (SEQ ID NO: 323), CRE0071.3 (SEQ ID NO: 293), CRE0071.4 (SEQ ID NO: 294), CRE0071.5 (SEQ ID NO: 537), CRE0071.6 (SEQ ID NO: 295), CRE0071.7 (SEQ ID NO: 331), CRE0071.8 (SEQ ID NO: 296), CRE0071.9 (SEQ ID NO: 297), CRE0071.10 (SEQ ID NO: 332), CRE0071.11 (SEQ ID NO: 333), CRE0071.12 (SEQ ID NO: 334), CRE0071.13 (SEQ ID NO: 397), CRE0071.14 (SEQ ID NO: 398), CRE0071.15 (SEQ ID NO: 399), CRE0071.16 (SEQ ID NO: 533), CRE0071.17 (SEQ ID NO: 534), CRE0071.18 (SEQ ID NO: 535), CRE0071.19 (SEQ ID NO: 536), CRE0071.20 (SEQ ID NO: 538), CRE0071.21 (SEQ ID NO: 539), CRE0071.22 (SEQ ID NO: 540), CRE0071.23 (SEQ ID NO: 541), CRE0071.24 (SEQ ID NO: 543) are functional variants of CRE0071 (SEQ ID NO: 321) and vice versa. CRE0074 (SEQ ID NO: 325) and CRE0075 (SEQ ID NO: 326) are functional variants of CRE0073 (SEQ ID NO: 324) and vice versa. CRE0077 (SEQ ID NO: 298) are functional variants of CRE0076 (SEQ ID NO: 327) and vice versa. CRE0092 (SEQ ID NO: 420) is a functional variant of CRE0081 (SEQ ID NO: 402) and vice versa. CRE0091 (SEQ ID NO: 410) is a functional variant of CRE0090 (SEQ ID NO: 409) and vice versa.
[0847] The relatively small size of certain CREs according to the present invention is advantageous because it allows for the CREs, more specifically promoters containing them, to be provided in vectors while taking up the minimal amount of the payload of the vector. This is particularly important when a CRE is used in a vector with limited capacity, such as an AAV-based vector.
[0848] CREs of the present invention comprise certain muscle-specific TFBS. It is generally desired that in functional variants of the CREs these muscle-specific TFBS remain functional. The skilled person is well aware that TFBS sequences can vary yet retain functionality. In view of this, the sequence for a TFBS is typically illustrated by a consensus sequence from which some degree of variation is typically present. Further information about the variation that occurs in a TFBS can be illustrated using a positional weight matrix (PWM), which represents the frequency with which a given nucleotide is typically found at a given location in the consensus sequence. Details of TF consensus sequences and associated positional weight matrices can be found in, for example, the Jaspar or Transfac databases http://jaspar.genereg.net/and http://gene-regulation.com/pub/databases.html). This information allows the skilled person to modify the sequence in any given TFBS of a CRE in a manner which retains, and in some cases even increases, CRE functionality. In view of this the skilled person has ample guidance on how the TFBS for any given TF can be modified, while maintaining ability to bind the desired TF; the Jaspar system will, for example, score a putative TFBS based on its similarity to a given PWM. Furthermore, CREs can be scanned against all PWM from JASPAR database to identify/analyse all TFBS. The skilled person can of course find additional guidance in the literature, and, moreover, routine experimentation can be used to confirm TF binding to a putative TFBS in any variant CRE. It will be apparent that significant sequence modification in a CRE, even within TFBS in a CRE, can be made while retaining function.
[0849] Synthetic Muscle-Specific CRMs and Functional Variants Thereof:
[0850] Various synthetic muscle-specific CRMs are disclosed herein that can be used in the constructions of synthetic muscle-specific promoters. CRMs of the present invention can be used in combination with a wide range of suitable minimal promoters or muscle-specific proximal promoters.
[0851] Functional variants of a CRM include sequences which vary from the reference CRM element, but which substantially retain activity as muscle-specific CRMs. It will be appreciated by the skilled person that it is possible to vary the sequence of a CRM while retaining its ability to recruit suitable muscle-specific transcription factors (TFs) and thereby enhance expression. A functional variant of a CRM can comprise substitutions, deletions and/or insertions compared to a reference CRM, provided they do not render the CRM substantially non-functional.
[0852] In some embodiments, a functional variant of a CRM can be viewed as a CRM which, when substituted in place of a reference CRM in a promoter, substantially retains its activity. For example, a muscle-specific promoter which comprises a functional variant of a given CRM preferably retains at least 80% of its activity, more preferably at least 90% of its activity, more preferably at least 95% of its activity, and yet more preferably 100% of its activity (compared to the reference promoter comprising the unmodified CRM).
[0853] Suitably, functional variants of a CRM retain a significant level of sequence identity to a reference CRM. Suitably functional variants comprise a sequence that is at least 70% identical to the reference CRM, more preferably at least 80%, 90%, 95% or 99% identical to the reference CRM.
[0854] Retention of activity can be assessed by comparing expression of a suitable reporter under the control of the reference promoter with an otherwise identical promoter comprising the substituted CRE under equivalent conditions. Suitable assays for assessing muscle-specific promoter activity are disclosed herein, e.g. in the examples.
[0855] Functional variants of a given CRM can, in some embodiments, comprise functional variants of one or more of the CREs present in the reference CRM. For example, functional variants of a given CRM can comprise functional variants of 1, 2, 3, 4, 5, or 6 of the CREs present in the reference CRM.
[0856] Functional variants of a given CRM can, in some embodiments, comprise the same combination CREs as a reference CRM, but the CREs can be present in a different order from the reference CRM. It is usually preferred that the CREs are present in the same order as the reference CRM (thus, the functional variant of a CRM suitably comprises the same permutation of the CREs as set out in a reference CRM).
[0857] Functional variants of a given CRM can, in some embodiments, comprise one or more additional CREs to those present in a reference CRM. Additional CREs can be provided upstream of the CREs present in the reference CRM, downstream of the CREs present in the reference CRM, and/or between the CREs present in the reference CRM. The additional CREs can be CREs disclosed herein, or they can be other CREs. Generally, it is preferred that a functional variant of a given CRM comprises the same CREs (or functional variants thereof) and does not comprise additional CREs.
[0858] Functional variants of a given CRM can comprise one or more additional regulatory elements compared to a reference CRM. For example, they may comprise an inducible or repressible element, a boundary control element, an insulator, a locus control region, a response element, a binding site, a segment of a terminal repeat, a responsive site, a stabilizing element, a de-stabilizing element, and a splicing element, etc., provided that they do not render the CRM substantially non-functional.
[0859] Functional variants of a given CRM can comprise additional spacers between adjacent CREs or, if one or more spacer are present in the reference CRM, said one or more spacers can be longer or shorter than in the reference CRM.
[0860] It will be apparent that the CRMs as disclosed herein, or functional variants thereof, can be combined with any suitable promoter elements in order to provide a synthetic muscle-specific promoter according to the present invention.
[0861] In many instances, shorter promoter sequences are preferred, particularly for use in situations where a vector (e.g. a viral vector such as AAV) has limited capacity. Accordingly, in some embodiments the synthetic muscle-specific CRM has length of 500 or fewer nucleotides, for example 450, 400, 350, 300, 250, 200, 150, 100, 75, 60, 50 or fewer nucleotides.
[0862] Promoter Elements and Functional Variants Thereof:
[0863] CREs and CRMs of the present invention can be used in combination with a wide range of suitable minimal promoters or muscle-specific proximal promoters, collectively called promoter elements.
[0864] Functional variants of promoter elements include sequences which vary from the reference promoter element, but which substantially retain activity as muscle-specific promoter element. It will be appreciated by the skilled person that it is possible to vary the sequence of a promoter element while retaining its ability to promote expression. A functional variant of a promoter element can comprise substitutions, deletions and/or insertions compared to a reference promoter element, provided they do not render the promoter element substantially non-functional.
[0865] In some embodiments, a functional variant of a promoter element can be viewed as a promoter element which, when substituted in place of a reference promoter element in a synthetic promoter, substantially retains its activity. For example, a muscle-specific synthetic promoter which comprises a functional variant of a given promoter preferably retains at least 80% of its activity, more preferably at least 90% of its activity, more preferably at least 95% of its activity, and yet more preferably 100% of its activity (compared to the reference promoter comprising the unmodified promoter element).
[0866] Suitably, functional variants of a promoter element retain a significant level of sequence identity to a reference promoter element. Suitably functional variants comprise a sequence that is at least 70% identical to the reference promoter element, more preferably at least 80%, 90%, 95% or 99% identical to the reference promoter element.
[0867] Retention of activity can be assessed by comparing expression of a suitable reporter under the control of the reference promoter with an otherwise identical promoter comprising the substituted promoter element under equivalent conditions. Suitable assays for assessing muscle-specific promoter activity are disclosed herein, e.g. in the examples.
[0868] Functional variants of some promoter elements according to the present invention are shown in Table 11. For example, CRE0055 (SEQ ID NO: 282), CRE0056 (SEQ ID NO: 283) and CRE0072 (SEQ ID NO: 286) are functional variants of CRE0010_ITGB1BP2 (SEQ ID NO: 272) and vice versa. CRE0034 (SEQ ID NO: 274) is a functional variant of CRE0049 (SEQ ID NO: 278) and vice versa. CRE0053. 2 (SEQ ID NO: 280) is a functional variant of CRE0053 (SEQ ID NO: 279) and vice versa. CRE0054 (SEQ ID NO: 281) and CRE0046 (SEQ ID NO: 276) are functional variants of CRE0070 (SEQ ID NO: 284) and vice versa.
[0869] Synthetic Muscle-Specific Promoters and Functional Variants Thereof:
[0870] Various synthetic muscle-specific promoters are disclosed herein. A functional variant of a reference synthetic muscle-specific promoter is a promoter which comprise a sequence which varies from the reference synthetic muscle-specific promoter, but which substantially retains muscle-specific promoter activity. It will be appreciated by the skilled person that it is possible to vary the sequence of a synthetic muscle-specific promoter while retaining its ability to recruit suitable muscle-specific transcription factors (TFs) and to recruit RNA polymerase II to provide muscle-specific expression of an operably linked sequence (e.g. an open reading frame). A functional variant of a synthetic muscle-specific promoter can comprise substitutions, deletions and/or insertions compared to a reference promoter, provided such substitutions, deletions and/or insertions do not render the synthetic muscle-specific promoter substantially non-functional compared to the reference promoter.
[0871] Accordingly, in some embodiments, a functional variant of a synthetic muscle-specific promoter can be viewed as a variant which substantially retains the muscle-specific promoter activity of the reference promoter. For example, a functional variant of a synthetic muscle-specific promoter preferably retains at least 70% of the activity of the reference promoter, more preferably at least 80% of its activity, more preferably at least 90% of its activity, more preferably at least 95% of its activity, and yet more preferably 100% of its activity.
[0872] Functional variants of a synthetic muscle-specific promoter often retain a significant level of sequence similarity to a reference synthetic muscle-specific promoter. In some embodiments, functional variants comprise a sequence that is at least 70% identical to the reference synthetic muscle-specific promoter, more preferably at least 80%, 90%, 95% or 99% identical to the reference synthetic muscle-specific promoter.
[0873] Activity in a functional variant can be assessed by comparing expression of a suitable reporter under the control of the reference synthetic muscle-specific promoter with the putative functional variant under equivalent conditions. Suitable assays for assessing muscle-specific promoter activity are disclosed herein, e.g. in the examples.
[0874] Functional variants of a given synthetic muscle-specific promoter can comprise functional variants of one or more CREs present in the reference synthetic muscle-specific promoter. For example, functional variant of a given CRM can comprise 1, 2, 3, 4, 5, or 6 of the CREs present in the reference CRM. Functional variants of CREs are discussed above.
[0875] Functional variants of a given synthetic muscle-specific promoter can comprise functional variants of the promoter element, or a different promoter element when compare to the reference synthetic muscle-specific promoter.
[0876] Functional variants of a given synthetic muscle-specific promoter can comprise the same CREs as a reference synthetic muscle-specific promoter, but the CREs can be present in a different order from the reference synthetic muscle-specific promoter.
[0877] Functional variants of a given synthetic muscle-specific promoter can comprise one or more additional CREs to those present in a reference synthetic muscle-specific promoter. Additional CREs can be provided upstream of the CREs present in the reference CRM, downstream of the CREs present in the reference synthetic muscle-specific promoter, and/or between the CREs present in the reference synthetic muscle-specific promoter. The additional CREs can be CREs disclosed herein, or they can be other CREs.
[0878] Functional variants of a given CRM can comprise one or more additional regulatory elements compared to a reference CRM. For example, they may comprise an inducible elements, an intronic element, a boundary control element, an insulator, a locus control region, a response element, a binding site, a segment of a terminal repeat, a responsive site, a stabilizing element, a de-stabilizing element, and a splicing element, etc., provided that they do not render the promoter substantially non-functional.
[0879] Functional variants of a given synthetic muscle-specific promoter can comprise additional spacers between adjacent CREs and promoter elements or, if one or more spacer are present in the reference synthetic muscle-specific promoter, said one or more spacers can be longer or shorter than in the reference synthetic muscle-specific promoter.
[0880] It will be apparent that synthetic muscle-specific promoters of the present invention can comprise a CRM of the present invention and additional regulatory sequences. For example, they may comprise one or more additional CRMs, an inducible or repressible element, a boundary control element, an insulator, a locus control region, a response element, a binding site, a segment of a terminal repeat, a responsive site, a stabilizing element, a de-stabilizing element, and a splicing element, etc., provided that they do not render the promoter substantially non-functional.
[0881] Preferred synthetic muscle-specific promoters of the present invention exhibit muscle-specific promoter activity which is at least 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350% or 400% of the activity exhibited by the CBA or RSV promoter in muscle cells. In many cases higher levels of promoter activity is preferred, but this is not always the case; thus, in some cases more moderate levels of expression may be preferred. In some cases, it is desirable to have available a range of promoters of different activity levels to allow the level of expression to by tailored to requirements; the present disclose provides promoters with such a range of activities. Activity of a given synthetic muscle-specific promoter of the present invention compared to CBA or RSV can be assessed by comparing muscle-specific expression of a reporter gene under control of the synthetic muscle-specific promoter with expression of the same reporter under control of the CBA or RSV promoter, when the two promoters are provided in otherwise equivalent expression constructs and under equivalent conditions.
[0882] In some embodiments a synthetic muscle-specific promoter of the invention is able to increase expression of a gene (e.g. a therapeutic gene or gene of interest) in the muscle of a subject or in a muscle cell by at least 20%, at least 40%, at least 60%, at least 80%, at least 100%, at least 200%, at least 300%, at least 500%, at least 1000% or more relative to a known muscle-specific promoter, suitably the SPc5-12 promoter (Gene Ther. 2008 November; 15(22):1489-99).
[0883] Preferred synthetic muscle-specific promoters of the present invention exhibit activity in non-muscle cells (e.g. Huh7 and HEK293 cells) which is 50% or less when compared to CMV-IE, preferably 25% or less than CMV-IE, more preferably 10% or less than CMV-IE, and in some cases 5% or less than CMV-IE, or 1% or less than CMV-IE.
[0884] In many instances, shorter promoter sequences are preferred, particularly for use in situations where a vector (e.g. a viral vector such as AAV) has limited capacity. Accordingly, in some embodiments the synthetic muscle-specific promoter has length of 700 or fewer nucleotides, for example, 600, 500, 450, 400, 350, 300, 250, 200, 150, 100, 75, 70, 68 or fewer nucleotides.
[0885] Particularly preferred synthetic muscle-specific promoters are those that are both short and which exhibit high levels of activity.
[0886] Synthetic Muscle-Specific Expression Cassettes:
[0887] The present invention also provides a synthetic muscle-specific expression cassette comprising a synthetic muscle-specific promoter of the present invention operably linked to a sequence encoding an expression product, suitably a gene (e.g. a transgene).
[0888] The gene typically encodes a desired gene expression product such as a polypeptide (protein) or RNA. The gene may be a full-length cDNA or genomic DNA sequence, or any fragment, subunit or mutant thereof that has at least some desired biological activity.
[0889] Where the gene encodes a protein, it can be essentially any type of protein. By way of non-limiting example, the protein can be an enzyme, an antibody or antibody fragment (e.g. a monoclonal antibody), a viral protein (e.g. REP-CAP, REV, VSV-G, or RD114), a therapeutic protein, or a toxic protein (e.g. Caspase 3, 8 or 9).
[0890] In some preferred embodiments of the present invention, the gene encodes a therapeutic expression product, preferably a therapeutic polypeptide suitable for use in treating a disease or condition associated with aberrant gene expression, optionally in the muscle, optionally in cardiac muscle.
[0891] In some embodiments, therapeutic expression products include those useful in the treatment of muscle diseases. The term “muscular disease” is, in principle, understood by the skilled person. The term relates to a disease amenable to treatment and/or prevention by administration of an active compound to a muscle, in particular to a muscle cell. In some embodiments, the muscular disease is a skeletal muscle disease. In some embodiments, the muscular disease is a cardiac muscle disease.
[0892] In some embodiments, the muscular disease is a vascular disease, a muscular dystrophy, a cardiomyopathy, a myotonia, a muscular atrophy, a myoclonus dystonia (affected gene: SGCE), a mitochondrial myopathy, a rhabdomyolysis, a fibromyalgia, and/or a myofascial pain syndrome.
[0893] In one embodiment, the disease may be cardiovascular condition or heart disease and disorders. In one embodiment, the disease may be heart failure such as congestive heart failure. In one embodiment, the disease may be selected from ischemia, arrhythmia, myocardial infarction (MI), abnormal heart contractility, non-ischemic cardiomyopathy, peripheral arterial occlusive disease, and abnormal Ca2+ metabolism, and combinations thereof. In some embodiments, the disease may be selected from the group of: congestive heart failure, cardiomyopathy, myocardial infarction, tissue ischemia, cardiac ischemia, vascular disease, acquired heart disease, congenital heart disease, atherosclerosis, dysfunctional conduction systems, dysfunctional coronary arteries, pulmonary heart hypertension. In some embodiments, the disease may be selected from congestive heart failure, coronary artery disease, myocardial infarction, myocardial ischemia, atherosclerosis, cardiomyopathy, idiopathic cardiomyopathy, cardiac arrhythmias, muscular dystrophy, muscle mass abnormality, muscle degeneration, infective myocarditis, drug- or toxin-induced muscle abnormalities, hypersensitivity myocarditis, an autoimmune endocarditis and congenital heart disease.
[0894] In some embodiments, the cardiomyopathy is hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia, dilated cardiomyopathy, restrictive cardiomyopathy, left ventricular noncompaction, Takotsubo cardiomyopathy, myocarditis, eosinophilic myocarditis, and ischemic cardiomyopathy. Preferably, the hypertrophic cardiomyopathy is CMH1 (Gene: MYH7), CMH2 (Gene: TNNT2), CMH3 (Gene: TPM1), CMH4 (Gene: MYBPC3), CMH5, CMH6 (Gene: PRKAG2), CMH7 (Gene: TNN13), CMH8 (Gene: MYL3), CMH9 (Gene: TTN), CMH10 (Gene: MYL2), CMH11 (Gene: ACTC1), or CMH12 (Gene: CSRP3). Preferably, the arrhythmogenic right ventricular dysplasia is ARVD1 (Gene: TGFB3), ARVD2 (Gene: RYR2), ARVD3, ARVD4, ARVD5 (Gene: TMEM43), ARVD6, ARVD7 (Gene: DES), ARVD8 (Gene: DSP), ARVD9 (Gene: PKP2), ARVD10 (Gene: DSG2), ARVD11 (Gene: DSC2), and/or ARVD12 (Gene: JUP).
[0895] In some embodiments, the muscular disease is a vascular disease. Vascular disease may be coronary artery disease, peripheral arterial disease, cerebrovascular disease, renal artery stenosis or aortic aneurysm. In some embodiments, the muscular disease may be cardiomyopathy. The cardiomyopathy may be hypertensive heart disease, heart failure (such as congestive heart failure), pulmonary heart disease, cardiac dysrhythmias, inflammatory heart disease (such as endocarditis, inflammatory cardiomegaly, myocarditis), valvular heart disease, congenital heart disease and rheumatic heart disease.
[0896] In some embodiments, the muscular dystrophy is Duchenne muscular dystrophy (gene affected: DMD), Becker muscular dystrophy (gene affected: DMD), Limb girdle muscular dystrophy (Subtypes and affected genes: LGMD1A (Gene: TTID), LGMD1B (Gene: LMNA), LGMD1C (Gene: CAV3), LGMD1D (Gene: DNAJB6), LGMD1E (Gene: DES), LGMD1F (Gene: TNP03), LGMD1G (Gene: HNRPDL), LGMD1H, LGMD2A (Gene: CAPN3), LGMD2B (Gene: DYSF), LGMD2C (Gene: SGCG), LGMD2D (Gene: SGCA), LGMD2E (Gene: SGCB), LGMD2F (Gene: SGCD), LGMD2G (Gene: TCAP), LGMD2H (Gene: TRIM32), LGMD2I (Gene: FKRP), LGMD2J (Gene: TTN), LGMD2K (Gene: POMT1), LGMD2L (Gene: AN05), LGMD2M (Gene: FKTN), LGMD2N (Gene: POMT2), LGMD20 (Gene: POMGNT1), LGMD2Q (Gene: PLEC1)), Congenital muscular dystrophy, Distal muscular dystrophy (Subtypes and affected genes: Miyoshi myopathy (Gene: DYSF), Distal myopathy with anterior tibial onset (Gene: DYSF), Welander distal myopathy (Gene: TIA1), Gowers-Laing distal myopathy (Gene: MYH7), Nonaka distal myopathy, hereditary inclusion-body myositis type 1, distal myopathy with vocal cord and pharyngeal weakness, ZASP-related myopathy), Facioscapulohumeral muscular dystrophy (Subtypes and affected genes: Type 1 (Gene: DUX4), Type 2 (Gene: SMCHD1)), Oculopharyngeal muscular dystrophy (affected gene: PABPN1), and/or myotonic dystrophy (Subtypes and affected genes: DM1 (Gene: DMPK) and DM2 (Gene: ZNF9)).
[0897] In some embodiments, the myotonia is congenital myotonia (affected gene: CLCN1; subtypes: Type Thomsen, Type Becker) and/or Paramyotonia congenital (affected gene: SCN4A).
[0898] In some embodiments, the muscular disease is Duchenne muscular dystrophy (Gene: DMD), a myotubular myopathy (Gene: MTM1), Spinal muscular atrophy (Gene: SMA), Glycogen storage disease type II (Pompe disease, Gene: GAA), or a cardiomyopathy.
[0899] In some embodiments the gene encodes a non-disease mediating variant, e.g. a wildtype variant of at least one human gene selected from the group consisting of consisting of DMD GALGT2, SMA, GAA, MTM1, TTID, LMNA, CAV3, DNAJB6, DES, TNP03, HNRPDL, CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TCAP, TRIM32, FKRP, TTN, POMT1, AN05, FKTN, POMT2, PFEC1, DYSF, TIA1, MYH7, DUX4, SMCHD, PABPN1, DMPK, ZNF9, CFCN1, SCN4A, MYH7, TNNT2, TPM1, MYBPC3, PRKAG2, TNNI3, MYF3, TTN, MYF2, ACTC1, CSRP3, TGFB3, RYR2, TMEM43, DES, DSP, PKP2, DSG2, DSC2, JUP, and HYPP.
[0900] Further exemplary muscle tissue-related diseases include but are not limited to Acid Maltase Deficiency (AMD), alpha-1 antitrypsin deficiency, Amyotrophic Lateral Sclerosis (ALS), Andersen-Tawil Syndrome, Becker Muscular Dystrophy (BMD), Becker Myotonia Congenita, Bethlem Myopathy, Carnitine Deficiency, Carnitine Palmityl Transferase Deficiency (CPT Deficiency), Central Core Disease (CCD), Centronuclear Myopathy, Charcot-Marie-Tooth Disease (CMT), Congenital Myasthenic Syndromes (CMS), Congenital Myotonic Dystrophy, Cori Disease (Debrancher Enzyme Deficiency), Debrancher Enzyme Deficiency, Dejerine-Sottas Disease (DSD), Dermatomyositis (DM), Endocrine Myopathies, Eulenberg Disease (Paramyotonia Congenita), Forbes Disease (Debrancher Enzyme Deficiency), Friedreich's Ataxia (FA), Glycogenosis Type 10, Glycogenosis Type 11, Glycogenosis Type 2, Glycogenosis Type 3, Glycogenosis Type 5, Glycogenosis Type 7, Glycogenosis Type 9, Gowers-Laing Distal Myopathy, Hauptmann-Thanheuser MD (Emery-Dreifuss Muscular Dystrophy), Hereditary Inclusion-Body Myositis, Hereditary Motor and Sensory Neuropathy (Charcot-Marie-Tooth Disease), Hyperthyroid Myopathy, Hypothyroid Myopathy, Inclusion-Body Myositis (IBM), Inherited Myopathies, Integrin-Deficient Congenital Muscular Dystrophy, Lactate Dehydrogenase Deficiency, Lambert-Eaton Myasthenic Syndrome (LEMS), McArdle Disease (Phosphorylase Deficiency), Metabolic Diseases of Muscle, Mitochondrial Myopathy, Miyoshi Distal Myopathy, Motor Neurone Disease, Muscle-Eye-Brain Disease, Myasthenia Gravis (MG), Myoadenylate Deaminase Deficiency, Myofibrillar Myopathy, Myophosphorylase Deficiency, Myotonia Congenita (MC), Myotonic Muscular Dystrophy (MMD), Myotubular Myopathy (MTM or MM), Nemaline Myopathy, Nonaka Distal Myopathy, Oculopharyngeal Muscular Dystrophy (OPMD), Paramyotonia Congenita, Pearson Syndrome, Periodic Paralysis, Peroneal Muscular Atrophy (Charcot-Marie-Tooth Disease), Phosphofructokinase Deficiency, Phosphogly cerate Kinase Deficiency, Phosphogly cerate Mutase Deficiency, Phosphorylase Deficiency, Phosphorylase Deficiency, Polymyositis (PM), Pompe Disease (Acid Maltase Deficiency), Progressive External Ophthalmoplegia (PEO), Rod Body Disease (Nemaline Myopathy), Spinal Muscular Atrophy (SMA), Spinal-Bulbar Muscular Atrophy (SBMA), Steinert Disease (Myotonic Muscular Dystrophy), Tarui Disease (Phosphofructokinase Deficiency), Thomsen Disease (Myotonia Congenita), Ullrich Congenital Muscular Dystrophy, Walker-Warburg Syndrome (Congenital Muscular Dystrophy), Welander Distal Myopathy, and ZASP-Related Myopathy.
[0901] In some preferred embodiments, the muscular disease is a cardiac muscle disease. In some preferred embodiments the muscular disease is congestive heart failure.
[0902] In some embodiments, useful expression products include dystrophins (including micro-dystrophins), beta 1,4-n-acetylgalactosamine galactosyltransferase (GALGT2), carbamoyl synthetase I, alpha-1 antitrypsin, ornithine transcarbamylase, arginosuccinate synthetase, arginosuccinate lyase, arginase, fumarylacetacetate hydrolase, phenylalanine hydroxylase, glucose-6-phosphatase, porphobilinogen deaminase, cystathione beta-synthase, branched chain ketoacid decarboxylase, albumin, isovaleryl-coA dehydrogenase, propionyl CoA carboxylase, methyl malonyl CoA mutase, glutaryl CoA dehydrogenase, insulin, beta-glucosidase, pyruvate carboxylate, hepatic phosphorylase, phosphorylase kinase, glycine decarboxylase, H-protein, T-protein, and a cystic fibrosis transmembrane regulator (CFTR).
[0903] Still other useful expression products include enzymes useful in enzyme replacement therapy, and which are useful in a variety of conditions resulting from deficient activity of enzyme. For example, enzymes containing mannose-6-phosphate may be utilized in therapies for lysosomal storage diseases (e.g., a suitable gene includes that encoding β-glucuronidase (GUSB)).
[0904] In some embodiments, exemplary polypeptide expression products include neuroprotective polypeptides and anti-angiogenic polypeptides. Suitable polypeptides include, but are not limited to, glial derived neurotrophic factor (GDNF), fibroblast growth factor 2 (FGF-2), nurturin, ciliary neurotrophic factor (CNTF), nerve growth factor (NGF; e.g., nerve growth factor-. Beta.), brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), neurotrophin-6 (NT-6), epidermal growth factor (EGF), pigment epithelium derived factor (PEDF), a Wnt polypeptide, soluble Fit-1, angiostatin, endostatin, VEGF, an anti-VEGF antibody, a soluble VEGFR, Factor VIII (FVIII), Factor IX (FIX), and a member of the hedgehog family (sonic hedgehog, Indian hedgehog, and desert hedgehog, etc.).
[0905] In some embodiments, useful therapeutic expression product include hormones and growth and differentiation factors including, without limitation, insulin, glucagon, growth hormone (GH), parathyroid hormone (PTH), growth hormone releasing factor (GRF), follicle stimulating hormone (FSH), luteinizing hormone (LH), human chorionic gonadotropin (hCG), vascular endothelial growth factor (VEGF), angiopoietins, angiostatin, granulocyte colony stimulating factor (GCSF), erythropoietin (EPO), connective tissue growth factor (CTGF), basic fibroblast growth factor (bFGF), acidic fibroblast growth factor (aFGF), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), insulin growth factors I and II (IGF-I and IGF-II), any one of the transforming growth factor alpha superfamily, including TGFa., activins, inhibins, or any of the bone morphogenic proteins (BMP) BMPs 1-15, any one of the heregluin/neuregulin/ARIA/neu differentiation factor (NDF) family of growth factors, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophins NT-3 and NT-4/5, ciliary neurotrophic factor (CNTF), glial cell line derived neurotrophic factor (GDNF), neurturin, agrin, any one of the family of semaphorins/collapsins, netrin-1 and netrin-2, hepatocyte growth factor (HGF), ephrins, noggin, sonic hedgehog and tyrosine hydroxylase.
[0906] In some embodiments, useful expression products include proteins that regulate the immune system including, without limitation, cytokines and lymphokines such as thrombopoietin (TPO), interleukins (IL) IL-1 through IL-25 (including IL-2, IL-4, IL-12 and IL-18), monocyte chemoattractant protein, leukemia inhibitory factor, granulocyte-macrophage colony stimulating factor, Fas ligand, tumor necrosis factors alpha and beta., interferons (alpha, beta, and gamma), stem cell factor, flk-2/flt3 ligand. Gene products produced by the immune system are also useful in the present invention. These include, without limitations, immunoglobulins IgG, IgM, IgA, IgD and IgE, chimeric immunoglobulins, humanized antibodies, single chain antibodies, T cell receptors, chimeric T cell receptors, single chain T cell receptors, class I and class II MHC molecules, as well as engineered immunoglobulins and MHC molecules. Useful gene products also include complement regulatory proteins such as complement regulatory proteins, membrane cofactor protein (MCP), decay accelerating factor (DAF), CR1, CF2 and CD59.
[0907] In some embodiments, useful expression product include any one of the receptors for the hormones, growth factors, cytokines, lymphokines, regulatory proteins and immune system proteins. Useful heterologous nucleic acid sequences also include receptors for cholesterol regulation and/or lipid modulation, including the low-density lipoprotein (LDL) receptor, high density lipoprotein (HDL) receptor, the very low density lipoprotein (VLDL) receptor, and scavenger receptors. The invention also encompasses the use of gene products such as members of the steroid hormone receptor superfamily including glucocorticoid receptors and estrogen receptors, Vitamin D receptors and other nuclear receptors. In addition, useful gene products include transcription factors such as jun, fos, max, mad, serum response factor (SRF), AP-1, AP-2, myb, MyoD and myogenin, ETS-box containing proteins, TFE3, E2F, ATF1, ATF2, ATF3, ATF4, ZF5, NFAT, CREB, HNF-4, C/EBP, SP1, CCAAT-box binding proteins, interferon regulation factor (IRF-1), Wilms tumor protein, ETS-binding protein, STAT, GATA-box binding proteins, e.g., GATA-3, and the forkhead family of winged helix proteins.
[0908] In some embodiments, useful expression products include those used for treatment of hemophilia, including hemophilia B (including Factor IX) and hemophilia A (including Factor VIII and its variants, such as the light chain and heavy chain of the heterodimer and the B-deleted domain; U.S. Pat. Nos. 6,200,560 and 6,221,349).
[0909] In some embodiments, the useful expression product may be a modulator of phosphatase activity, e.g., type 1 phosphatase activity. The modulator may be a protein that inhibits phosphatase activity, e.g., type 1 phosphatase activity. The modulator may be a nucleic acid that increases expression of an endogenous nucleic acid that encodes a protein that inhibits phosphatase activity such as a transcription factor. The modulator may be a regulatory sequence that integrates in or near the endogenous nucleic acid that encodes a protein that inhibits phosphatase activity. The modulator may be a nucleic acid that can provide a nucleic acid modulator of gene expression such as a siRNA.
[0910] In some embodiments, the useful expression product may be inhibitor of protein phosphate 1 (PP1) e.g., a I-1 polypeptide. The phosphatase inhibitor-1 (or “I-1”) protein is an endogenous inhibitor of type 1 phosphatase. Increasing I-1 levels or activity can restore β-adrenergic responsiveness in failing human cardiomyocytes. Suitably, the I-1 protein may be constitutively active such as a I-1 protein where threonine 35 is replaced with glutamic acid instead of aspartic acid. The therapeutic expression product may be any one or more of the inhibitors selected from: phosphatase inhibitor 2 (PP2); okadaic acid or caliculin; and nippl which is an endogenous nuclear inhibitor of protein phosphatase 1.
[0911] In some embodiments, the useful expression product may be any protein that modulates cardiac activity such as a phosphatase type 1 inhibitor, e.g., I-1 or a sacroplasmic reticulum Ca2+ ATPase (SERCA), e.g., SERCA1 (e.g., 1a or 1b), SERCA2 (e.g., 2a or 2b), or SERCA3.
[0912] In some embodiments, the useful expression product may be a nucleic acid sequence encoding a mutant form of phosphatase inhibitor-1 protein, wherein the mutant form comprises at least one amino acid at a position that is a PKC-α phosphorylation site in the wild type, wherein the at least one amino acid is constitutively unphosphorylated or mimics an unphosphorylated state in the mutant form. The therapeutic expression product may be adenylyl cyclase 6 (AC6, also referred to as adnenylyl cyclase VI), S100A1, β-adrenergic receptor kinase-ct (βARKct), sarco/endoplasmic reticulum (SR) Ca-ATPase (SERCA2a), IL-18, VEGF, VEGF activators, urocortins, and B-cell lymphoma 2 (Bcl2)-associated anthanogene-3 (BAG3).
[0913] In some embodiments, the useful expression product may be an inhibitor of a cytokine such as an IL-18 inhibitor. The therapeutic expression product may be encode a beta-adrenergic signalling protein (beta-ASPs) (including beta-adrenergic receptors (beta-Ars), G-protein receptor kinase inhibitors (GRK inhibitors) and adenylylcyclases (Acs)) to enhance cardiac function.
[0914] In some embodiments, the useful expression product may be an angiogenic protein. Angiogenic proteins promote development and differentiation of blood vessels. Examples of angiogenic proteins include members of the fibroblast growth factor (FGF) family such as aFGF (FGF-1), bFGF (FGF-2), FGF-4 (also known as “hst/KS3”), FGF-5 and FGF-6, the vascular endothelial growth factor (VEGF) family, the platelet-derived growth factor (PDGF) family, the insulin-like growth factor (IGF) family, and others.
[0915] In some embodiments, useful expression products include non-naturally occurring polypeptides, such as chimeric or hybrid polypeptides having a non-naturally occurring amino acid sequence containing insertions, deletions or amino acid substitutions.
[0916] Further suitable expression products include micro RNA (miRNA), interfering RNA, antisense RNA, ribozymes, and aptamers.
[0917] In some preferred embodiments, the expression product is an inhibitor of protein phosphate 1 (PP1).
[0918] In some embodiments of the invention, the synthetic muscle-specific expression cassette comprises a gene useful for gene editing, e.g. a gene encoding a site-specific nuclease, such as a meganuclease, zinc finger nuclease (ZFN), transcription activator-like effector-based nuclease (TALEN), or the clustered regularly interspaced short palindromic repeats system (CRISPR-Cas). Suitably the site-specific nuclease is adapted to edit a desired target genomic locus by making a cut (typically a site-specific double-strand break) which is then repaired via non-homologous end-joining (NHEJ) or homology dependent repair (HDR), resulting in a desired edit. The edit can be the partial or complete repair of a gene that is dysfunctional, or the knock-down or knock-out of a functional gene. Alternatively, the edit can be via base editing or prime editing, using suitable systems which are known in the art.
[0919] Suitably the synthetic muscle-specific expression cassette comprises sequences providing or coding for one or more of, and preferably all of, a ribosomal binding site, a start codon, a stop codon, and a transcription termination sequence. Suitably the expression cassette comprises a nucleic acid encoding a posttranscriptional regulatory element. Suitably the expression cassette comprises a nucleic acid encoding a polyA element.
[0920] Vectors and Viral Particles:
[0921] The present invention further provides a vector comprising a synthetic muscle-specific promoter, or expression cassette according to the present invention.
[0922] In some embodiments of the invention, the vector is a plasmid. Such a plasmid may include a variety of other functional nucleic acid sequences, such as one or more selectable markers, one or more origins of replication, multiple cloning sites and the like. In some embodiments of the invention, the vector is a viral vector.
[0923] In some embodiments of the invention, the vector is an expression vector for expression in eukaryotic cells. Examples of eukaryotic expression vectors include, but are not limited to, pW-LNEO, pSV2CAT, pOG44, pXTI and pSG available from Stratagene; pSVK3, pBPV, pMSG and pSVL available from Amersham Pharmacia Biotech; and pCMVDsRed2-express, pIRES2-DsRed2, pDsRed2-Mito, pCMV-EGFP available from Clontech. Many other vectors are well-known and commercially available. For mammalian cells adenoviral vectors, the pSV and the pCMV series of vectors are particularly well-known non-limiting examples. There are many well-known yeast expression vectors including, without limitation, yeast integrative plasmids (Yip) and yeast replicative plasmids (Yrp). For plants the Ti plasmid of agrobacterium is an exemplary expression vector, and plant viruses also provide suitable expression vectors, e.g. tobacco mosaic virus (TMV), potato virus X, and cowpea mosaic virus.
[0924] In some preferred embodiments, the vector is a gene therapy vector. Various gene therapy vectors are known in the art, and mention can be made of AAV vectors, adenoviral vectors, retroviral vectors and lentiviral vectors. Where the vector is a gene therapy vector the vector preferably comprises a nucleic acid sequence operably linked to the synthetic muscle-specific promoter of the invention that encodes a therapeutic product, suitably a therapeutic protein. The therapeutic protein may be a secretable protein. Non-limiting examples of secretable proteins are discussed above, and exemplary secretable therapeutic proteins, include clotting factors, such as factor VIII or factor IX, insulin, erythropoietin, lipoprotein lipase, antibodies or nanobodies, growth factors, cytokines, chemokines, plasma factors, toxic proteins, etc.
[0925] In some embodiments of the invention, the vector is a viral vector, such as a retroviral, lentiviral, adenoviral, or adeno-associated viral (AAV) vector. In some preferred embodiments the vector is an AAV vector. In some preferred embodiments the AAV has a serotype suitable for muscle transduction. In some embodiments, the AAV is selected from the group consisting of: AAV2, AAV5, AAV6, AAV7, AAV8, AAV9 BNP116, rh10, AAV2.5, AAV2i8, AAVDJ8 and AAV2G9, or derivatives thereof. AAV vectors are preferably used as self-complementary, double-stranded AAV vectors (scAAV) in order to overcome one of the limiting steps in AAV transduction (i.e. single-stranded to double-stranded AAV conversion), although the use of single-stranded AAV vectors (ssAAV) is also encompassed herein. In some embodiments of the invention, the AAV vector is chimeric, meaning it comprises components from at least two AAV serotypes, such as the ITRs of an AAV2 and the capsid protein of an AAV5. AAV9 is known to effectively transduce skeletal muscle and cardiac muscle particularly effectively, and thus AAV9 and derivatives thereof are of particular interest for targeting skeletal and cardiac muscle. AAV1, AAV6, AAV7 and AAV8 are also known to target skeletal muscle, and thus these AAV serotypes and derivates thereof are also of particular interest for targeting skeletal muscle. AAV1 and AAV8 are also known to target cardiac muscle, and thus these AAV serotypes and derivates thereof are also of particular interest for targeting cardiac muscle. In some embodiments, the rAAV vector is a AAV3b serotype, including, but not limited to, an AAV3b265D virion, an AAV3b265D549A virion, an AAV3b549A virion, an AAV3bQ263Y virion, or an AAV3bSASTG virion (i.e., a virion comprising a AAV3b capsid comprising Q263A/T265 mutations). In some embodiments, the virion can be rational haploid, or a chimeric or any mutant, such as capsids can be tailored for increased update at a desired location, e.g., the heart. Other capsids can include capsids from any of the known AAV serotypes, including AAV1, AAV3, AAV4, AAV5, AAV7, AAV10, etc.
[0926] The invention further provides recombinant virions (viral particles) comprising a vector as described above.
[0927] Pharmaceutical Compositions:
[0928] The vectors or virions of the present invention may be formulated in a pharmaceutical composition with a pharmaceutically acceptable excipient, i.e., one or more pharmaceutically acceptable carrier substances and/or additives, e.g., buffers, carriers, excipients, stabilisers, etc. The pharmaceutical composition may be provided in the form of a kit. Pharmaceutical compositions and delivery systems appropriate for the AAV vectors or and methods and uses of are known in the art.
[0929] Accordingly, a further aspect of the invention provides a pharmaceutical composition comprising a vector or virion as described herein.
[0930] Therapeutic and Other Methods and Uses:
[0931] The present invention also provides a synthetic muscle-specific promoter, expression cassette, vector, virion or pharmaceutical composition according to various aspects of the present invention for use in the treatment of a disease, preferably a disease associated with aberrant gene expression, optionally in the muscle (e.g. a genetic muscle disease). In one embodiment, the present invention provides a synthetic muscle-specific promoter, expression cassette, vector, virion or pharmaceutical composition according to various aspects of the present invention for use in the treatment of a skeletal muscle disease. In one embodiment, the present invention also provides a synthetic muscle-specific promoter, expression cassette, vector, virion or pharmaceutical composition according to various aspects of the present invention for use in the treatment of a cardiac muscle disease.
[0932] Relevant conditions, diseases and therapeutic expression products are discussed above.
[0933] The present invention also provides a synthetic muscle-specific promoter, expression cassette, vector, virion according to the various aspects of the present invention for use in the manufacture of a pharmaceutical composition for treatment of any condition or disease mentioned herein.
[0934] The present invention further provides a cell comprising a synthetic muscle-specific promoter, expression cassette, vector, virion according to the various aspects of the invention. Suitably the cell is a eukaryotic cell. The eukaryotic cell can suitably be a fungal cell (e.g. yeast cell), an animal (metazoan) cell (e.g. a mammalian cell), or a plant cell. Alternatively, the cell may be a prokaryotic cell.
[0935] In some embodiments of the invention, the cell is ex vivo, e.g. in cell culture. In other embodiments of the invention the cell may be part of a tissue or multicellular organism.
[0936] In a preferred embodiment, the cell is a muscle cell (myocyte), which may be ex vivo or in vivo. In a preferred embodiment, the cell is a cardiac muscle cell, which may be ex vivo or in vivo. In an alternative preferred embodiment, the cell is a skeletal muscle cell, which may be ex vivo or in vivo. The muscle cell may be a primary muscle cell or a cell of a muscle-derived cell line, e.g. an immortalised cell line. The cell may be present within a muscle tissue environment (e.g. within a muscle of an animal) or may be isolated from muscle tissue, e.g. it may be in cell culture. Suitably the cell is a human cell.
[0937] The skeletal muscle cells may be from fast twitch or slow twitch muscles.
[0938] The cardiac muscle cells may be selected from ventricular cardiomyocytes, atrial cardiomyocytes, cardiac fibroblasts, or endothelial cells (EC) in the heart, as well as peri-vascular cells and pacemaker cells.
[0939] The synthetic muscle-specific promoter, expression cassette, or vector, according to the invention may be inserted into the genome of the cell, or it may be episomal (e.g. present in an episomal vector).
[0940] In a further aspect the present invention provides a method for producing an expression product, the method comprising providing a synthetic muscle-specific expression cassette according to the present invention (preferably in a vector as set out above) in a cell, preferably a muscle cell, and expressing the gene present in the synthetic muscle-specific expression cassette. The method suitably comprises maintaining said muscle cell under suitable conditions for expression of the gene. In culture this may comprise incubating the cell, or tissue comprising the cell, under suitable culture conditions. The expression may of course be in vivo, e.g. in one or more cells in the muscle of a subject. In one embodiment, the muscle cell/s are cardiac muscle cell/s. In one embodiment, the muscle cell/s are skeletal muscle cell/s.
[0941] Suitably the method comprises the step of introducing the synthetic muscle-specific expression cassette into the muscle cell. A wide range of methods of transfecting muscle cells are well-known in the art. A preferred method of transfecting muscle cells is transducing the cells with a viral vector comprising the synthetic muscle-specific expression cassette, e.g. an AAV vector.
[0942] It will be evident to the skilled person that a synthetic muscle-specific promoter, expression cassette, vector or virion according to various aspects of the invention may be used for gene therapy. Accordingly, the use of the such nucleic acid constructs in gene therapy forms part of the present invention.
[0943] The invention thus provides, in some embodiments, an expression cassette, vector or virion according to the present invention for use in gene therapy in a subject, preferably gene therapy through muscle-specific expression of a therapeutic gene. Suitably through cardiac muscle-specific expression of a therapeutic gene and/or skeletal muscle-specific expression of a therapeutic gene. The therapy may involve treatment of a disease through secretion of a therapeutic product from muscle cells, suitably a disease involving aberrant gene expression in the muscle are discussed above.
[0944] The present invention also provides a method of expressing a therapeutic transgene in a muscle cell, the method comprising introducing into the muscle cell an expression cassette or vector according to the present invention. The muscle cell can be in vivo or ex vivo. In one embodiment, the muscle cell/s are cardiac muscle cell/s. In one embodiment, the muscle cell/s are skeletal muscle cell/s.
[0945] The present invention also provides a method of gene therapy of a subject, preferably a human, in need thereof, the method comprising: [0946] administering to the subject (suitably introducing into the muscle of the subject) a synthetic muscle-specific expression cassette, vector, virion or pharmaceutical composition of the present invention, which comprises a gene encoding a therapeutic product.
[0947] In one embodiment, the muscle is cardiac muscle. In one embodiment, the muscle is skeletal muscle.
[0948] The method suitably comprises expressing a therapeutic amount of the therapeutic product from the gene in the muscle of said subject. Various conditions and diseases that can be treated are discussed above. In one embodiment, the muscle is cardiac muscle. In one embodiment, the muscle is skeletal muscle.
[0949] Genes encoding suitable therapeutic products are discussed above.
[0950] The method suitably comprises administering a vector or virion according to the present invention to the subject. Suitably the vector is a viral gene therapy vector, for example an AAV vector.
[0951] In some embodiments, the method comprises administering the viral gene therapy vector systemically. Systemic administration may be enteral (e.g. oral, sublingual, and rectal) or parenteral (e.g. injection). Preferred routes of injection include intravenous, intramuscular, subcutaneous, intra-arterial, intra-articular, intrathecal, and intradermal injections.
[0952] In some embodiments, the viral gene therapy vector may be administered concurrently or sequentially with one or more additional therapeutic agents or with one or more saturating agents designed to prevent clearance of the vectors by the reticular endothelial system.
[0953] Where the vector is an AAV vector, the dosage of the vector may be from 1×10.sup.10 gc/kg to 1×10.sup.15 gc/kg or more, suitably from 1×10.sup.12 gc/kg to 1×10.sup.14 gc/kg, suitably from 5×10.sup.12 gc/kg to 5×10.sup.13 gc/kg.
[0954] In general, the subject in need thereof will be a mammal, and preferably primate, more preferably a human. Typically, the subject in need thereof will display symptoms characteristic of a disease. The method typically comprises ameliorating the symptoms displayed by the subject in need thereof, by expressing the therapeutic amount of the therapeutic product.
[0955] Gene therapy protocols for therapeutic gene expression in target cells in vitro and in vivo, are well-known in the art and will not be discussed in detail here. Briefly, they include intramuscular injection, interstitial injection, instillation in airways, application to endothelium, intra-hepatic parenchyme, and intravenous or intra-arterial administration (e.g. intra-hepatic artery, intra-hepatic vein) of plasmid DNA vectors (naked or in liposomes) or viral vectors. Various devices have been developed for enhancing the availability of DNA to the target cell. While a simple approach is to contact the target cell physically with catheters or implantable materials containing the relevant vector, more complex approaches can use jet injection devices an suchlike. Gene transfer into mammalian muscle cells has been performed using both ex vivo and in vivo procedures. The ex vivo approach typically requires harvesting of the muscle cells, in vitro transduction with suitable expression vectors, followed by reintroduction of the transduced myocytes the muscle. In vivo gene transfer has been achieved by injecting DNA or viral vectors into the muscle.
[0956] According to some preferred embodiments, the methods set out above may be used for the treatment of a subject with a muscle-related disease as discussed above, e.g. a muscular dystrophy or congestive heart failure.
[0957] Definitions and General Points: While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.
[0958] The discussion of the background to the invention herein is included to explain the context of the invention. This is not to be taken as an admission that any of the material referred to was published, known, or part of the common general knowledge in any country as of the priority date of any of the claims.
[0959] Throughout this disclosure, various publications, patents and published patent specifications are referenced by an identifying citation. All documents cited in the present specification are hereby incorporated by reference in their entirety. In particular, the teachings or sections of such documents herein specifically referred to are incorporated by reference.
[0960] The practice of the present invention will employ, unless otherwise indicated, conventional techniques of cell biology, cell culture, molecular biology, transgenic biology, microbiology, recombinant DNA, and immunology, which are within the skill of the art. Such techniques are explained fully in the literature. See, for example, Current Protocols in Molecular Biology (Ausubel, 2000, Wiley and son Inc, Library of Congress, USA); Molecular Cloning: A Laboratory Manual, Third Edition, (Sambrook et al, 2001, Cold Spring Harbor, New York: Cold Spring Harbor Laboratory Press); Oligonucleotide Synthesis (M. J. Gait ed., 1984); U.S. Pat. No. 4,683,195; Nucleic Acid Hybridization (Harries and Higgins eds. 1984); Transcription and Translation (Hames and Higgins eds. 1984); Culture of Animal Cells (Freshney, Alan R. Liss, Inc., 1987); Immobilized Cells and Enzymes (IRL Press, 1986); Perbal, A Practical Guide to Molecular Cloning (1984); the series, Methods in Enzymology (Abelson and Simon, eds. -in-chief, Academic Press, Inc., New York), specifically, Vols. 154 and 155 (Wu et al. eds.) and Vol. 185, “Gene Expression Technology” (Goeddel, ed.); Gene Transfer Vectors For Mammalian Cells (Miller and Calos eds., 1987, Cold Spring Harbor Laboratory); Immunochemical Methods in Cell and Molecular Biology (Mayer and Walker, eds., Academic Press, London, 1987); Handbook of Experimental Immunology, Vols. I-IV (Weir and Blackwell, eds., 1986); and Manipulating the Mouse Embryo, (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1986).
[0961] To facilitate the understanding of this invention, a number of terms are defined or explained below. Terms used herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.
[0962] The term “muscle” is well understood by the skilled person. Preferably, the muscle is a skeletal muscle (including the diaphragm) or a heart muscle. The promoters of the present invention can be active in skeletal muscle and/or cardiac muscle. Preferably, the muscle is a muscle of a vertebrate, more preferably of a mammal, even more preferably of a human subject. Preferably, the muscle is a striated muscle.
[0963] The term “muscle cell” or “myocyte” relates in the present to cells which are found in muscles (muscle tissue) or which are derived from muscle tissue. Muscle cells can be primary cells or a cell line (such as C2C12 or H2K cells (skeletal muscle cell line) or H9C2 cells (cardiac cell line)). The muscle cells can in in vivo (e.g. in muscle tissue) or in vitro (e.g. in cell culture). Myocytes as found in muscle tissue are typically long, tubular cells that develop from myoblasts to form muscles in a process known as myogenesis. The term muscle cells or myocytes as used herein includes myocytes from skeletal muscle and from cardiac muscle (cardiomyocytes). The promoters of the present invention can be active in skeletal muscle cells and/or cardiac muscle cells.
[0964] The term “cis-regulatory element” or “CRE”, is a term well-known to the skilled person, and means a nucleic acid sequence such as an enhancer, promoter, insulator, or silencer, that can regulate or modulate the transcription of a neighbouring gene (i.e. in cis). CREs are found in the vicinity of the genes that they regulate. CREs typically regulate gene transcription by binding to TFs, i.e. they include TFBS. A single TF may bind to many CREs, and hence control the expression of many genes (pleiotropy). CREs are usually, but not always, located upstream of the transcription start site (TSS) of the gene that they regulate. “Enhancers” in the present context are CREs that enhance (i.e. upregulate) the transcription of genes that they are operably associated with, and can be found upstream, downstream, and even within the introns of the gene that they regulate. Multiple enhancers can act in a coordinated fashion to regulate transcription of one gene. “Silencers” in this context relates to CREs that bind TFs called repressors, which act to prevent or downregulate transcription of a gene. The term “silencer” can also refer to a region in the 3′ untranslated region of messenger RNA, that bind proteins which suppress translation of that mRNA molecule, but this usage is distinct from its use in describing a CRE. Generally, the CREs of the present invention are muscle-specific, cardiac muscle-specific, or skeletal muscle-specific enhancer elements (often referred to as muscle-specific, cardiac muscle-specific, or skeletal muscle-specific CREs, or muscle-specific, cardiac muscle-specific, or skeletal muscle-specific CRE enhancers, or suchlike). In the present context, it is preferred that the CRE is located 2500 nucleotides or less from the transcription start site (TSS), more preferably 2000 nucleotides or less from the TSS, more preferably 1500 nucleotides or less from the TSS, and suitably 1000, 750, 500, 250, 200, 150, or 100 nucleotides or less from the TSS. CREs of the present invention are preferably comparatively short in length, preferably 500 nucleotides or less in length, for example they may be 400, 300, 200, 175, 150, 90, 80, 70, 60 or 50 nucleotides or less in length. The CREs of the present invention are typically provided in combination with an operably linked promoter element, which can be a minimal promoter or proximal promoter; the CREs of the present invention enhance muscle-specific, cardiac muscle-specific, or skeletal muscle-specific activity of the promoter element. In any of the combinations of CREs, or functional variants thereof, disclosed herein, some or all of the recited CREs and promoter elements may suitably be positioned adjacent to one other in the promoter (i.e. without any intervening CREs or other regulatory elements). The CREs may be contiguous or non-contiguous (i.e. they can be positioned immediately adjacent to one another or they can be separated by a spacer or other sequence). The CRE's may be in any order. In some preferred embodiments, the CREs, or functional variants thereof, are provided in the recited order and are adjacent to one another. For example, the synthetic muscle-specific regulatory nucleic acid may comprise CRE0107 immediately upstream of CRE0033, and so forth. In some embodiments it is preferred that some or all of the CREs are contiguous.
[0965] The term “cis-regulatory module” or “CRM” means a functional regulatory nucleic acid module, which usually comprises two or more CREs; in the present invention the CREs are typically muscle-specific, cardiac muscle-specific, or skeletal muscle-specific enhancers and thus the CRM is a synthetic muscle-specific, cardiac muscle-specific, or skeletal muscle-specific regulatory nucleic acid. Thus, in the present application a CRM typically comprises a plurality of muscle-specific, cardiac muscle-specific, or skeletal muscle-specific CREs. Typically, the multiple CREs within the CRM act together (e.g. additively or synergistically) to enhance the transcription of a gene that a promoter comprising the CRM is operably associated with. There is considerable scope to shuffle (i.e. reorder), invert (i.e. reverse orientation), and alter spacing of CREs within a CRM. Accordingly, functional variants of CRMs of the present invention include, inter alia, variants of the referenced CRMs wherein CREs within them have been shuffled and/or inverted, and/or the spacing between CREs has been altered. In the case of a tandem promoter, CRM may be used to describe the combination of promoter element and one or more CREs which are operably linked to a further promoter element. For example, in tandem promoter SP0268, the combination of CRE0035 and promoter element CRE0010 may be considered a CRM.
[0966] As used herein, the phrase “promoter” refers to a region of DNA that generally is located upstream of a nucleic acid sequence to be transcribed that is needed for transcription to occur, i.e. which initiates transcription. Promoters permit the proper activation or repression of transcription of a coding sequence under their control. A promoter typically contains specific sequences that are recognized and bound by plurality of TFs. TFs bind to the promoter sequences and result in the recruitment of RNA polymerase, an enzyme that synthesizes RNA from the coding region of the gene. Many diverse promoters are known in the art.
[0967] In some cases, the term “promoter” or “composite promoter” is used herein to refer to a combination of a promoter and additional regulatory elements, e.g. regulatory sequences located immediately downstream of the transcription start site (TSS), for example a 5′ UTR and or a 5′UTR and an intron. Such sequences downstream of the TSS can contribute to regulation of expression at the transcriptional and/or translational stages. In some cases, the term “promoter” or “composite promoter” is used herein to refer to a ‘tandem promoter’ as defined elsewhere herein.
[0968] The term “synthetic promoter” as used herein relates to a promoter that does not occur in nature. In the present context it typically comprises a CRE and/or CRM of the present invention operably linked to a minimal (or core) promoter or muscle-specific, cardiac muscle-specific, or skeletal muscle-specific proximal promoter (promoter element). The CREs and/or CRMs of the present invention serve to enhance muscle-specific, cardiac muscle-specific, or skeletal muscle-specific transcription of a gene operably linked to the synthetic promoter. Parts of the synthetic promoter may be naturally occurring (e.g. the minimal promoter or one or more CREs in the promoter), but the synthetic promoter as an entity is not naturally occurring.
[0969] As used herein, “minimal promoter” (also known as the “core promoter”) refers to a typically short DNA segment which is inactive or largely inactive by itself, but can mediate transcription when combined with other transcription regulatory elements. Minimal promoter sequences can be derived from various different sources, including prokaryotic and eukaryotic genes. Examples of minimal promoters are discussed above, and include the desmin minimum promoter, dopamine beta-hydroxylase gene minimum promoter, cytomegalovirus (CMV) immediate early gene minimum promoter (CMV-MP), and the herpes thymidine kinase minimal promoter (MinTK). A minimal promoter typically comprises the transcription start site (TSS) and elements directly upstream, a binding site for RNA polymerase II, and general transcription factor binding sites (often a TATA box). A minimal promoter may also include some elements downstream of the TSS, but these typically have little functionality absent additional regulatory elements.
[0970] As used herein, “proximal promoter” relates to the minimal promoter plus at least some additional regulatory sequence, typically the proximal sequence upstream of the gene that tends to contain primary regulatory elements. It often extends approximately 250 base pairs upstream of the TSS, and includes specific TFBS. A proximal promoter may also include one or more regulatory elements downstream of the TSS, for example a UTR or an intron. In the present case, the proximal promoter may suitably be a naturally occurring muscle-specific, cardiac muscle-specific, or skeletal muscle-specific proximal promoter that can be combined with one or more CREs or CRMs of the present invention. However, the proximal promoter can be synthetic.
[0971] As used herein, “promoter element” refers to either a minimal promoter or proximal promoter as defined above. In the context of the present invention a promoter element is typically combined with one or more CREs in order to provide a synthetic muscle-specific, cardiac muscle-specific, or skeletal muscle-specific promoter of the present invention.
[0972] A “functional variant” of a CRE, CRM, promoter element, promoter or other regulatory nucleic acid in the context of the present invention is a variant of a reference sequence that retains the ability to function in the same way as the reference sequence, e.g. as a muscle-specific, cardiac muscle-specific, skeletal muscle-specific CRE, muscle-specific, cardiac muscle-specific, skeletal muscle-specific CRM or muscle-specific, cardiac muscle-specific, skeletal muscle-specific promoter. Alternative terms for such functional variants include “biological equivalents” or “equivalents”.
[0973] It will be appreciated that the ability of a given CRE, CRM, promoter or other regulatory sequence to function as a muscle-specific, cardiac muscle-specific, or skeletal muscle-specific enhancer is determined significantly by the ability of the sequence to bind the same muscle-specific, cardiac muscle-specific, or skeletal muscle-specific TFs that bind to the reference sequence. Accordingly, in most cases, a functional variant of a CRE or CRM will contain TFBS for the most or all of same TFs as the reference CRE, CRM or promoter. It is preferred, but not essential, that the TFBS of a functional variant are in the same relative positions (i.e. order and general position) as the reference CRE, CRM or promoter. It is also preferred, but not essential, that the TFBS of a functional variant are in the same orientation as the reference sequence (it will be noted that TFBS can in some cases be present in reverse orientation, e.g. as the reverse complement vis-à-vis the sequence in the reference sequence). It is also preferred, but not essential, that the TFBS of a functional variant are on the same strand as the reference sequence. Thus, in preferred embodiments, the functional variant comprises TFBS for the same TFs, in the same order, the same position, in the same orientation and on the same strand as the reference sequence. It will also be appreciated that the sequences lying between TFBS (referred to in some cases as spacer sequences, or suchlike) are of less consequence to the function of the CRE or CRM. Such sequences can typically be varied considerably, and their lengths can be altered. However, in preferred embodiments the spacing (i.e. the distance between adjacent TFBS) is substantially the same (e.g. it does not vary by more than 20%, preferably by not more than 10%, and more preferably it is approximately the same) in a functional variant as it is in the reference sequence. It will be apparent that in some cases a functional variant of a CRE can be present in the reverse orientation, e.g. it can be the reverse complement of a CRE as described above, or a variant thereof.
[0974] Levels of sequence identity between a functional variant and the reference sequence can also be an indicator or retained functionality. High levels of sequence identity in the TFBS of the CRE, CRM or promoter is of generally higher importance than sequence identity in the spacer sequences (where there is little or no requirement for any conservation of sequence). However, it will be appreciated that even within the TFBS, a considerable degree of sequence variation can be accommodated, given that the sequence of a functional TFBS does not need to exactly match the consensus sequence.
[0975] The ability of one or more TFs to bind to a TFBS in a given functional variant can determined by any relevant means known in the art, including, but not limited to, electromobility shift assays (EMSA), binding assays, chromatin immunoprecipitation (ChIP), and ChIP-sequencing (ChIP-seq). In a preferred embodiment the ability of one or more TFs to bind a given functional variant is determined by EMSA. Methods of performing EMSA are well-known in the art. Suitable approaches are described in Sambrook et al. cited above. Many relevant articles describing this procedure are available, e.g. Hellman and Fried, Nat Protoc. 2007; 2(8): 1849-1861.
[0976] “Muscle-specific” or “muscle-specific expression” refers to the ability of a cis-regulatory element, cis-regulatory module or promoter to enhance or drive expression of a gene in muscle cells (or in muscle-derived cells) in a preferential or predominant manner as compared to other tissues (e.g. liver, kidney, spleen, heart, lung, and brain). Expression of the gene can be in the form of mRNA or protein. In preferred embodiments, muscle-specific expression is such that there is negligible expression in other (i.e. non-muscle) tissues or cells, i.e. expression is highly muscle-specific. For example, expression in muscle cells as opposed to other cells is at least 75%, 80%, 85%, 90%, or 95%. “Cardiac muscle-specific” or “Cardiac muscle-specific expression” refers to the ability of a cis-regulatory element, cis-regulatory module, promoter element or promoter to enhance or drive expression of a gene in the cardiac muscle in a preferential or predominant manner as compared to other tissues (e.g. spleen, liver, lung, and brain) and compared to the skeletal muscle tissue. “Skeletal muscle-specific” or “Skeletal muscle-specific expression” refers to the ability of a cis-regulatory element, cis-regulatory module, promoter element or promoter to enhance or drive expression of a gene in the skeletal muscle in a preferential or predominant manner as compared to other tissues (e.g. spleen, liver, lung, and brain) and compared to the cardiac muscle tissue. There can be instances where lower degrees of specificity are desired and are part of this invention.
[0977] The ability of a CRE, CRM or promoter to function as a muscle-specific, cardiac muscle-specific, or skeletal muscle-specific CRE, CRM or promoter can be readily assessed by the skilled person. The skilled person can thus easily determine whether any variant of the specific CRE, CRM or promoter recited above remains functional (i.e. it is a functional variant as defined above). For example, any given CRM to be assessed can be operably linked to a minimal promoter (e.g. positioned upstream of CMV-MP) and the ability of the cis-regulatory element to drive muscle-specific, cardiac muscle-specific, or skeletal muscle-specific expression of a gene (typically a reporter gene) is measured. Alternatively, a variant of a CRE or CRM can be substituted into a synthetic muscle-specific, cardiac muscle-specific or skeletal muscle-specific promoter in place of a reference CRE or CRM, and the effects on muscle-specific, cardiac muscle-specific or skeletal muscle-specific expression driven by said modified promoter can be determined and compared to the unmodified form. Similarly, the ability of a promoter to drive muscle-specific, cardiac muscle-specific or skeletal muscle-specific expression can be readily assessed by the skilled person (e.g. as described in the examples below). Expression levels of a gene driven by a variant of a reference promoter can be compared to the expression levels driven by the reference promoter. In some embodiments, where muscle-specific, cardiac muscle-specific or skeletal muscle-specific expression levels driven by a variant promoter are at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% of the expression levels driven by the reference promoter, it can be said that the variant remains functional. Suitable nucleic acid constructs and reporter assays to assess muscle-specific, cardiac muscle-specific or skeletal muscle-specific expression enhancement can easily be constructed, and the examples set out below give suitable methodologies.
[0978] Muscle-specificity, cardiac muscle-specificity or skeletal muscle-specificity can be identified wherein the expression of a gene (e.g. a therapeutic or reporter gene) occurs preferentially or predominantly in muscle-derived cells, cardiac muscle-derived cells or skeletal muscle. Preferential or predominant expression can be defined, for example, where the level of expression is significantly greater in muscle-derived, cardiac muscle-derived or skeletal muscle-derived cells than in other types of cells (i.e. non-muscle-derived cells, non-cardiac muscle-derived cells or non-skeletal muscle-derived cells). For example, expression in muscle-derived, cardiac muscle-derived or skeletal muscle-derived cells is suitably at least 5-fold higher than in non-muscle cells, non-cardiac muscle cells or non-skeletal muscle cells, preferably at least 10-fold higher than in non-muscle cells, non-cardiac muscle cells or non-skeletal muscle cells, and it may be 50-fold higher or more in some cases. For convenience, muscle-specific expression can suitably be demonstrated via a comparison of expression levels in a muscle cell line (e.g. muscle-derived cell line such as C2C12 or H2K cells (skeletal muscle) or H9C2 cells (cardiac), compared with expression levels in a liver-derived cell line (e.g. Huh7 or HepG2), kidney-derived cell line (e.g. HEK-293), a cervical tissue-derived cell line (e.g. HeLa) and/or a lung-derived cell line (e.g. A549). Cardiac muscle-specific expression can suitably be demonstrated via a comparison of expression levels in a cardiac muscle cell line (e.g. cardiac muscle derived cell line such as H9C2) or primary cardiomyocyte compared with expression levels in in a liver-derived cell line (e.g. Huh7 or HepG2), a kidney-derived cell line (e.g. HEK-293), a cervical tissue-derived cell line (e.g. HeLa), a lung-derived cell line (e.g. A549) and/or skeletal muscle-derived cells (e.g. C2C12 or H2K). Skeletal muscle-specific expression can suitably be demonstrated via a comparison of expression levels in a skeletal muscle-derived cells (e.g. C2C12 or H2K) or primary skeletal muscle cells compared with expression levels in in a liver-derived cell line (e.g. Huh7 or HepG2), a kidney-derived cell line (e.g. HEK-293), a cervical tissue-derived cell line (e.g. HeLa), a lung-derived cell line (e.g. A549) and/or cardiac muscle cell line (e.g. H9C2).
[0979] The synthetic muscle-specific, cardiac muscle-specific or skeletal muscle-specific promoters of the present invention preferably exhibit reduced expression in non-muscle-derived cells, suitably in Huh7, HEK-293, HeLa, and/or A549 cells when compared to a non-tissue specific promoter such as CMV-IE. The synthetic muscle-specific, cardiac muscle-specific or skeletal muscle-specific promoters of the present invention preferably have an activity of 50% or less than the CMV-IE promoter in non-muscle-derived cells (suitably in Huh7, HEK-293, HeLa, and/or A549 cells), suitably 25% or less, 20% or less, 15% or less, 10% or less, 5% or less or 1% or less. Generally, it is preferred that expression in non-muscle-derived cells is minimized, but in some cases this may not be necessary. Even if a synthetic promoter of the present invention has higher expression in, e.g., one or two non-muscle cells, as long as it generally has higher expression overall in a range of muscle cells versus non-muscle cell, it can still a muscle-specific promoter. In some embodiments, a muscle-specific promoter expresses a gene at least 25%, or at least 35%, or at least 45%, or at least 55%, or at least 65%, or at least 75%, or at least 80%, or at least 85%, or at least 90%, or at least 95%, or any integer between 25%-95% higher in muscle cells as compared to non-muscle cells.
[0980] The synthetic muscle-specific promoters of the present invention are preferably suitable for promoting expression in the muscle of a subject, e.g. driving muscle-specific expression of a transgene, preferably a therapeutic transgene. The synthetic cardiac muscle-specific promoters of the present invention are preferably suitable for promoting expression in the heart of a subject, e.g. driving cardiac muscle-specific expression of a transgene, preferably a therapeutic transgene. The synthetic skeletal muscle-specific promoters of the present invention are preferably suitable for promoting expression in the skeletal muscles of a subject, e.g. driving skeletal muscle-specific expression of a transgene, preferably a therapeutic transgene. Preferred synthetic muscle-specific promoters of the present invention are suitable for promoting muscle-specific transgene expression and have an activity in muscle cells which is at least 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 125%, 150%, 175%, 200%, 250%, 300%, 350% or 400% of the activity of the CBA promoter. In some embodiments, the synthetic muscle-specific promoters of the invention are suitable for promoting muscle-specific transgene expression at a level at least 100% of the activity of the CBA promoter, preferably 150%, 200%, 300% or 500% of the activity of the CBA or the spc5-12 promoter. In some embodiments, the synthetic cardiac muscle-specific promoters of the invention are suitable for promoting cardiac muscle-specific transgene expression at a level at least 100% of the activity of the Tnnt2 or Myl2 promoter, preferably 150%, 200%, 300% or 500% of the activity of the Tnnt2 or Myl2 promoter. In some embodiments, the synthetic skeletal muscle-specific promoters of the invention are suitable for promoting skeletal muscle-specific transgene expression at a level at least 100% of the activity of the Tnnt2 or Myl2 promoter, preferably 150%, 200%, 300% or 500% of the activity of the spc5-12 promoter. Such muscle-specific expression is suitably determined in muscle-derived cells, e.g. as C2C12 or H2K cells (skeletal muscle) or H9C2 cells (cardiac) or primary muscle cells (suitably primary human myocytes).
[0981] Synthetic muscle-specific, cardiac muscle-specific or skeletal muscle-specific promoters of the present invention may also be able to promote muscle-specific, cardiac muscle-specific or skeletal muscle-specific expression of a gene at a level at least 50%, 100%, 150% or 200% compared to CMV-IE in muscle-derived cells (e.g. c2c12 or H2K cells (skeletal muscle) or h9C2 cells (cardiac)).
[0982] The term “nucleic acid” as used herein typically refers to an oligomer or polymer (preferably a linear polymer) of any length composed essentially of nucleotides. A nucleotide unit commonly includes a heterocyclic base, a sugar group, and at least one, e.g. one, two, or three, phosphate groups, including modified or substituted phosphate groups. Heterocyclic bases may include inter alia purine and pyrimidine bases such as adenine (A), guanine (G), cytosine (C), thymine (T) and uracil (U) which are widespread in naturally-occurring nucleic acids, other naturally-occurring bases (e.g., xanthine, inosine, hypoxanthine) as well as chemically or biochemically modified (e.g., methylated), non-natural or derivatised bases. Sugar groups may include inter alia pentose (pentofuranose) groups such as preferably ribose and/or 2-deoxyribose common in naturally-occurring nucleic acids, or arabinose, 2-deoxyarabinose, threose or hexose sugar groups, as well as modified or substituted sugar groups. Nucleic acids as intended herein may include naturally occurring nucleotides, modified nucleotides or mixtures thereof. A modified nucleotide may include a modified heterocyclic base, a modified sugar moiety, a modified phosphate group or a combination thereof. Modifications of phosphate groups or sugars may be introduced to improve stability, resistance to enzymatic degradation, or some other useful property. The term “nucleic acid” further preferably encompasses DNA, RNA and DNA RNA hybrid molecules, specifically including hnRNA, pre-mRNA, mRNA, cDNA, genomic DNA, amplification products, oligonucleotides, and synthetic (e.g., chemically synthesised) DNA, RNA or DNA RNA hybrids. A nucleic acid can be naturally occurring, e.g., present in or isolated from nature; or can be non-naturally occurring, e.g., recombinant, i.e., produced by recombinant DNA technology, and/or partly or entirely, chemically or biochemically synthesised. A “nucleic acid” can be double-stranded, partly double stranded, or single-stranded. Where single-stranded, the nucleic acid can be the sense strand or the antisense strand. In addition, nucleic acid can be circular or linear.
[0983] By “isolated” is meant, when referring to a nucleic acid is a nucleic acid molecule devoid, in whole or part, of sequences normally associated with it in nature; or a sequence, as it exists in nature, but having heterologous sequences in association therewith; or a molecule disassociated from the chromosome.
[0984] The terms “identity” and “identical” and the like refer to the sequence similarity between two polymeric molecules, e.g., between two nucleic acid molecules, such as between two DNA molecules. Sequence alignments and determination of sequence identity can be done, e.g., using the Basic Local Alignment Search Tool (BLAST) originally described by Altschul et al. 1990 (J Mol Biol 215: 403-10), such as the “Blast 2 sequences” algorithm described by Tatusova and Madden 1999 (FEMS Microbiol Lett 174: 247-250).
[0985] Methods for aligning sequences for comparison are well-known in the art. Various programs and alignment algorithms are described in, for example: Smith and Waterman (1981) Adv. Appl. Math. 2:482; Needleman and Wunsch (1970) J. Mol. Biol. 48:443; Pearson and Lipman (1988) Proc. Natl. Acad. Sci. U.S.A. 85:2444; Higgins and Sharp (1988) Gene 73:237-44; Higgins and Sharp (1989) CABIOS 5:151-3; Corpet et al. (1988) Nucleic Acids Res. 16:10881-90; Huang et al. (1992) Comp. Appl. Biosci. 8:155-65; Pearson et al. (1994) Methods Mol. Biol. 24:307-31; Tatiana et al. (1999) FEMS Microbiol. Lett. 174:247-50. A detailed consideration of sequence alignment methods and homology calculations can be found in, e.g., Altschul et al. (1990) J. Mol. Biol. 215:403-10.
[0986] The National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST™; Altschul et al. (1990)) is available from several sources, including the National Center for Biotechnology Information (Bethesda, Md.), and on the internet, for use in connection with several sequence analysis programs. A description of how to determine sequence identity using this program is available on the internet under the “help” section for BLAST™. For comparisons of nucleic acid sequences, the “Blast 2 sequences” function of the BLAST™ (Blastn) program may be employed using the default parameters. Nucleic acid sequences with even greater similarity to the reference sequences will show increasing percentage identity when assessed by this method. Typically, the percentage sequence identity is calculated over the entire length of the sequence.
[0987] For example, a global optimal alignment is suitably found by the Needleman-Wunsch algorithm with the following scoring parameters: Match score: +2, Mismatch score: −3; Gap penalties: gap open 5, gap extension 2. The percentage identity of the resulting optimal global alignment is suitably calculated by the ratio of the number of aligned bases to the total length of the alignment, where the alignment length includes both matches and mismatches, multiplied by 100.
[0988] The term “hybridising” means annealing to two at least partially complementary nucleotide sequences in a hybridization process. In order to allow hybridisation to occur complementary nucleic acid molecules are generally thermally or chemically denatured to melt a double strand into two single strands and/or to remove hairpins or other secondary structures from single-stranded nucleic acids. The stringency of hybridisation is influenced by conditions such as temperature, salt concentration and hybridisation buffer composition. Conventional hybridisation conditions are described in, for example, Sambrook (2001) Molecular Cloning: a laboratory manual, 3.sup.1d Edition Cold Spring Harbor Laboratory Press, CSH, New York, but the skilled craftsman will appreciate that numerous different hybridisation conditions can be designed in function of the known or the expected homology and/or length of the nucleic acid sequence. High stringency conditions for hybridisation include high temperature and/or low sodium/salt concentration (salts include sodium as for example in NaCl and Na-citrate) and/or the inclusion of formamide in the hybridisation buffer and/or lowering the concentration of compounds such as SDS (sodium dodecyl sulphate detergent) in the hybridisation buffer and/or exclusion of compounds such as dextran sulphate or polyethylene glycol (promoting molecular crowding) from the hybridisation buffer. By way of non-limiting example, representative salt and temperature conditions for stringent hybridization are: 1×SSC, 0.5% SDS at 65° C. The abbreviation SSC refers to a buffer used in nucleic acid hybridization solutions. One litre of a 20× (twenty times concentrate) stock SSC buffer solution (pH 7.0) contains 175.3 g sodium chloride and 88.2 g sodium citrate. A representative time period for achieving hybridisation is 12 hours.
[0989] The term “transcription factor binding site” (TFBS) is well known in the art. Disclosed herein are various specific TFBS sequences. It will be apparent to the skilled person that alternative TFBS sequences can be used, provided that they are bound by the intended TF. Consensus sequences for the various TFBS disclosed herein are known in the art, and the skilled person can readily use this information to determine alternative TFBS. Furthermore, the ability of a TF to bind to a given putative sequence can readily be determined experimentally by the skilled person (e.g. by EMSA and other approaches well known in the art and discussed herein).
[0990] The meaning of “consensus sequence” is well-known in the art. In the present application, the following notation is used for the consensus sequences, unless the context dictates otherwise. Considering the following exemplary DNA sequence:
TABLE-US-00007 A[CT]N{A}YR
[0991] A means that an A is always found in that position; [CT] stands for either C or T in that position; N stands for any base in that position; and {A} means any base except A is found in that position. Y represents any pyrimidine, and R indicates any purine.
[0992] “Synthetic” in the present application means a nucleic acid molecule that does not occur in nature. Synthetic nucleic acids of the present invention are produced artificially, typically by recombinant technologies or de novo synthesis. Such synthetic nucleic acids may contain naturally occurring sequences (e.g. promoter, enhancer, intron, and other such regulatory sequences), but these are present in a non-naturally occurring context. For example, a synthetic gene (or portion of a gene) typically contains one or more nucleic acid sequences that are not contiguous in nature (chimeric sequences), and/or may encompass substitutions, insertions, and deletions and combinations thereof.
[0993] “Complementary” or “complementarity”, as used herein, refers to the Watson-Crick base-pairing of two nucleic acid sequences. For example, for the sequence 5′-AGT-3′ binds to the complementary sequence 3′-TCA-5′. Complementarity between two nucleic acid sequences may be “partial”, in which only some of the bases bind to their complement, or it may be complete as when every base in the sequence binds to its complementary base. The degree of complementarity between nucleic acid strands has significant effects on the efficiency and strength of hybridisation between nucleic acid strands.
[0994] “Transfection” in the present application refers broadly to any process of deliberately introducing nucleic acids into cells, and covers introduction of viral and non-viral vectors, and includes or is equivalent to transformation, transduction and like terms and processes. Examples include, but are not limited to: transfection with viral vectors; transformation with plasmid vectors; electroporation (Fromm et al. (1986) Nature 319:791-3); lipofection (Feigner et al. (1987) Proc. Natl. Acad. Sci. USA 84:7413-7); microinjection (Mueller et al. (1978) Cell 15:579-85); Agrobacterium-mediated transfer (Fraley et al. (1983) Proc. Natl. Acad. Sci. USA 80:4803-7); direct DNA uptake; whiskers-mediated transformation; and microprojectile bombardment (Klein et al. (1987) Nature 327:70).
[0995] As used herein, the phrase “transgene” refers to an exogenous nucleic acid sequence. In one example, a transgene is a gene encoding an industrially or pharmaceutically useful compound, or a gene encoding a desirable trait. In yet another example, the transgene encodes useful nucleic acid such as an antisense nucleic acid sequence, wherein expression of the antisense nucleic acid sequence inhibits expression of a target nucleic acid sequence. The transgene preferably encodes a therapeutic product, e.g. a protein.
[0996] The term “vector” is well known in the art, and as used herein refers to a nucleic acid molecule, e.g. double-stranded DNA, which may have inserted into it a nucleic acid sequence according to the present invention. A vector is suitably used to transport an inserted nucleic acid molecule into a suitable host cell. A vector typically contains all of the necessary elements that permit transcribing the insert nucleic acid molecule, and, preferably, translating the transcript into a polypeptide. A vector typically contains all of the necessary elements such that, once the vector is in a host cell, the vector can replicate independently of, or coincidental with, the host chromosomal DNA; several copies of the vector and its inserted nucleic acid molecule may be generated. Vectors of the present invention can be episomal vectors (i.e., that do not integrate into the genome of a host cell), or can be vectors that integrate into the host cell genome. This definition includes both non-viral and viral vectors. Non-viral vectors include but are not limited to plasmid vectors (e.g. pMA-RQ, pUC vectors, bluescript vectors (pBS) and pBR322 or derivatives thereof that are devoid of bacterial sequences (minicircles)) transposons-based vectors (e.g. PiggyBac (PB) vectors or Sleeping Beauty (SB) vectors), etc. Larger vectors such as artificial chromosomes (bacteria (BAC), yeast (YAC), or human (HAC)) may be used to accommodate larger inserts. Viral vectors are derived from viruses and include but are not limited to retroviral, lentiviral, adeno-associated viral, adenoviral, herpes viral, hepatitis viral vectors or the like. Typically, but not necessarily, viral vectors are replication-deficient as they have lost the ability to propagate in a given cell since viral genes essential for replication have been eliminated from the viral vector. However, some viral vectors can also be adapted to replicate specifically in a given cell, such as e.g. a cancer cell, and are typically used to trigger the (cancer) cell-specific (onco)lysis. Virosomes are a non-limiting example of a vector that comprises both viral and non-viral elements, in particular they combine liposomes with an inactivated HIV or influenza virus (Yamada et al., 2003). Another example encompasses viral vectors mixed with cationic lipids.
[0997] The term “operably linked”, “operably connected” or equivalent expressions as used herein refer to the arrangement of various nucleic acid elements relative to each other such that the elements are functionally connected and are able to interact with each other in the manner intended. Such elements may include, without limitation, a promoter, a CRE (e.g. enhancer or other regulatory element), a promoter element, a polyadenylation sequence, one or more introns and/or exons, and a coding sequence of a gene of interest to be expressed. The nucleic acid sequence elements, when properly oriented or operably linked, act together to modulate the activity of one another, and ultimately may affect the level of expression of an expression product. By modulate is meant increasing, decreasing, or maintaining the level of activity of a particular element. The position of each element relative to other elements may be expressed in terms of the 5′ terminus and the 3′ terminus of each element or their position upstream or downstream of another element or position (such as a TSS or promoter element), and the distance between any particular elements may be referenced by the number of intervening nucleotides, or base pairs, between the elements. As understood by the skilled person, operably linked implies functional activity, and is not necessarily related to a natural positional link. Indeed, when used in nucleic acid expression cassettes, CREs will typically be located immediately upstream of the promoter element (although this is generally the case, it should definitely not be interpreted as a limitation or exclusion of positions within the nucleic acid expression cassette), but this needs not be the case in vivo, e.g., a regulatory element sequence naturally occurring downstream of a gene whose transcription it affects is able to function in the same way when located upstream of the promoter. Hence, according to a specific embodiment, the regulatory or enhancing effect of the regulatory element can be position-independent.
[0998] A “spacer sequence” or “spacer” as used herein is a nucleic acid sequence that separates two functional nucleic acid sequences (e.g. TFBS, CREs, CRMs, promoter element, etc.). It can have essentially any sequence, provided it does not prevent the functional nucleic acid sequence (e.g. cis-regulatory element) from functioning as desired (e.g. this could happen if it includes a silencer sequence, prevents binding of the desired transcription factor, or suchlike). Typically, it is non-functional, as in it is present only to space adjacent functional nucleic acid sequences from one another. In some embodiments, spacers may have a length of 75, 50, 40, 30, 30 or 10 nucleotides or fewer.
[0999] The term “pharmaceutically acceptable” as used herein is consistent with the art and means compatible with the other ingredients of the pharmaceutical composition and not deleterious to the recipient thereof.
[1000] “Therapeutically effective amount” and like phrases mean a dose or plasma concentration in a subject that provides the desired specific pharmacological effect, e.g. to express a therapeutic gene in the muscle. A therapeutically effective amount may not always be effective in treating the conditions described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art. The therapeutically effective amount may vary based on the route of administration and dosage form, the age and weight of the subject, and/or the disease or condition being treated.
[1001] The term “AAV vector” as used herein is well known in the art, and generally refers to an AAV vector nucleic acid sequence including various nucleic acid sequences. An AAV vector as used herein typically comprise a heterologous nucleic acid sequence not of AAV origin as part of the vector. This heterologous nucleic acid sequence typically comprises a promoter as disclosed herein as well as other sequences of interest for the genetic transformation of a cell. In general, the heterologous nucleic acid sequence is flanked by at least one, and generally by two AAV inverted terminal repeat sequences (ITRs). An “AAV virion” or “AAV virus” or “AAV viral particle” or “AAV vector particle” refers to a viral particle composed of at least one AAV capsid polypeptide (including both variant AAV capsid polypeptides and non-variant parent capsid polypeptides) and an encapsidated polynucleotide AAV vector. If the particle comprises a heterologous nucleic acid (i.e. a polynucleotide other than a wild-type AAV genome, such as a transgene to be delivered to a mammalian cell), it can be referred to as an “AAV vector particle” or simply an “AAV vector”. Thus, production of AAV virion or AAV particle necessarily includes production of AAV vector as such a vector is contained within an AAV virion or AAV particle.
[1002] A “small interfering” or “short interfering RNA” or siRNA is a RNA duplex of nucleotides targeted to a gene interest (a “target gene”). An “RNA duplex” refers to the structure formed by the complementary pairing between two regions of a RNA molecule. siRNA is “targeted” to a gene and the nucleotide sequence of the duplex portion of the siRNA is complementary to a nucleotide sequence of the targeted gene. In some embodiments, the length of the duplex of siRNAs is less than 30 nucleotides. In some embodiments, the duplex can be 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11 or 10 nucleotides in length. In some embodiments, the length of the duplex is 19-25 nucleotides in length. The RNA duplex portion of the siRNA can be part of a hairpin structure. In addition to the duplex portion, the hairpin structure may contain a loop portion positioned between the two sequences forming the duplex. The loop can vary in length. In some embodiments the loop is 5, 6, 7, 8, 9, 10, 11, 12 or 13 nucleotides in length. The hairpin structure can also contain 3′ or 5′ overhang portions. In some embodiments, the overhang is a 3′ or a 5′ overhang 0, 1, 2, 3, 4 or 5 nucleotides in length.
[1003] As used herein, the term “microRNA” refers to any type of interfering RNAs, including but not limited to, endogenous microRNAs and artificial microRNAs (e.g., synthetic miRNAs). Endogenous microRNAs are small RNAs naturally encoded in the genome capable of modulating the productive utilization of mRNA. An artificial microRNA can be any type of RNA sequence, other than endogenous microRNA, capable of modulating the activity of an mRNA. A microRNA sequence can be an RNA molecule composed of any one or more of these sequences. MicroRNA (or “miRNA”) sequences have been described in publications such as Lim, et al, 2003, Genes & Development, 17, 991-1008, Lim et al, 2003, Science, 299, 1540, Lee and Ambrose, 2001, Science, 294, 862, Lau et al, 2001, Science 294, 858-861, Lagos-Quintana et al, 2002, Current Biology, 12, 735-739, Lagos-Quintana et al., 2001, Science, 294, 853-857, and Lagos-Quintana et al., 2003, RNA, 9, 175-179. Examples of microRNAs include any RNA fragment of a larger RNA or is a miRNA, siRNA, stRNA, sncRNA, tncRNA, snoRNA, smRNA, shRNA, snRNA, or other small non-coding RNA. See, e.g., US Patent Applications 20050272923, 20050266552, 20050142581, and 20050075492. A “microRNA precursor” (or “pre-miRNA”) refers to a nucleic acid having a stem-loop structure with a microRNA sequence incorporated therein. A “mature microRNA” (or “mature miRNA”) includes a microRNA cleaved from a microRNA precursor (a “pre-miRNA”), or synthesized (e.g., synthesized in a laboratory by cell-free synthesis), and has a length of from about 19 nucleotides to about 27 nucleotides, e.g., a mature microRNA can have a length of 19 nt, 20 nt, 21 nt, 22 nt, 23 nt, 24 nt, 25 nt, 26 nt, or 27 nt. A mature microRNA can bind to a target mRNA and inhibit translation of the target mRNA.
[1004] The terms “treatment” or “treating” refer to reducing, ameliorating or eliminating one or more signs, symptoms, or effects of a disease or condition. “Treatment,” as used herein thus includes any treatment of a disease in a mammal, particularly in a human, and includes: (a) preventing the disease from occurring in a subject predisposed to the disease or at risk of acquiring the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
[1005] The “administration” of an agent to a subject includes any route of introducing or delivering to a subject the agent to perform its intended function. Administration can be carried out by any suitable route, including orally, intranasally, intraocularly, ophthalmically, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), or topically. Administration includes self-administration and the administration by another. Intramuscular administration is of particular interest in the present invention.
[1006] The terms “individual,” “subject,” and “patient” are used interchangeably, and refer to any individual subject with a disease or condition in need of treatment. For the purposes of the present disclosure, the subject may be a primate, preferably a human, or another mammal, such as a dog, cat, horse, pig, goat, or bovine, and the like.
EXAMPLES
[1007] The strength of the synthetic muscle-specific promoters according to embodiments of this invention were tested by operably linking each synthetic muscle-specific promoter to the reporter gene luciferase. The expression cassette comprising of the muscle-specific promoter to be tested and the luciferase gene was inserted into a suitable plasmid which was then transfected into a variety of cell types to test the expression from the synthetic muscle-specific promoters in these cells.
Example 1—In Vitro Testing of First Generation Designs
[1008] Materials and Methods
[1009] DNA preparations were transfected into H9C2 (a rat BDIX heart myoblast cell line, available from ATCC), C2C12 (an immortalized mouse myoblast cell line, available from ATCC), H2K 2B4 (an immortal satellite cell-derived cell-line, see PloS One. 2011; 6(9): e24826), Huh7 (a well-known hepato-cellular carcinoma cell line, sourced from JCRB Cell Bank (JCRB0403)), or HEK293 (a well-known human embryonic kidney cells, ECACC cell bank) to assess transcriptional activity.
[1010] H9C2 Cell Culture and Transfection
[1011] H9C2 are a rat BDIX heart myoblast cell line. They have cardiac muscle properties, e.g. myotubes formed at confluency respond to acetylcholine.
[1012] Cell Maintenance
[1013] H9C2 cells were cultured in DMEM (High Glucose, D6546, Sigma) with 1% FBS (Heat inactivated-Gibco 10270-106, lot number 42G2076K), 1% Glutamax (35050-038, Gibco), 1% Penicillin-streptomycin solution (15140-122, Gibco), in T-75 flasks. Cells were passaged at a sub confluent stage (70-80%) to avoid risk of the cells becoming confluent and fusing to form myotubes.
[1014] For passaging during cell maintenance, culture media was removed, cells were washed twice with 5 ml DPBS without CaCl.sub.2, without MgCl.sub.2 (14190-094, Gibco). The cells were detached from the flask by incubating with 1 ml Trypsin EDTA (25200-056, Gibco) for approximately 5 minutes. Then, 4 ml of culture medium was added to the flask and the mixture was gently pipetted up and down to help detach the cells from the flask surface. Cells were pelleted at 100 g for 3 minutes. Supernatant was disposed and cells were resuspended in 3 ml of culture medium. Cells were counted on the Countess automated cell counter, seeded at 1:3 to 1:10 i.e. seeding 1-3×10,000 cells/cm.sup.2 and incubated at 37° C. 5% CO.sub.2.
[1015] Cell Transfection and Differentiation
[1016] H9C2 cells were collected from two T-75 flasks of approximately 70-80% confluency, by washing with DPBS, detaching from the flask using 1 ml Trypsin EDTA, washing off the flask's surface with 4 ml of culture medium and pelleting at 100 g for 3 minutes, as described above. Cells were resuspended in 45 ml culture medium and seed at a density of 40,000 cells/well in a 48 well flat bottom plate (300 μl/well) (353230, Corning). Cells in 48-well plates were incubated at 37° C. 5% CO.sub.2.
[1017] Twenty-four hours later, the culture medium on the cells was replaced with 300 μl antibiotic-free culture medium (i.e DMEM (High Glucose, D6546, Sigma) with 1% FBS (Heat inactivated-Gibco 10270-106, lot number 42G2076K), 1% Glutamax (35050-038, Gibco)). 300 ng of DNA per well was transfected with viafect (E4981, Promega) in a total complex volume of 30 μl per well. Plates were gently mixed following transfection and incubated at 37° C. 5% CO.sub.2.
[1018] Twenty-four hours later, culture medium was removed from transfected cells and replaced with 300 μl differentiation media consisting of DMEM (High Glucose, D6546, Sigma), 1% Glutamax (35050-038, Gibco), 1% FBS (Heat inactivated-Gibco 10270-106, lot number 42G2076K), 1% Penicillin/streptomycin solution (15140-122, Gibco) and 0.1% Retinoid Acid (Sigma-R2625). Plates were incubated at 37° C. 5% CO2 for 7 days to induce differentiation. After differentiation, cell morphology was observed to confirm differentiation into myotubes.
[1019] Cells were then washed with 500 μl DPBS, and lysed with 100 μl Luciferase Cell Culture Lysis 5× Reagent (E1531, Promega) diluted to 1× using Milli-Q water. Cell lysis reagent was pipetted up and down ten times and plates were then vortexed on a medium power for 30 minutes to promote cell lysis. Plates were sealed and stored at −80° C. prior to completing a luciferase assay. All data collected from luciferase assays following transfections in H9C2 cells is based on three technical replicates of at least three biological replicates.
[1020] H2K 2B4 (H2K) Cell Culture and Transfection
[1021] Cell Maintenance
[1022] H2K cells were cultured in DMEM (High Glucose, D6546, Sigma) with 20% FBS (Heat inactivated-Gibco 10500-064, lot number 08Q2771K), 1% Glutamax (35050-038, Gibco), 1% Penicillin-streptomycin solution (15140-122, Gibco), 0.5% Chicken embryo extract (MD-OO4E-UK, LSP, lot number A20418), 0.2% Mouse IFN-γ (315-05, Peprotech, lot number 061798C2918) in T-75 flasks. Cells were passaged every 3-4 days when the cells had reached a confluency of 4-6.7×10.sup.4 cells/cm.sup.2. To passage, culture media was removed, cells were washed twice with 5 ml DPBS without CaCl.sub.2), without MgCl.sub.2 (14190-094, Gibco) and cells were detached from the flask using 1 ml Trypsin EDTA (25200-056, Gibco). Cells were incubated with Trypsin EDTA for approximately 2 minutes, before adding 4 ml of culture medium to the flask and gently pipetting up and down to wash the cells from the flask surface. Cells were pelleted at 100 g for 3 minutes. Supernatant was disposed and cells were resuspended in 6 ml of culture medium. Cells were counted on the Countess automated cell counter, seeded at 4 densities of 4000, 2700, 2000 or 1300 cells/cm.sup.2 and incubated at 33° C. 10% CO.sub.2.
[1023] Cell Transfection and Differentiation
[1024] H2K cells were collected from three T-75 flasks of approximately 20-40% confluency, by washing with DPBS, detaching from the flask using 1 ml Trypsin EDTA for approximately 2 minutes, washing off flask surface with 4 ml of culture medium and pelleting at 100 g for 3 minutes. Cells were resuspended in 45 ml culture medium at a density of 8000 cells/100 μl culture medium. 100 μl of cell suspension was then dispensed into each well of a 96-well Matrigel-coated (Corning, ref. 354234, lot. 8085009) plate using a BioFill Solo Reagent Dispenser (Brooks Automation Ltd, Catalog #34-1000). Cells in 96-well plates were incubated at 33° C. 10% CO.sub.2.
[1025] Twenty-four hours later, the culture medium on the cells was replaced with 100 μl antibiotic-free culture medium (i.e. DMEM (High Glucose, D6546, Sigma) with 20% FBS (Heat inactivated-Gibco 10500-064, lot number 08Q2771K), 1% Glutamax (35050-038, Gibco), 0.5% Chicken embryo extract (MD-OO4E-UK, LSP, lot number A20418), 0.2% Mouse IFN-γ (315-05, Peprotech, lot number 061798C2918). 150 ng of DNA per well was transfected with 0.3 μl Lipofectamine 3000 in a total complex volume of 10 μl per well. Plates were gently mixed following transfection and incubated at 33° C. 10% CO.sub.2. Twenty-four hours later, culture medium was removed from transfected cells and replaced with 200 μl differentiation media consisting of DMEM (High Glucose, D6546, Sigma), 0.1% Glutamax (35050-038, Gibco), 0.2% Horse serum (GIBCO, ref. 16050-122, lot. 1671317), 0.02% Chicken embryo extract (MD-OO4E-UK, LSP, lot number A20418), 0.1% Penicillin/streptomycin solution (15140-122, Gibco). Plates were incubated at 37° C. 5% CO.sub.2 for 72 hours to induce differentiation. After differentiation, cell morphology was observed to confirm differentiation into myotubes. Cells were then washed with 250 μl DPBS, followed by lysis with 50 μl Luciferase Cell Culture Lysis 5× Reagent (E1531, Promega) diluted to 1× using Milli-Q water. Cell lysis reagent was pipetted up and down ten times and plates were then vortexed on a medium power for 10 minutes to promote cell lysis. Plates were sealed and stored at −80° C. prior to completing a luciferase assay.
[1026] Luciferase Assay Preparation
[1027] 96-well plates containing lysed cells were thawed at room temperature, vortexed on a medium power for 10 minutes and centrifuged for 1 minute at 2250 g. 10 μl of lysate was transferred from each well into a white Microplate FluoroNunc 96 well flat bottom (Fisher Scientific, 10346331). Luciferase read-outs were generated using LAR (Promega, catalog #E4550) injections on a BMG Labtech FLUOstar Omega plate reader as described below. All data collected from luciferase assays following transfections in H2K cells is based on four technical replicates and three biological replicates (apart from SP0346 and SP0347 for which only one biological replicate is available).
[1028] C2C12 Cell Culture and Transfection
[1029] Cell Maintenance
[1030] C2C12 cells were cultured in DMEM (High Glucose, D6546, Sigma) with 10% FBS (Heat inactivated-Gibco 10500-064), 1% Glutamax (35050-038, Gibco), 1% Penicillin-streptomycin solution (15140-122, Gibco) in T-75 flasks. Cells were fed every 2-3 days with fresh medium and passaged when they reached 70% confluency. To passage, culture media was removed, cells were washed twice with 5 ml DPBS without CaCl.sub.2), without MgCl.sub.2 (14190-094, Gibco) and cells were detached from the flask (T-75) using 1 ml Trypsin EDTA (25200-056, Gibco). Cells were incubated at 37° C. (in CO.sub.2 incubator) for 3 to 5 mins, until the cells detached as determined under the microscope. 4 ml of complete culture medium was added to the flask to inactivate Trypsin and cell suspension was transferred to a 15 ml tube. Cells were pelleted at 250 g for 3 minutes. Supernatant was disposed of and cells were resuspended in 6 ml of culture medium. Cells were counted on the Countess automated cell counter, seeded at a 1:10 dilution and incubated at 37° C. 5% CO.sub.2.
[1031] Cell Transfection and Differentiation
[1032] C2C12 cells were collected from T-75 flasks once they reached 80% confluency by washing with DPBS, detaching from the flask using 1 ml Trypsin EDTA for approximately 3-5 minutes, washing off the flask surface with 4 ml of culture medium and pelleting at 250 g for 3 minutes. Cells were resuspended at specific densities depending on the passage number (see table below for details).
TABLE-US-00008 SEEDING CELL DENSITY PRIOR TO Passages of C2C12 TRANSFECTION (48 WELL-PLATE) p.4, p.5, p.6 45,000 cells/300 μl media p.7, p.8, p.9 40,000 cells/300 μl media p. 10, p.11, p.12 38,000 cells/300 μl media
[1033] 300 μl of appropriate cell suspension (based on passage number) was then dispensed into each well of a 48-well plate. Cells in 48-well plates were incubated at 37° C. 5% CO.sub.2.
[1034] Twenty-four hours later, the culture medium on the cells was replaced with 300 μl of pre-warmed transfection medium containing DMEM (High Glucose, D6546, Sigma) and 1% Glutamax. 300 ng of DNA was transfected with 0.9 μl Viafect (E4981, Promega) in a total complex volume of 30 μl per well. Plates were gently mixed following transfection and incubated at 37° C. 5% CO.sub.2.
[1035] Twenty-four hours later, culture medium was removed from transfected cells and replaced with differentiation media consisting of DMEM (high glucose, no sodium pyruvate, 11960-044, Gibco), 1% Glutamax, 2% Horse Serum (Heat Inactivated, 16050-122, Gibco). Plates were incubated at 37° C. 5% CO.sub.2 for a further 5.5 days to induce differentiation. After differentiation, cell morphology was observed to confirm differentiation into myotubes. Cells were then washed with 300 μl DPBS, followed by lysis with 100 μl Luciferase Cell Culture Lysis 5× Reagent (E1531, Promega) diluted to 1× using Milli-Q water. Plates were sealed and stored at −80° C. prior to completing a luciferase assay.
[1036] Luciferase Assay Preparation
[1037] 48-well plates containing lysed cells were thawed at room temperature, vortexed on a medium power for 10 minutes and centrifuged for 1 minute, 2250×g. 10 μl of lysate was transferred from each well into a white Microplate FluoroNunc 96 well flat bottom (Fisher Scientific, 10346331). Luciferase read-outs were generated using LAR (Promega, catalog #E4550) injections on a BMG Labtech FLUOstar Omega plate reader as described below. All data collected from luciferase assays following transfections in C2C12 cells is based on three technical replicates and at least three biological replicates.
[1038] Huh7 Cell Culture and Transfection
[1039] Materials [1040] Huh7 cells, which are a human liver cell line [1041] DPBS: without CaCl.sub.2), without MgCl.sub.2 (Gibco, 14190-094) [1042] DMEM (Sigma, D6546) [1043] FBS (Sigma, F9665) [1044] Pen-Strep (Sigma, P4333) [1045] Promega Fugene-HD (E2311) [1046] LARII (Dual Luciferase Reporter 1000 assay system, Promega, E1980)
[1047] Method
[1048] Day 1
[1049] Cells were seeded onto a 48 well plate at a density of 25,000 cells/300 μl.
[1050] HEK293 cell culture and transfection
[1051] Day 2 [1052] On the day of transfection, DNA to be transfected was diluted to a 100 ng/μl stock solution. [1053] Per 48 well transfection, 45 ng of DNA was mixed with 4.1 μl of Optimem medium. 0.5 μl of Fusion HD was mixed with 4 μl of Optimem medium. These 2 solutions were mixed and incubated at room temperature for 15 minutes and then added to the well dropwise.
[1054] Day 3
[1055] Luciferase activity was measured as detailed below.
[1056] HEK293 Cell Culture and Transfection
[1057] HEK293-T are seeded at a density of 20%. Once they reached a confluence between 60 and 80%, the media is changed with DMEM (#21885-025—Thermo Scientific) supplemented with 10% FBS (Gibco, 26140). After 3 hours, the cells were transfected by a transfection mix. The transfection mix is prepared by adding DNA (2 pg per 6 well plate) and PEI 25 kDA (#23966-1—Polyscience) in a ratio of 1:3 in sterile DPBS (#14190169—ThermoFisher Scientific). After mixing, the transfection mix is incubated at room temperature for 30 minutes and then added directly to the cells.
[1058] 24 h, after transfection, luciferase activity was measured as described below.
[1059] Measurement of Luciferase Activity [1060] Luciferase activity was measured using LARII (Dual Luciferase Reporter 1000 assay system, Promega, E1980) [1061] 24 h after transfection, the media was removed from the cells [1062] The cells were washed once in 300 μl of DPBS. [1063] Cells were lysed using 100 μl of passive lysis buffer and incubated with rocking for 15 minutes. [1064] The cell debris was pelleted by centrifugation of the plate at max speed in a benchtop centrifuge for 1 min [1065] 10 μl sample was transferred into white 96-well plate and luminescence measured by injection of 50 μl of LARII substrate on a BMG Labtech FLUOstar Omega plate reader
[1066] Results generated from these cell cultures are shown in
Example 2— In Vivo Testing
[1067] Expression cassettes comprising each of SP0173, SP0270, SP0268, SP0320, SP0134, SP0279, SP0057, SP0229, SP0310, SP0067, and SP0267, or the control promoters CBA and CK8 driving the luciferase gene were created and AAV2/9 comprising these expression cassettes were purified through high performance liquid chromatography (HPLC). AAVs were diluted in 0.9% saline and delivered via tail vein into 8 8-week old male Balb/c (wild type) mice at 200 μl/mouse at a dose of 1e+12 vg/mouse. Mice were sacrificed 6 weeks after, and the diaphragm (skeletal muscle), heart (cardiac muscle), intestine (skeletal muscle), kidney (specificity control tissue), liver (specificity control tissue), lung (specificity control tissue), quadriceps (skeletal muscle), spleen (specificity control tissue), and tibialis anterior (skeletal muscle) were collected, and divided into 3 parts. Samples were snap-frozen in liquid nitrogen, immediately after dissection, and stored at −80° C. The readouts for Diaphragm, Heart, Intestine, Liver, Quadriceps, and Tibialis anterior were created by protein quantification (using BCA Pierce protein assay kit; Promega 23225) and Luciferase quantification (using ONE-Glo Luciferase Assay System; Promega E6120). RLU values were calculated as pg/ml.
[1068] The x axis in
[1069] The synthetic promoters tested in vivo were much more active in the heart, diaphragm, quadriceps and tibialis anterior than in the liver and intestine as shown in
[1070] Some promoters such as SP0270 and SP0268 (
[1071]
Example 3— Identifying High-Performance CREs and Promoter Elements and Combinations Thereof
[1072] Skeletal and Cardiac Muscle:
[1073] A large group of over 100 synthetic promoters comprising various combinations of CREs and/or promoter elements expected to be useful to enhance muscle-specific gene expression was assembled (this includes the synthetic promoters of Examples 1 and 2 as well as additional muscle-specific promoters) and tested in skeletal and cardiac muscle. These promoters represent a large group of muscle-specific promoters which is useful for assessing the contribution made to expression in cardiac and skeletal muscle by various CREs, promoter elements and combinations thereof. The large group of promoters tested in both cardiac and skeletal muscle (H9C2 and C2C12 cells) is termed ‘ALL’ in
[1074] The group was analysed to identify groups of CREs, groups of promoter elements and combinations thereof that correlate particularly strongly with high levels of muscle-specific expression in both cardiac and skeletal muscle.
[1075] Out of the group of all tested promoters, a particular subset of muscle-specific promoters comprising two or more operably linked “core” skeletal and cardiac CREs selected from the group consisting of CRE0035, CRE0036, CRE0029, CRE0071, CRE0020 and CRE0031 was found to correlate particularly well with high levels of activity in both skeletal and cardiac muscle. This preferred group of promoters is referred to in
[1076] Additionally, a further subset of muscle-specific promoters comprising at least one of the abovementioned Core cardiac and skeletal CREs operably linked to one of the core cardiac and skeletal promoter elements CRE0037, CRE0070, SKM_18, CRE0010, CRE0049, CRE0048, CRE0011, SKM_14 and CRE0046 was found to correlate particularly well with high activity. This preferred group of promoters is referred to in
[1077] Furthermore, a subset of muscle-specific promoters comprising at two core cardiac and skeletal promoter elements selected from CRE0037, CRE0070, SKM_18, CRE0010, CRE0049, CRE0048, CRE0011, SKM_14 and CRE0046 was found to correlate particularly well with high activity. This preferred group of promoters is referred to in
[1078] To illustrate the particularly high activity of promoters of ‘Group 1’ the average activity of group ‘ALL’ (n=103) and ‘Group 1’ (n=9) in skeletal and cardiac muscles shown in
[1079] Without wishing to be bound by theory, the superior performance of ‘Group 1’ may be due to the presence of one or more of the core skeletal and cardiac CREs. In the group of all promoters tested in skeletal and cardiac muscle (group ‘ALL’), the number of CRE present in each promoter was counted. Additionally, the number of core skeletal and cardiac CRE present in each promoter was counted, wherein again the core CREs are the CRE0035, CRE0036, CRE0029, CRE0071, CRE0020 and CRE0031. The mean activity of promoters which have a specific number of core CREs versus any CREs was calculated and is presented in
[1080] To illustrate the particularly high activity of promoters of ‘Group 2’ the average activity of group ‘ALL’ (n=103) and ‘Group 2’ (n=20) in skeletal and cardiac muscles is shown in
[1081] Without wishing to be bound by theory, the superior performance of ‘Group 2’ may be due to the presence of skeletal and cardiac CREs and the core skeletal and cardiac promoter elements. In the group of all promoters tested in cardiac and skeletal muscle (group ‘ALL), the number of elements present in each promoter was counted, i.e. each promoter element, CRE, 5’ UTR/Intron was counted as one element. Additionally, the number of core skeletal and cardiac CRE and core skeletal and cardiac promoter elements present in each promoter was counted. The mean activity of promoters which have a specific number of core CREs and promoter elements versus any element was calculated and is presented in
[1082] To illustrate the particularly high activity of promoters of ‘Group 3’ the average activity of group ‘ALL’ (n=103) and ‘Group 3’ (n=2) in cardiac and skeletal muscles is shown in
[1083] Without wishing to be bound by theory, the superior performance of ‘Group 3’ may be due to the presence of the core skeletal and cardiac promoter elements. In the group of all promoters tested in cardiac and skeletal muscle (group ‘ALL), the number of elements present in each promoter was counted, i.e. each promoter elements, CRE, 5’ UTR/Intron was counted as 1 element. Additionally, the number of core skeletal and cardiac promoter elements present in each promoter was counted. The mean activity of promoters which have a specific number of core skeletal and cardiac promoter elements versus any element was calculated and is presented in
[1084] Skeletal Muscle:
[1085] A large group of over 100 synthetic promoters comprising various combinations of CREs and/or promoter elements expected to be useful to enhance muscle-specific gene expression was assembled (this includes the synthetic promoters of Examples 1 and 2 as well as additional muscle-specific promoters) and tested in skeletal muscle. These promoters represent a large group of muscle-specific promoters which is useful for assessing the contribution made to expression in skeletal muscle by various CREs, promoter elements and combinations thereof. The large group of promoters tested in skeletal muscle (C2C12 cells) is termed ‘ALL’ in
[1086] The group was analysed to identify groups of CREs and groups of promoter elements that correlate particularly strongly with high levels of muscle-specific expression in skeletal muscle.
[1087] Out of the group of all tested promoters, a particular subset of muscle-specific promoters comprising two or more operably linked “core” skeletal CREs selected from the group consisting of RE0035, CRE0050, CRE0020, CRE0031, CRE0047, CRE0071 and DES_MT_enhancer_48 bp was found to correlate particularly well with high levels of activity in skeletal muscle. This preferred group of promoters is referred to in
[1088] Additionally, a further subset of muscle-specific promoters comprising at least one of the abovementioned Core skeletal CREs operably linked to one of the core skeletal promoter elements CRE0049, CRE0037, SKM_14_CRE0048, CRE0011_RSV, CRE0070, CRE0046 was found to correlate particularly well with high activity in skeletal muscle. This preferred group of promoters is referred to in
[1089] To illustrate the particularly high activity of promoters of ‘Group 4’ the average activity of group ‘ALL’ (n=104) and ‘Group 4’ (n=6) shown in
[1090] Without wishing to be bound by theory, the superior performance of ‘Group 4’ in skeletal muscle may be due to the presence of one or more of the core skeletal CREs. In the group of all promoters tested in skeletal muscle (group ‘ALL’), the number of CRE present in each promoter was counted. Additionally, the number of core skeletal CRE present in each promoter was counted, wherein again the core skeletal CREs are CRE0035, CRE0050, CRE0020, CRE0031, CRE0047, CRE0071 and DES_MT_enhancer_48 bp. The mean activity of promoters which have a specific number of core skeletal CREs versus any CREs was calculated and is presented in
[1091] To illustrate the particularly high activity of promoters of ‘Group 5’ the average activity of group ‘ALL’ (n=104) and ‘Group 5’ (n=16) shown in
[1092] Without wishing to be bound by theory, the superior performance of ‘Group 5’ may be due to the presence of the core skeletal CREs and the core skeletal promoter elements. In the group of all promoters (group ‘ALL’) tested in skeletal muscle, the number of elements present in each promoter was counted, i.e. each promoter element, CRE or 5′ UTR/Intron was counted as one element. Additionally, the number of core skeletal CRE and core skeletal promoter elements present in each promoter was counted. The mean activity of promoters which have a specific number of core skeletal CREs and promoter elements versus any element was calculated and is presented in
[1093] Skeletal and Cardiac Muscle:
[1094] A large group of over 250 synthetic promoters comprising various combinations of CREs and/or promoter elements expected to be useful to enhance muscle-specific gene expression was assembled (this includes the synthetic promoters of Examples 1 and 2 as well as additional muscle-specific promoters) and tested in cardiac muscle. These promoters represent a large group of muscle-specific promoters which is useful for assessing the contribution made to expression in cardiac muscle by various CREs, promoter elements and combinations thereof. The large group of promoters tested in cardiac muscle (H9C2 cells) is termed ‘ALL’ in
[1095] The group was analysed to identify groups of CREs, groups of promoter elements and combinations thereof that correlate particularly strongly with high levels of muscle-specific expression in cardiac muscle.
[1096] Out of the group of all tested promoters, a particular subset of muscle-specific promoters comprising two or more operably linked “core” cardiac CREs selected from the group consisting of CRE0035, CRE0029, CRE0069, CRE0071, CRE0036, CRE0096, CRE0079, CRE0051, CRE0031 and CRE0020 was found to correlate particularly well with high levels of activity in cardiac muscle. This preferred group of promoters is referred to in
[1097] Additionally, a further subset of muscle-specific promoters comprising at least one of the abovementioned core cardiac CREs operably linked to one of the core cardiac promoter elements SKM_18, CRE0070, CRE0010_ITGB1BP2, CRE0037, DES_mp_V1, CRE0046 was found to correlate particularly well with high activity in cardiac muscle. This preferred group of promoters is referred to in
[1098] Furthermore, a subset of muscle-specific promoters comprising at two core cardiac promoter elements selected from SKM_18, CRE0070, CRE0010_ITGB1BP2, CRE0037, DES_mp_V1, CRE0046 was found to correlate particularly well with high activity in cardiac muscle. This preferred group of promoters is referred to in
[1099] To illustrate the particularly high activity of promoters of ‘Group 6’ the average activity of group ‘ALL’ (n=285) and ‘Group 6’ (n=49) in cardiac muscles shown in
[1100] Without wishing to be bound by theory, the superior performance of ‘Group 6’ may be due to the presence of one or more of the core cardiac CREs. In the group of all promoters tested in cardiac muscle (group ‘ALL’), the number of CRE present in each promoter was counted. Additionally, the number of core cardiac CRE present in each promoter was counted, wherein again the core CREs are the CRE0035, CRE0029, CRE0069, CRE0071, CRE0036, CRE0096, CRE0079, CRE0051, CRE0031 and CRE0020.
[1101] The mean activity of promoters which have a specific number of core cardiac CREs versus any CREs was calculated and is presented in
[1102] To illustrate the particularly high activity of promoters of ‘Group 7’ the average activity of group ‘ALL’ (n=285) and ‘Group 7’ (n=73) in cardiac muscles is shown in
[1103] Without wishing to be bound by theory, the superior performance of ‘Group 7’ may be due to the presence of cardiac CREs and the core cardiac promoter elements. In the group of all promoters tested in cardiac muscle (group ‘ALL), the number of elements present in each promoter was counted, i.e. each promoter element, CRE, 5’ UTR/Intron was counted as one element. Additionally, the number of core cardiac CREs and core cardiac promoter elements present in each promoter was counted. The mean activity of promoters which have a specific number of core cardiac CREs and promoter elements versus any element was calculated and is presented in
[1104] To illustrate the particularly high activity of promoters of ‘Group 8’ the average activity of group ‘ALL’ (n=285) and ‘Group 8’ (n=2) in cardiac muscles is shown in
[1105] Without wishing to be bound by theory, the superior performance of ‘Group 8’ may be due to the presence of the core cardiac promoter elements. In the group of all promoters tested in cardiac muscle (group ‘ALL), the number of elements present in each promoter was counted, i.e. each promoter elements, CRE, 5’ UTR/Intron was counted as 1 element. Additionally, the number of core cardiac promoter elements present in each promoter was counted. The mean activity of promoters which have a specific number of core cardiac promoter elements versus any element was calculated and is presented in
[1106] Analysis:
[1107] Activity for some of the synthetic promoters has been normalized to known promoters CBA while the activity for other synthetic promoters has been normalized to known promoter RSV. The activity of known promoter CBA and known promoter RSV in our assays is approximately 1:1 so the activity of synthetic promoters normalized to CBA and the activity of synthetic promoters normalized to RSV has been collated and analyzed together to identify high-performance CREs and promoter elements and combinations thereof. Therefore, activity of synthetic promoters shown in
[1108] It should be noted that some promoters fall within more than one group out of ‘Group 1’, ‘Group 2’, ‘Group 3’, ‘Group 4’, ‘Group 5’, ‘Group 6’, ‘Group 7’ and ‘Group 8’.
[1109] The abovementioned analysis does not provide an exclusive list of CREs and/or promoter elements which contribute to activity in skeletal and/or cardiac muscle. There are other CREs and/or promoter elements which when added to promoter elements or synthetic promoters, contribute to activity in skeletal and/or cardiac muscle.
[1110] For example, addition of cis-regulatory element CRE0033 to promoter element SKM_18 (resulting in synthetic promoter SP0067), results in increased activity in cardiac muscle (H9C2 cells) compared to SKM_18 alone as shown in
[1111] Similarly, addition of cis-regulatory element CRE0090 to synthetic promoter SP0409 (which in turn consist of CRE0083 and SKM_18), resulting in synthetic promoter SP0418 results in increased activity in cardiac muscle (H9C2 cells) compared to SP0409 as shown in
[1112] Furthermore, addition of cis-regulatory element CRE0096 to synthetic promoter SP0067 (which in turn consists of CRE0033 and SKM_18), resulting in synthetic promoter SP0451 results in increased activity in cardiac muscle (H9C2 cells) compared to SP0067 as shown in
[1113] Sequence Information
TABLE-US-00009 TABLE 1 Muscle-Specific Promoters NAME SEQUENCE Length SP0010 gtttcttagcagctgctgctgtgtccaaggcttggaattgctgtggtgaa 298 tctaaaactgtctcagtagtggtgagctgacctcacccaagttcaaagcc ctactctgcctgatccttttttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaattgaagttcccttgcccatgt taggaggtgtacgcctcctgaactaaagatagaaacagctggcccttcca ggcagctaaaagcctccagactaagaggtgttccccattcgggccacc (SEQ ID NO: 1) SP0020 gggccccacagcagctgggggcatttatgggccttcctataaacttctga 354 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtccaccgcctgctgcca cggccggccgtataaatagaggcgaggagcagctgggctctcttggcagt cacc (SEQ ID NO: 2) SP0033 gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 270 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgccaccg cctgctgccacggccggccgtataaatagaggcgaggagcagctgggctc tcttggcagtcaccgccacc (SEQ ID NO: 3) SP0038 taagtccgggcagggtcctgtccataaaaggcttttcccgggccggctcc 286 ccgccggcagcgtgccccgccccggcccgctccatctccaaagcatgcag agaatgtctcggcagccccggtagactgctccaacttggtgtctttcccc aaatatggagcctgtgtggagtcactgggggagccgggggtggggagcgg agccggcttcctctagccaccgcctgctgccacggccggccgtataaata gaggcgaggagcagctgggctctcttggcagtcacc (SEQ ID NO: 4) SP0040 ctgagattttcctagcattttgtgtttcatgactaaatatggtttgtgtt 315 tcaagaccaatgagctgggaactgtactgttctttcccctcccatcaact catttttggcacaagacgcactctagtcagttggagcaaatcccctgacc cgggtgcagttccaaaagcagacactcgagcgtgttttacctaattagga aatgctttgctccaaaccgaactgctcattcaggttagagaggagccacc gcctgctgccacggccggccgtataaatagaggcgaggagcagctgggct ctcttggcagtcacc (SEQ ID NO: 5) SP0042 ctgagattttcctagcattttgtgtttcatgactaaatatggtttgtgtt 421 tcaagaccaatgagctgggaactgtactgttctttcccctcccatcaact catttttggcacaagacgcactctagtcagttggagcaaatcccctgacc cgggtgcagttccaaaagcagacactcgagcgtgttttacctaattagga aatgctttgctccaaaccgaactgctcattcaggttagagaggagaggtc cctatatggttgtgttagagtgaacggccagcttcagcccgtctttgctc cttgtttgggaagcgagtgggaggggatcagagcaaggggctatataacc cttcagcgttcagcctcccgggacaccacccacccagagtggagaagccc agccagtcgctgtcagccacc (SEQ ID NO: 6) SP0051 gggccccacagcagctgggggcatttatgggccttcctataaacttctga 524 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtttctcctctataaata cccgctctggtatttggggttggcagctgttgctgccagggagatggttg ggttgacgggatcttgcagctgtcaggggaggggaggcgggggctgatgt caggagggatacaaatagtgccgacggctgggggccctgtctcccctcgc cgcatccactctccggccggccgcctgcccgccgcctcctccgtgcgccc gccagcctcgcccgcgccgtcacc (SEQ ID NO: 7) SP0057 ctctgtctcctcaggtgcctggctcccagtccccagaacgcctctcctgt 601 accttgcttcctagctgggcctttccttctcctctataaataccagctct ggtatttcgccttggcagctgttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtggtgtgagtgggtgtgggcggt gtgagtagggggatgaatcagagagggggccaccgcggtggcggccgtcc gccctcggcaccatcctcacgacacccaaatatggcgacgggtgaggaat ggtggggagttatttttagagcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagttatttttagagcggaggaatg gtggacacccaaatatggcgacggttcctcacccgtcgccatatttgggt gtccgccctcggccggggccgcattcctgggggccgggcggtgctcccgc ccgcctcgataaaaggctccggggccggcggcggcccacgagctacccgg aggagcgggaggcgccaagctctagaactagtggatcccgcggccgccac c (SEQ ID NO: 8) SP0058 ccttgcctgactattggcaggcggacctggtggtcagacctcagtgatcc 531 tcagggaccagtgaatatttcaggctggggctgagcatcacctgctccct tggccccacttatagggcaaaggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgctctggccccacctcgccctct cccctacttggaagttcctttcctgaaccactgactgccaaagcttgagg gattaaataaatcatctggcccaaactcgggggccaggcactggcgctga cgcaggctagcagggcgccactggctggtccccacccacctcggtgggtt gggggatgggcgcaccagcccctcctgggtgagccctagcctggggcttc ctatttcgggagccgggggcgtgggccacgtctcctcatgtgatgcgagg gctatttaaagcggcagcccgggcagggagccgccgtcggagcccttgca cgcctgctctcttgtagctgcggccgccacc (SEQ ID NO: 9) SP0061 ccttgcctgactattggcaggcggacctggtggtcagacctcagtgatcc 528 tcagggaccagtgaatatttcaggctggggctgagcatcacctgctccct tggccccacttatagggcaaaggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgctctggccccacctcgccctct cccctacttggaagttcctttcctgaaccactgactgccaaagcttgagg gattaaataaatcatctggcccaaataaatacccgctctggtatttgggg ttctcctctataaatacccgctctggtatttggggttggcagctgttgcg ggatcttgcagctgtcaggggaggggaggcgggggctgatgtcaggaggg atacaaatagtgccgacggctgggggccctgtctcccctcgccgcatcca ctctccggccggccgcctgcccgccgcctcctccgtgcgcccgccagcct cgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 10) SP0062 Ctgtgtgtttctgtggctgagtcagatggaggagtcctcatgtttcactg 454 cttagcagtttttgtccttcctagtacccgttcccagcccacaagatgca gaaagagctgttgctagcgtgagttatttttgtcagctgagtcaccacgc cagaaagcaagaaatgacccgctttatgtctgctctgaggagctggaacc ataaatacccgctctggtatttggggttctcctctataaatacccgctct ggtatttggggttggcagctgttgcgggatcttgcagctgtcaggggagg ggaggcgggggctgatgtcaggagggatacaaatagtgccgacggctggg ggccctgtctcccctcgccgcatccactctccggccggccgcctgcccgc cgcctcctccgtgcgcccgccagcctcgcccgcgccgtcaccgcggccgc cacc (SEQ ID NO: 11) SP0064 Tacatcatttacctagaaaagaggacagctgtcctttcccaaagctccgg 484 tgaccctgccccgcccagtgtgactagcccaggttggtgattctgatctg ttgccaaaccaaactggctccccggggagccatttggtaatgttccctgg agtcatttccttgcgaagcattccttttcggtgagaggacatttttttca tccctgataaacaaccacagcctgcgccagataaatacccgctctggtat ttggggttctcctctataaatacccgctctggtatttggggttggcagct gttgcgggatcttgcagctgtcaggggaggggaggcgggggctgatgtca ggagggatacaaatagtgccgacggctgggggccctgtctcccctcgccg catccactctccggccggccgcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 12) SP0065 taagtgtgatgcacagtgcttgcattttcttgatacgttagtcatatgag 465 agctgacaaagaaggaaaaagagcagcgatgtggtgcaatattaacaggc agctgtcccctggcttcccgatacgtgggatgactcgcattgctgagcgg tgtggtcactgccaaaggaatgaccctctcacatttcttcctgattcgca tacgccgcggcataaatacccgctctggtatttggggttctcctctataa atacccgctctggtatttggggttggcagctgttgcgggatcttgcagct gtcaggggaggggaggcgggggctgatgtcaggagggatacaaatagtgc cgacggctgggggccctgtctcccctcgccgcatccactctccggccggc cgcctgcccgccgcctcctccgtgcgcccgccagcctcgcccgcgccgtc accgcggccgccacc (SEQ ID NO: 13) SP0066 ctctgtctcctcaggtgcctggctcccagtccccagaacgcctctcctgt 484 accttgcttcctagctgggcctttccttctcctctataaataccagctct ggtatttcgccttggcagctgttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtggtgtgagtgggtgtgggcggt gtgagtagggggatgaatcagagagggggcataaatacccgctctggtat ttggggttctcctctataaatacccgctctggtatttggggttggcagct gttgcgggatcttgcagctgtcaggggaggggaggcgggggctgatgtca ggagggatacaaatagtgccgacggctgggggccctgtctcccctcgccg catccactctccggccggccgcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 14) SP0067 cccttcagattaaaaataactgaggtaagggcctgggtaggggaggtggt 443 gtgagacgctcctgtctctcctctatctgcccatcggccctttggggagg aggaatgtgcccaaggactaaaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggggccctgctgataaatacccg ctctggtatttggggttctcctctataaatacccgctctggtatttgggg ttggcagctgttgcgggatcttgcagctgtcaggggaggggaggcggggg ctgatgtcaggagggatacaaatagtgccgacggctgggggccctgtctc ccctcgccgcatccactctccggccggccgcctgcccgccgcctcctccg tgcgcccgccagcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 15) SP0068 gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 448 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgataaat acccgctctggtatttggggttctcctctataaatacccgctctggtatt tggggttggcagctgttgcgggatcttgcagctgtcaggggaggggaggc gggggctgatgtcaggagggatacaaatagtgccgacggctgggggccct gtctcccctcgccgcatccactctccggccggccgcctgcccgccgcctc ctccgtgcgcccgccagcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 16) SP0069 ccttgcctgactattggcaggcggacctggtggtcagacctcagtgatcc 518 tcagggaccagtgaatatttcaggctggggctgagcatcacctgctccct tggccccacttatagggcaaaggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgctctggccccacctcgccctct cccctacttggaagttcctttcctgaaccactgactgccaaagcttgagg gattaaataaatcatctggcccaaatttttaaagactgaggaattaggca cctgtcatttttgccagctggtgtagatgttaaaaattactgtcactctt ccgcctgctactttattttgcacctgctgttacttgagttacaggcattt cacacatggtaatttaataaggttagttcccatgacacaccgcctgctgc cacggccggccgtataaatagaggcgaggagcagctgggctctcttggca gtcaccgcggccgccacc (SEQ ID NO: 17) SP0070 ctgtgtgtttctgtggctgagtcagatggaggagtcctcatgtttcactg 444 cttagcagtttttgtccttcctagtacccgttcccagcccacaagatgca gaaagagctgttgctagcgtgagttatttttgtcagctgagtcaccacgc cagaaagcaagaaatgacccgctttatgtctgctctgaggagctggaacc atttttaaagactgaggaattaggcacctgtcatttttgccagctggtgt agatgttaaaaattactgtcactcttccgcctgctactttattttgcacc tgctgttacttgagttacaggcatttcacacatggtaatttaataaggtt agttcccatgacacaccgcctgctgccacggccggccgtataaatagagg cgaggagcagctgggctctcttggcagtcaccgcggccgccacc (SEQ ID NO: 18) SP0071 gcgccctgatgaatatgcatcgcggcgcgcccgcccccggctcctccttt 404 cggtttccttcccgccgccaggcggaagcgaagagccgcgcttcccgcgc gcccaggccggccgtggtagggtggggcggggcgggccgcgagccggaga aagagaaagcatttttaaagactgaggaattaggcacctgtcatttttgc cagctggtgtagatgttaaaaattactgtcactcttccgcctgctacttt attttgcacctgctgttacttgagttacaggcatttcacacatggtaatt taataaggttagttcccatgacacaccgcctgctgccacggccggccgta taaatagaggcgaggagcagctgggctctcttggcagtcaccgcggccgc cacc (SEQ ID NO: 19) SP0075 cccttcagattaaaaataactgaggtaagggcctgggtaggggaggtggt 433 gtgagacgctcctgtctctcctctatctgcccatcggccctttggggagg aggaatgtgcccaaggactaaaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggggccctgctgatttttaaaga ctgaggaattaggcacctgtcatttttgccagctggtgtagatgttaaaa attactgtcactcttccgcctgctactttattttgcacctgctgttactt gagttacaggcatttcacacatggtaatttaataaggttagttcccatga cacaccgcctgctgccacggccggccgtataaatagaggcgaggagcagc tgggctctcttggcagtcaccgcggccgccacc (SEQ ID NO: 20) SP0076 gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 438 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgattttt aaagactgaggaattaggcacctgtcatttttgccagctggtgtagatgt taaaaattactgtcactcttccgcctgctactttattttgcacctgctgt tacttgagttacaggcatttcacacatggtaatttaataaggttagttcc catgacacaccgcctgctgccacggccggccgtataaatagaggcgagga gcagctgggctctcttggcagtcaccgcggccgccacc (SEQ ID NO: 21) SP0132 gggccccacagcagctgggggcatttatgggccttcctataaacttctga 538 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtataaatacccgctctg gtatttggggttctcctctataaatacccgctctggtatttggggttggc agctgttgcgggatcttgcagctgtcaggggaggggaggcgggggctgat gtcaggagggatacaaatagtgccgacggctgggggccctgtctcccctc gccgcatccactctccggccggccgcctgcccgccgcctcctccgtgcgc ccgccagcctcgcccgcgccgtcaccgcggccgocacc (SEQ ID NO: 22) SP0133 gggccccacagcagctgggggcatttatgggccttcctataaacttctga 528 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtatttttaaagactgag gaattaggcacctgtcatttttgccagctggtgtagatgttaaaaattac tgtcactcttccgcctgctactttattttgcacctgctgttacttgagtt acaggcatttcacacatggtaatttaataaggttagttcccatgacacac cgcctgctgccacggccggccgtataaatagaggcgaggagcagctgggc tctcttggcagtcaccgcggccgccacc (SEQ ID NO: 23) SP0134 gggccccacagcagctgggggcatttatgggccttcctataaacttctga 655 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacccaaatatggcgacgggtgag gaatggtggggagttatttttagagcggtgaggaaggtgggcaggcagca ggtgttggcgctctaaaaataactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggttcctcacccgtcgccatattt gggtgtccgccctcggccggggccgcattcctgggggccgggcggtgctc ccgcccgcctcgataaaaggctccggggccggcggcggcccacgagctac ccggaggagcgggaggcgccaagctctagaactagtggatcccgcggccg ccacc (SEQ ID NO: 24) SP0136 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 588 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtgtttcttagcagctgc tgctgtgtccaaggcttggaattgctgtggtgaatctaaaactgtctcag tagtggtgagctgacctcacccaagttcaaagccctactctgcctgatcc ttttttcctgagcctcagagctaaaatgcccccgagctctttcctattgg ctggaaagacgaattgaagttcccttgcccatgttaggaggtgtacgcct cctgaactaaagatagaaacagctggcccttccaggcagctaaaagcctc cagactaagaggtgttccccattcgggcggccgccacc (SEQ ID NO: 25) SP0146 Ctagactagcatgctgcccatgtaaggaggcaaggcctggggacacccga 660 gatgcctggttataattaacccagacatgtggctgcccccccccccccaa cacctgctgcctctaaaaataaccctgcatgccatgttcccggcgaaggg ccagctgtcccccgccagctagactcagcacttagtttaggaaccagtga gcaagtcagcccttggggcagcccatacaaggccatggggctgggcaagc tgcacgcctgggtccggggtgggcacggtgcccgggcaacgagctgaaag ctcatctgctctcaggggcccctccctggggacagcccctcctggctagt cacaccctgtaggctcctctatataacccaggggcacaggggctgccctc attctaccaccacctccacagcacagacagacactcaggagccagccagc caggtagggactgtactagcagctacaatccagctaccattctgctttta ttttatggttgggataaggctggattattctgagtccaagctaggccctt ttgctaatcatgttcatacctcttatcttcctcccacagctcctgggcaa cgtgctggtctgtgtgctggcccatcactttggcaaagaattgcgatcgc ctctagaacc (SEQ ID NO: 26) SP0147 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 806 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtcatgttcccggcgaag ggccagctgtcccccgccagctagactcagcacttagtttaggaaccagt gagcaagtcagcccttggggcagcccatacaaggccatggggctgggcaa gctgcacgcctgggtccggggtgggcacggtgcccgggcaacgagctgaa agctcatctgctctcaggggcccctccctggggacagcccctcctggcta gtcacaccctgtaggctcctctatataacccaggggcacaggggctgccc tcattctaccaccacctccacagcacagacagacactcaggagccagcca gccaggtagggactgtactagcagctacaatccagctaccattctgcttt tattttatggttgggataaggctggattattctgagtccaagctaggccc ttttgctaatcatgttcatacctcttatcttcctcccacagctcctgggc aacgtgctggtctgtgtgctggcccatcactttggcaaagaattgcgatc gccacc (SEQ ID NO: 27) SP0148 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 938 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtcaattctcatgtttga cagcttatcatcgcagatccgtatggtgcactctcagtacaatctgctct gatgccgcatagttaagccagtatctgctccctgcttgtgtgttggaggt cgctgagtagtgcgcgagcaaaatttaagctacaacaaggcaaggcttga ccgacaattgcatgaagaatctgcttagggttaggcgttttgcgctgctt cgcgatgtacgggccagatatacgcgtatctgaggggactagggtgtgtt taggcgaaaagcggggcttcggttgtacgcggttaggagtcccctcagga tatagtagtttcgcttttgcatagggagggggaaatgtagtcttatgcaa tactcttgtagtcttgcaacatggtaacgatgagttagcaacatgcctta caaggagagaaaaagcaccgtgcatgccgattggtggaagtaaggtggta cgatcgtgccttattaggaaggcaacagacgggtctgacatggattggac gaaccactgaattccgcattgcagagatattgtatttaagtgcctagctc gatacaataaacgccatttgaccattcaccacattggtgtgcacctccaa gctgggtaccgcgggcccgggatccaccggtcgccacc (SEQ ID NO: 28) SP0150 Gcgccctgatgaatatgcatcgcggcgcgcccgcccccggctcctccttt 814 cggtttccttcccgccgccaggcggaagcgaagagccgcgcttcccgcgc gcccaggccggccgtggtagggtggggcggggcgggccgcgagccggaga aagagaaagccaattctcatgtttgacagcttatcatcgcagatccgtat ggtgcactctcagtacaatctgctctgatgccgcatagttaagccagtat ctgctccctgcttgtgtgttggaggtcgctgagtagtgcgcgagcaaaat ttaagctacaacaaggcaaggcttgaccgacaattgcatgaagaatctgc ttagggttaggcgttttgcgctgcttcgcgatgtacgggccagatatacg cgtatctgaggggactagggtgtgtttaggcgaaaagcggggcttcggtt gtacgcggttaggagtcccctcaggatatagtagtttcgcttttgcatag ggagggggaaatgtagtcttatgcaatactcttgtagtcttgcaacatgg taacgatgagttagcaacatgccttacaaggagagaaaaagcaccgtgca tgccgattggtggaagtaaggtggtacgatcgtgccttattaggaaggca acagacgggtctgacatggattggacgaaccactgaattccgcattgcag agatattgtatttaagtgcctagctcgatacaataaacgccatttgacca ttcaccacattggtgtgcacctccaagctgggtaccgcgggcccgggatc caccggtcgccacc (SEQ ID NO: 29) SP0153 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 418 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgcccggc agacgctccttatacggcccggcctcgctcacctgggccgcggccaggag cgccttctttgggcagcgccgggccggggccgcgccgggcccgacaccca aatatggcgacggccggggccgcattcctgggggccgggcggcgctcccg cccgcctcgataaaaggctccggggccggcggcggcccacgagctacccg gaggagcgggaggccacc (SEQ ID NO: 30) SP0155 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 508 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgttctcc tctataaatacccgctctggtatttggggttggcagctgttgttctcctc tataaatacccgctctggtatttggggttggcagctgttgcccggcagac gctccttatacggcccggcctcgctcacctgggccgcggccaggagcgcc ttctttgggcagcgccgggccggggccgcgccgggcccgacacccaaata tggcgacggccggggccgcattcctgggggccgggcggcgctcccgcccg cctcgataaaaggctccggggccggcggcggcccacgagctacccggagg agcgggag (SEQ ID NO: 31) SP0156 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 718 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctggggccc cacagcagctgggggcatttatgggccttcctataaacttctgagagggt aactttatcctgcttctttcagccaagtatcctcctccagcagctggtca caaagctggttaatctcccagagtgctcagcttaaaacccgtgactcaca gcacagccagtgtgggggagggggtggctgcctccaatacgtggcgccca gagtcagctgttctggggccttctctggtttctccaactgagtcctgagg tttggggccttgtcttccttcctggagtttctcctctataaatacccgct ctggtatttggggttggcagctgttgctgccagggagatggttgggttga cgggatcttgcagctgtcaggggaggggaggcgggggctgatgtcaggag ggatacaaatagtgccgacggctgggggccctgtctcccctcgccgcatc cactctccggccggccgcctgcccgccgcctcctccgtgcgcccgccagc ctcgcccgcgccgtcacc (SEQ ID NO: 32) SP0157 Ctagactagcatgctgcccatgtaaggaggcaaggcctggggacacccga 202 gatgcctggttataattaacccagacatgtggctgcccccccccccccaa cacctgctgcctctaaaaataaccctgcatgcccaccgcctgctgccacg gccggccgtataaatagaggcgaggagcagctgggctctcttggcagtca cc (SEQ ID NO: 33) SP0158 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 705 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtctgagattttcctagc attttgtgtttcatgactaaatatggtttgtgtttcaagaccaatgagct gggaactgtactgttctttcccctcccatcaactcatttttggcacaaga cgcactctagtcagttggagcaaatcccctgacccgggtgcagttccaaa agcagacactcgagcgtgttttacctaattaggaaatgctttgctccaaa ccgaactgctcattcaggttagagaggagaggtccctatatggttgtgtt agagtgaacggccagcttcagcccgtctttgctccttgtttgggaagcga gtgggaggggatcagagcaaggggctatataacccttcagcgttcagcct cccgggacaccacccacccagagtggagaagcccagccagtcgctgtcag ccacc (SEQ ID NO: 34) SP0159 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 615 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgctgaga ttttcctagcattttgtgtttcatgactaaatatggtttgtgtttcaaga ccaatgagctgggaactgtactgttctttcccctcccatcaactcatttt tggcacaagacgcactctagtcagttggagcaaatcccctgacccgggtg cagttccaaaagcagacactcgagcgtgttttacctaattaggaaatgct ttgctccaaaccgaactgctcattcaggttagagaggagaggtccctata tggttgtgttagagtgaacggccagcttcagcccgtctttgctccttgtt tgggaagcgagtgggaggggatcagagcaaggggctatataacccttcag cgttcagcctcccgggacaccacccacccagagtggagaagcccagccag tcgctgtcagccacc (SEQ ID NO: 35) SP0160 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 586 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgtaagtc cgggcagggtcctgtccataaaaggcttttcccgggccggctccccgccg gcagcgtgccccgccccggcccgctccatctccaaagcatgcagagaatg tctcggcagccccggtagactgctccaacttggtgtctttccccaaatat ggagcctgtgtggagtcactgggggagccgggggtggggagcggagccgg cttcctctagaggtccctatatggttgtgttagagtgaacggccagcttc agcccgtctttgctccttgtttgggaagcgagtgggaggggatcagagca aggggctatataacccttcagcgttcagcctcccgggacaccacccaccc agagtggagaagcccagccagtcgctgtcagccacc (SEQ ID NO: 36) SP0161 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 740 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtctgagattttcctagc attttgtgtttcatgactaaatatggtttgtgtttcaagaccaatgagct gggaactgtactgttctttcccctcccatcaactcatttttggcacaaga cgcactctagtcagttggagcaaatcccctgacccgggtgcagttccaaa agcagacactcgagcgtgttttacctaattaggaaatgctttgctccaaa ccgaactgctcattcaggttagagaggagctgagtccttttgcatacatt tttcaaatgataactcactctacccaccccccttccctacccccaaggcg atttattgaaaaaaccaccttatatggtaatattgctaacacaccgtcag ctggcctttttagggactttgtttaaagaagatccgcctctggggtttta tattgctctggtattcatgccaaagacacaccaggccacc (SEQ ID NO: 37) SP0162 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 650 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgctgaga ttttcctagcattttgtgtttcatgactaaatatggtttgtgtttcaaga ccaatgagctgggaactgtactgttctttcccctcccatcaactcatttt tggcacaagacgcactctagtcagttggagcaaatcccctgacccgggtg cagttccaaaagcagacactcgagcgtgttttacctaattaggaaatgct ttgctccaaaccgaactgctcattcaggttagagaggagctgagtccttt tgcatacatttttcaaatgataactcactctacccaccccccttccctac ccccaaggcgatttattgaaaaaaccaccttatatggtaatattgctaac acaccgtcagctggcctttttagggactttgtttaaagaagatccgcctc tggggttttatattgctctggtattcatgccaaagacacaccaggccacc (SEQ ID NO: 38) SP0163 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 621 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgtaagtc cgggcagggtcctgtccataaaaggcttttcccgggccggctccccgccg gcagcgtgccccgccccggcccgctccatctccaaagcatgcagagaatg tctcggcagccccggtagactgctccaacttggtgtctttccccaaatat ggagcctgtgtggagtcactgggggagccgggggtggggagcggagccgg cttcctctagctgagtccttttgcatacatttttcaaatgataactcact ctacccaccccccttccctacccccaaggcgatttattgaaaaaaccacc ttatatggtaatattgctaacacaccgtcagctggcctttttagggactt tgtttaaagaagatccgcctctggggttttatattgctctggtattcatg ccaaagacacaccaggccacc (SEQ ID NO: 39) SP0164 Cccacccatgcctcctcaggtaccccctgccccccacagctcctctcctg 764 tgccttgtttcccagccatgcgttctcctctataaatacccgctctggta tttggggttggcagctgttgctgccagggagatggttgggttgacatgcg gctcctgacaaaacacaaacccctggtgtgtgtgggcgtgggtggtgtga gtagggggatgaatcagggagggggcggggggggccccacagcagctggg ggcatttatgggccttcctataaacttctgagagggtaactttatcctgc ttctttcagccaagtatcctcctccagcagctggtcacaaagctggttaa tctcccagagtgctcagcttaaaacccgtgactcacagcacagccagtgt gggggagggggtggctgcctccaatacgtggcgcccagagtcagctgttc tggggccttctctggtttctccaactgagtcctgaggtttggggccttgt cttccttcctggagtgactcaggggcgcaggcctcttgcgggggagctgg cctccccgcccccacggccacgggccgccctttcctggcaggacagcggg atcttgcagctgtcaggggaggggaggcgggggctgatgtcaggagggat acaaatagtgccgacggctgggggccctgtctcccctcgccgcatccact ctccggccggccgcctgcccgccgcctcctccgtgcgcccgccagcctcg cccgcgccgtcacc (SEQ ID NO: 40) SP0165 Cccacccatgcctcctcaggtaccccctgccccccacagctcctctcctg 480 tgccttgtttcccagccatgcgttctcctctataaatacccgctctggta tttggggttggcagctgttgctgccagggagatggttgggttgacatgcg gctcctgacaaaacacaaacccctggtgtgtgtgggcgtgggtggtgtga gtagggggatgaatcagggagggggcggggggactcaggggcgcaggcct cttgcgggggagctggcctccccgcccccacggccacgggccgccctttc ctggcaggacagcgggatcttgcagctgtcaggggaggggaggcgggggc tgatgtcaggagggatacaaatagtgccgacggctgggggccctgtctcc cctcgccgcatccactctccggccggccgcctgcccgccgcctcctccgt gcgcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 41) SP0166 Caccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaaa 894 tatggcgacgggtgaggaatggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacacccaaatatggcgacggttcctc acccgtcgccatatttgggtgtccgccctcggccggggcccaattctcat gtttgacagcttatcatcgcagatccgtatggtgcactctcagtacaatc tgctctgatgccgcatagttaagccagtatctgctccctgcttgtgtgtt ggaggtcgctgagtagtgcgcgagcaaaatttaagctacaacaaggcaag gcttgaccgacaattgcatgaagaatctgcttagggttaggcgttttgcg ctgcttcgcgatgtacgggccagatatacgcgtatctgaggggactaggg tgtgtttaggcgaaaagcggggcttcggttgtacgcggttaggagtcccc tcaggatatagtagtttcgcttttgcatagggagggggaaatgtagtctt atgcaatactcttgtagtcttgcaacatggtaacgatgagttagcaacat gccttacaaggagagaaaaagcaccgtgcatgccgattggtggaagtaag gtggtacgatcgtgccttattaggaaggcaacagacgggtctgacatgga ttggacgaaccactgaattccgcattgcagagatattgtatttaagtgcc tagctcgatacaataaacgccatttgaccattcaccacattggtgtgcac ctccaagctgggtaccgcgggcccgggatccaccggtcgccacc (SEQ ID NO: 42) SP0169 Ataaatacccgctctggtatttggggttctcctctataaatacccgctct 248 ggtatttggggttggcagctgttgcgggatcttgcagctgtcaggggagg ggaggcgggggctgatgtcaggagggatacaaatagtgccgacggctggg ggccctgtctcccctcgccgcatccactctccggccggccgcctgcccgc cgcctcctccgtgcgcccgccagcctcgcccgcgccgtcaccgccacc (SEQ ID NO: 43) SP0170 Caccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaaa 482 tatggcgacgggtgaggaatggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacacccaaatatggcgacggttcctc acccgtcgccatatttgggtgtccgccctcggccggggccataaataccc gctctggtatttggggttctcctctataaatacccgctctggtatttggg gttggcagctgttgcgggatcttgcagctgtcaggggaggggaggcgggg gctgatgtcaggagggatacaaatagtgccgacggctgggggccctgtct cccctcgccgcatccactctccggccggccgcctgcccgccgcctcctcc gtgcgcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 44) SP0171 Gtttcttagcagctgctgctgtgtccaaggcttggaattgctgtggtgaa 534 tctaaaactgtctcagtagtggtgagctgacctcacccaagttcaaagcc ctactctgcctgatccttttttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaattgaagttcccttgcccatgt taggaggtgtacgcctcctgaactaaagatagaaacagctggcccttcca ggcagctaaaagcctccagactaagaggtgttccccattcggataaatac ccgctctggtatttggggttctcctctataaatacccgctctggtatttg gggttggcagctgttgcgggatcttgcagctgtcaggggaggggaggcgg gggctgatgtcaggagggatacaaatagtgccgacggctgggggccctgt ctcccctcgccgcatccactctccggccggccgcctgcccgccgcctcct ccgtgcgcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 45) SP0173 Gtttcttagcagctgctgctgtgtccaaggcttggaattgctgtggtgaa 728 tctaaaactgtctcagtagtggtgagctgacctcacccaagttcaaagcc ctactctgcctgatccttttttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaattgaagttcccttgcccatgt taggaggtgtacgcctcctgaactaaagatagaaacagctggcccttcca ggcagctaaaagcctccagactaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaaggcctggggacacccgagatg cctggttataattaacccagacatgtggctgccccccccccccaacacct gctgcctgagcctcacccccaccccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaataaccctgataaatacccgctc tggtatttggggttctcctctataaatacccgctctggtatttggggttg gcagctgttgcgggatcttgcagctgtcaggggaggggaggcgggggctg atgtcaggagggatacaaatagtgccgacggctgggggccctgtctcccc tcgccgcatccactctccggccggccgcctgcccgccgcctcctccgtgc gcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 46) SP0227 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 608 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtcatgttcccggcgaag ggccagctgtcccccgccagctagactcagcacttagtttaggaaccagt gagcaagtcagcccttggggcagcccatacaaggccatggggctgggcaa gctgcacgcctgggtccggggtgggcacggtgcccgggcaacgagctgaa agctcatctgctctcaggggcccctccctggggacagcccctcctggcta gtcacaccctgtaggctcctctatataacccaggggcacaggggctgccc tcattctaccaccacctccacagcacagacagacactcaggagccagcca gcgccacc (SEQ ID NO: 47) SP0228 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 885 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtctctgtctcctcaggt gcctggctcccagtccccagaacgcctctcctgtaccttgcttcctagct gggcctttccttctcctctataaataccagctctggtatttcgccttggc agctgttgctgctagggagacggctggcttgacatgcatctcctgacaaa acacaaacccgtggtgtgagtgggtgtgggcggtgtgagtagggggatga atcagagagggggccaccgcggtggcggccgtccgccctcggcaccatcc tcacgacacccaaatatggcgacgggtgaggaatggtggggagttatttt tagagcggtgaggaaggtgggcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggaggaatggtggacacccaaatat ggcgacggttcctcacccgtcgccatatttgggtgtccgccctcggccgg ggccgcattcctgggggccgggcggtgctcccgcccgcctcgataaaagg ctccggggccggcggcggcccacgagctacccggaggagcgggaggcgcc aagctctagaactagtggatcccgcggccgccacc (SEQ ID NO: 48) SP0229 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 1003 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtctctgtctcctcaggt gcctggctcccagtccccagaacgcctctcctgtaccttgcttcctagct gggcctttccttctcctctataaataccagctctggtatttcgccttggc agctgttgctgctagggagacggctggcttgacatgcatctcctgacaaa acacaaacccgtggtgtgagtgggtgtgggcggtgtgagtagggggatga atcagagagggggccaccgcggtggcggccgtccgccctcggcaccatcc tcacgacacccaaatatggcgacgggtgaggaatggtggggagttatttt tagagcggtgaggaaggtgggcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggaggaatggtggacacccaaatat ggcgacggttcctcacccgtcgccatatttgggtgtccgccctcggccga taaatacccgctctggtatttggggttctcctctataaatacccgctctg gtatttggggttggcagctgttgcgggatcttgcagctgtcaggggaggg gaggcgggggctgatgtcaggagggatacaaatagtgccgacggctgggg gccctgtctcccctcgccgcatccactctccggccggccgcctgcccgcc gcctcctccgtgcgcccgccagcctcgcccgcgccgtcaccgcggccgcc acc (SEQ ID NO: 49) SP0230 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 953 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtatcaagcttggtacgg gccccacagcagctgggggcatttatgggccttcctataaacttctgaga gggtaactttatcctgcttctttcagccaagtatcctcctccagcagctg gtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtgact cacagcacagccagtgtgggggagggggtggctgcctccaatacgtggcg cccagagtcagctgttctggggccttctctggtttctccaactgagtcct gaggtttggggccttgtcttccttcctggagtcaccgcggtggcggccgt ccgccctcggcaccatcctcacgacacccaaatatggcgacgggtgagga atggtggggagttatttttagagcggtgaggaaggtgggcaggcagcagg tgttggcgctctaaaaataactcccgggagttatttttagagcggaggaa tggtggacacccaaatatggcgacggttcctcacccgtcgccatatttgg gtgtccgccctcggccggggccgcattcctgggggccgggcggtgctccc gcccgcctcgataaaaggctccggggccggcggcggcccacgagctaccc ggaggagcgggaggcgccaagctctagaactagtggatcccgcggccgcc acc (SEQ ID NO: 50) SP0231 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 773 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacccaaatatggcgacgggtgag gaatggtggggagttatttttagagcggtgaggaaggtgggcaggcagca ggtgttggcgctctaaaaataactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggttcctcacccgtcgccatattt gggtgtccgccctcggccgataaatacccgctctggtatttggggttctc ctctataaatacccgctctggtatttggggttggcagctgttgcgggatc ttgcagctgtcaggggaggggaggcgggggctgatgtcaggagggataca aatagtgccgacggctgggggccctgtctcccctcgccgcatccactctc cggccggccgcctgcccgccgcctcctccgtgcgcccgccagcctcgccc gcgccgtcaccgcggccgccacc (SEQ ID NO: 51) SP0232 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 683 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgcaccgc ggtggcggccgtccgccctcggcaccatcctcacgacacccaaatatggc gacgggtgaggaatggtggggagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaataactcccgggagttattttt agagcggaggaatggtggacacccaaatatggcgacggttcctcacccgt cgccatatttgggtgtccgccctcggccgataaatacccgctctggtatt tggggttctcctctataaatacccgctctggtatttggggttggcagctg ttgcgggatcttgcagctgtcaggggaggggaggcgggggctgatgtcag gagggatacaaatagtgccgacggctgggggccctgtctcccctcgccgc atccactctccggccggccgcctgcccgccgcctcctccgtgcgcccgcc agcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 52) SP0257 Gtttcttagcagctgctgctgtgtccaaggcttggaattgctgtggtgaa 710 tctaaaactgtctcagtagtggtgagctgacctcacccaagttcaaagcc ctactctgcctgatccttttttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaattgaagttcccttgcccatgt taggaggtgtacgcctcctgaactaaagatagaaacagctggcccttcca ggcagctaaaagcctccagactaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaaggcctggggacacccgagatg cctggttataattaacccagacatgtggctgccccccccccccaacacct gctgcctgagcctcacccccaccccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaataaccctgcccggcagacgctc cttatacggcccggcctcgctcacctgggccgcggccaggagcgccttct ttgggcagcgccgggccggggccgcgccgggcccgacacccaaatatggc gacggccggggccgcattcctgggggccgggcggcgctcccgcccgcctc gataaaaggctccggggccggcggcggcccacgagctacccggaggagcg ggaggccacc (SEQ ID NO: 53) SP0262 Gtttcttagcagctgctgctgtgtccaaggcttggaattgctgtggtgaa 943 tctaaaactgtctcagtagtggtgagctgacctcacccaagttcaaagcc ctactctgcctgatccttttttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaattgaagttcccttgcccatgt taggaggtgtacgcctcctgaactaaagatagaaacagctggcccttcca ggcagctaaaagcctccagactaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaaggcctggggacacccgagatg cctggttataattaacccagacatgtggctgccccccccccccaacacct gctgcctgagcctcacccccaccccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaataaccctgccagctgcctgccc cctgcctggcacagcccgtacctggccgcacgctccctcacaggtgaagc tcgaaaactccgtccccgtaaggagccccgctgccccccgaggcctcctc cctcacgcctcgctgcgctcccggctcccgcacggccctgggagaggccc ccaccgcttcgtccttaacgggcccggcggtgccgggggattatttcggc cccggccccgggggggcccggcagacgctccttatacggcccggcctcgc tcacctgggccgcggccaggagcgccttctttgggcagcgccgggccggg gccgcgccgggcccgacacccaaatatggcgacggccggggccgcattcc tgggggccgggcggcgctcccgcccgcctcgataaaaggctccggggccg gcggcggcccacgagctacccggaggagcgggaggcggccacc (SEQ I D NO: 54) SP0264 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 724 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctggccgcg aagaccggaagctggggcggccccgggccgcgcgcgctgggcctgggagg cgaaactcagcttccttcgtttccgacttttccatccgcgtcctccactt ccccgttccgccctcccccattgccaacattctggctgagtcacggcgcc ccagagcgcgccaggctgggggaaaggagcagaagggagggccctagcga cccgcgggatgtggtccgagtcacgtccgaggggggtggggagggatcgt gttctcggcgcccgccccttcctagcgcggcctctgggctgcgcctctcg ggggcggcccgtagcccagtccgtcgcctgccattggacgccgcccgctc ctcgtaaaggaaaaagctcggcggagggcggagtggtgcctttaaaaggc cgggcgccgccttccgcctgcccgcctcctgcgccgccccttccgaggct aaatcggctgcgttcctctcggaacgcgccgcagaaggggtcctggtgac gagtcccgcgttctctccgccacc (SEQ ID NO: 55) SP0265 Gtttcttagcagctgctgctgtgtccaaggcttggaattgctgtggtgaa 822 tctaaaactgtctcagtagtggtgagctgacctcacccaagttcaaagcc ctactctgcctgatccttttttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaattgaagttcccttgcccatgt taggaggtgtacgcctcctgaactaaagatagaaacagctggcccttcca ggcagctaaaagcctccagactaagaggtgttccccattcgggccgcgaa gaccggaagctggggcggccccgggccgcgcgcgctgggcctgggaggcg aaactcagcttccttcgtttccgacttttccatccgcgtcctccacttcc ccgttccgccctcccccattgccaacattctggctgagtcacggcgcccc agagcgcgccaggctgggggaaaggagcagaagggagggccctagcgacc cgcgggatgtggtccgagtcacgtccgaggggggtggggagggatcgtgt tctcggcgcccgccccttcctagcgcggcctctgggctgcgcctctcggg ggcggcccgtagcccagtccgtcgcctgccattggacgccgcccgctcct cgtaaaggaaaaagctcggcggagggcggagtggtgcctttaaaaggccg ggcgccgccttccgcctgcccgcctcctgcgccgccccttccgaggctaa atcggctgcgttcctctcggaacgcgccgcagaaggggtcctggtgacga gtcccgcgttctctccgccacc (SEQ ID NO: 56) SP0266 Gtttcttagcagctgctgctgtgtccaaggcttggaattgctgtggtgaa 1016 tctaaaactgtctcagtagtggtgagctgacctcacccaagttcaaagcc ctactctgcctgatccttttttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaattgaagttcccttgcccatgt taggaggtgtacgcctcctgaactaaagatagaaacagctggcccttcca ggcagctaaaagcctccagactaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaaggcctggggacacccgagatg cctggttataattaacccagacatgtggctgccccccccccccaacacct gctgcctgagcctcacccccaccccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaataaccctggccgcgaagaccgg aagctggggcggccccgggccgcgcgcgctgggcctgggaggcgaaactc agcttccttcgtttccgacttttccatccgcgtcctccacttccccgttc cgccctcccccattgccaacattctggctgagtcacggcgccccagagcg cgccaggctgggggaaaggagcagaagggagggccctagcgacccgcggg atgtggtccgagtcacgtccgaggggggtggggagggatcgtgttctcgg cgcccgccccttcctagcgcggcctctgggctgcgcctctcgggggcggc ccgtagcccagtccgtcgcctgccattggacgccgcccgctcctcgtaaa ggaaaaagctcggcggagggcggagtggtgcctttaaaaggccgggcgcc gccttccgcctgcccgcctcctgcgccgccccttccgaggctaaatcggc tgcgttcctctcggaacgcgccgcagaaggggtcctggtgacgagtcccg cgttctctccgccacc (SEQ ID NO: 57) SP0267 Cccttcagattaaaaataactgaggtaagggcctgggtaggggaggtggt 560 gtgagacgctcctgtctctcctctatctgcccatcggccctttggggagg aggaatgtgcccaaggactaaaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggggccctgctgcaccgcggtgg cggccgtccgccctcggcaccatcctcacgacacccaaatatggcgacgg gtgaggaatggtggggagttatttttagagcggtgaggaaggtgggcagg cagcaggtgttggcgctctaaaaataactcccgggagttatttttagagc ggaggaatggtggacacccaaatatggcgacggttcctcacccgtcgcca tatttgggtgtccgccctcggccggggccgcattcctgggggccgggcgg tgctcccgcccgcctcgataaaaggctccggggccggcggcggcccacga gctacccggaggagcgggaggcgccaagctctagaactagtggatcccgc ggccgccacc (SEQ ID NO: 58) SP0268 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 728 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctggtttct tagcagctgctgctgtgtccaaggcttggaattgctgtggtgaatctaaa actgtctcagtagtggtgagctgacctcacccaagttcaaagccctactc tgcctgatccttttttcctgagcctcagagctaaaatgcccccgagctct ttcctattggctggaaagacgaattgaagttcccttgcccatgttaggag gtgtacgcctcctgaactaaagatagaaacagctggcccttccaggcagc taaaagcctccagactaagaggtgttccccattcggataaatacccgctc tggtatttggggttctcctctataaatacccgctctggtatttggggttg gcagctgttgcgggatcttgcagctgtcaggggaggggaggcgggggctg atgtcaggagggatacaaatagtgccgacggctgggggccctgtctcccc tcgccgcatccactctccggccggccgcctgcccgccgcctcctccgtgc gcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 59) SP0270 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 562 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgtcaaag ccctactctgcctgatccttttttcctgagcctcagagctaaaatgcccc cgagctctttcctattggctggaaagacgaattgaagttcccttgcccat gttaggaggtgtacgcctcctgaactaaagatagaaacagctggcccttc caggcagctaaaagcctccagactaagaggtgttccccattcggcgggat cttgcagctgtcaggggaggggaggcgggggctgatgtcaggagggatac aaatagtgccgacggctgggggccctgtctcccctcgccgcatccactct ccggccggccgcctgcccgccgcctcctccgtgcgcccgccagcctcgcc cgcgccgtcacc (SEQ ID NO: 60) SP0271 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 451 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgtcaaag ccctactctgcctgatccttttttcctgagcctcagagctaaaatgcccc cgagctctttcctattggctggaaagacgaattgaagttcccttgcccat gttaggaggtgtacgcctcctgaactaaagatagaaacagctggcccttc caggcagctaaaagcctccagactaagaggtgttccccattcggcagcca gactccttgaaataccctttcagtaatcattcaaccaacgcttccgccac c (SEQ ID NO: 61) SP0279 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 883 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacccaaatatggcgacgggtgag gaatggtggggagttatttttagagcggtgaggaaggtgggcaggcagca ggtgttggcgctctaaaaataactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggttcctcacccgtcgccatattt gggtgtccgccctcggccggggccgcattcctgggggccgggcggtgctc ccgcccgcctcgataaaaggctccggggccggcggcggcccactcagatc gcctggagacgccatccacgctgttttgacctccatagaagacaccggga ccgatccagcctccgcggccgggaacggtgcattggaacgcggattcccc gtgccaagagtgacgtaagtaccgcctatagactctataggcacacccct ttggctcttatgcatgaacggtggagggcagtgtagtctgagcagtactc gttgctgccgcgcgcgccaccagacataatagctgacagactaacagact gttcctttccatgggtcttttctgcaggccacc (SEQ ID NO: 62) SP0286 Caccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaaa 616 tatggcgacgggtgaggaatggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacacccaaatatggcgacggttcctc acccgtcgccatatttgggtgtccgccctcggccggggccgcattcctgg gggccgggcggtgctcccgcccgcctcgataaaaggctccggggccggcg gcggcccactcagatcgcctggagacgccatccacgctgttttgacctcc atagaagacaccgggaccgatccagcctccgcggccgggaacggtgcatt ggaacgcggattccccgtgccaagagtgacgtaagtaccgcctatagact ctataggcacacccctttggctcttatgcatgaacggtggagggcagtgt agtctgagcagtactcgttgctgccgcgcgcgccaccagacataatagct gacagactaacagactgttcctttccatgggtcttttctgcagtcaccgt ccttgacacggccacc (SEQ ID NO: 63) SP0305 Gtttcttagcagctgctgctgtgtccaaggcttggaattgctgtggtgaa 562 tctaaaactgtctcagtagtggtgagctgacctcacccaagttcaaagcc ctactctgcctgatccttttttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaattgaagttcccttgcccatgt taggaggtgtacgcctcctgaactaaagatagaaacagctggcccttcca ggcagctaaaagcctccagactaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaaggcctggggacacccgagatg cctggttataattaacccagacatgtggctgccccccccccccaacacct gctgcctgagcctcacccccaccccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaataaccctgccaccgcctgctgc cacggccggccgtataaatagaggcgaggagcagctgggctctcttggca gtcaccgccacc (SEQ ID NO: 64) SP0306 Ctctgtctcctcaggtgcctggctcccagtccccagaacgcctctcctgt 500 accttgcttcctagctgggcctttccttctcctctataaataccagctct ggtatttcgccttggcagctgttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtggtgtgagtgggtgtgggcggt gtgagtagggggatgaatcagagagggggcgccactacgggtctaggctg cccatgtaaggaggcaaggcctggggacacccgagatgcctggttataat taacccagacatgtggctgccccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttaggctctgtacaccatggaggag aagctcgctctaaaaataaccctgccaccgcctgctgccacggccggccg tataaatagaggcgaggagcagctgggctctcttggcagtcaccgccacc (SEQ ID NO: 65) SP0307 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 554 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtgccactacgggtctag gctgcccatgtaaggaggcaaggcctggggacacccgagatgcctggtta taattaacccagacatgtggctgccccccccccccaacacctgctgcctg agcctcacccccaccccggtgcctgggtcttaggctctgtacaccatgga ggagaagctcgctctaaaaataaccctgccaccgcctgctgccacggccg gccgtataaatagaggcgaggagcagctgggctctcttggcagtcaccgc cacc (SEQ ID NO: 66) SP0309 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 636 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctggccact acgggtctaggctgcccatgtaaggaggcaaggcctggggacacccgaga tgcctggttataattaacccagacatgtggctgccccccccccccaacac ctgctgcctgagcctcacccccaccccggtgcctgggtcttaggctctgt acaccatggaggagaagctcgctctaaaaataaccctgataaatacccgc tctggtatttggggttctcctctataaatacccgctctggtatttggggt tggcagctgttgcgggatcttgcagctgtcaggggaggggaggcgggggc tgatgtcaggagggatacaaatagtgccgacggctgggggccctgtctcc cctcgccgcatccactctccggccggccgcctgcccgccgcctcctccgt gcgcccgccagcctcgcccgcgccgtcaccgccacc (SEQ ID NO: 67) SP0310 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 441 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgataaat acccgctctggtatttggggttctcctctataaatacccgctctggtatt tggggttggcagctgttgcgggatcttgcagctgtcaggggaggggaggc gggggctgatgtcaggagggatacaaatagtgccgacggctgggggccct gtctcccctcgccgcatccactctccggccggccgcctgcccgccgcctc ctccgtgcgcccgccagcctcgcccgcgccgtcaccgccacc (SEQ ID NO: 68) SP0311 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 318 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgttctcc tctataaatacccgctctggtatttggggttggcagctgttgccaccgcc tgctgccacggccggccgtataaatagaggcgaggagcagctgggctctc ttggcagtcaccgccacc (SEQ ID NO: 69) SP0312 Cccacccatgcctcctcaggtaccccctgccccccacagctcctctcctg 501 tgccttgtttcccagccatgcgttctcctctataaatacccgctctggta tttggggttggcagctgttgctgccagggagatggttgggttgacatgcg gctcctgacaaaacacaaacccctggtgtgtgtgggcgtgggtggtgtga gtagggggatgaatcagggagggggcggggggccactacgggtctaggct gcccatgtaaggaggcaaggcctggggacacccgagatgcctggttataa ttaacccagacatgtggctgccccccccccccaacacctgctgcctgagc ctcacccccaccccggtgcctgggtcttaggctctgtacaccatggagga gaagctcgctctaaaaataaccctgccaccgcctgctgccacggccggcc gtataaatagaggcgaggagcagctgggctctcttggcagtcaccgccac c (SEQ ID NO: 70) SP0313 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 395 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgcccctg ccccccacagctcctctcctgtgccttgtttcccagccatgcgttctcct ctataaatacccgctctggtatttggggttggcagctgttgctgccaggg agatggttgggttgacatgccaccgcctgctgccacggccggccgtataa atagaggcgaggagcagctgggctctcttggcagtcaccgccacc (SEQ ID NO: 71) SP0314 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 334 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgctctat aaatacccgctctggtatttggggttctctataaatacccgctctggtat ttggggttccaccgcctgctgccacggccggccgtataaatagaggcgag gagcagctgggctctcttggcagtcaccgccacc (SEQ ID NO: 72) SP0315 Ctagactagcatgctgcccatgtaaggaggcaaggcctggggacacccga 204 gatgcctggttataattaacccagacatgtggctgcccccccccccccaa cacctgctgcctctaaaaataaccctgcccaccgcctgctgccacggccg gccgtataaatagaggcgaggagcagctgggctctcttggcagtcaccgc cacc (SEQ ID NO: 73) SP0316 Ctagactagcatgctgcccatgtaaggaggcaaggcctggggacacccga 376 gatgcctggttataattaacccagacatgtggctgcccccccccccccaa cacctgctgcctctaaaaataaccctgcataaatacccgctctggtattt ggggttctcctctataaatacccgctctggtatttggggttggcagctgt tgcgggatcttgcagctgtcaggggaggggaggcgggggctgatgtcagg agggatacaaatagtgccgacggctgggggccctgtctcccctcgccgca tccactctccggccggccgcctgcccgccgcctcctccgtgcgcccgcca gcctcgcccgcgccgtcaccgccacc (SEQ ID NO: 74) SP0320 Gtttcttagcagctgctgctgtgtccaaggcttggaattgctgtggtgaa 944 tctaaaactgtctcagtagtggtgagctgacctcacccaagttcaaagcc ctactctgcctgatccttttttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaattgaagttcccttgcccatgt taggaggtgtacgcctcctgaactaaagatagaaacagctggcccttcca ggcagctaaaagcctccagactaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaaggcctggggacacccgagatg cctggttataattaacccagacatgtggctgccccccccccccaacacct gctgcctgagcctcacccccaccccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaataaccctgataaatacccgctc tggtatttggggttctcctctataaatacccgctctggtatttggggttg gcagctgttgcgggatcttgcagctgtcaggggaggggaggcgggggctg atgtcaggagggatacaaatagtgccgacggctgggggccctgtctcccc tcgctcagatcgcctggagacgccatccacgctgttttgacctccataga agacaccgggaccgatccagcctccgcggccgggaacggtgcattggaac gcggattccccgtgccaagagtgacgtaagtaccgcctatagactctata ggcacacccctttggctcttatgcatgaacggtggagggcagtgtagtct gagcagtactcgttgctgccgcgcgcgccaccagacataatagctgacag actaacagactgttcctttccatgggtcttttctgcaggccacc (SEQ ID NO: 75) SP0322 Agactggggcaggtgcaggctggattgggtttccagaggctatatatata 661 aaggctgccgggagccccagggccgctccctgagggcacaacactgtggg ggcccagccaggcccacattcctttccagaggccagctctccatttatag cccctgggcagagcagccaccgcggtggcggccgtccgccctcggcacca tcctcacgacacccaaatatggcgacgggtgaggaatggtggggagttat ttttagagcggtgaggaaggtgggcaggcagcaggtgttggcgctctaaa aataactcccgggagttatttttagagcggaggaatggtggacacccaaa tatggcgacggttcctcacccgtcgccatatttgggtgtccgccctcggc cggggccataaatacccgctctggtatttggggttctcctctataaatac ccgctctggtatttggggttggcagctgttgcgggatcttgcagctgtca ggggaggggaggcgggggctgatgtcaggagggatacaaatagtgccgac ggctgggggccctgtctcccctcgccgcatccactctccggccggccgcc tgcccgccgcctcctccgtgcgcccgccagcctcgcccgcgccgtcaccg cggccgccacc (SEQ ID NO: 76) SP0323 Agactggggcaggtgcaggctggattgggtttccagaggctatatatata 613 aaggctgccgggagcccacattcctttccagaggccagctctccatttat agcccctgggcagagcagccaccgcggtggcggccgtccgccctcggcac catcctcacgacacccaaatatggcgacgggtgaggaatggtggggagtt atttttagagcggtgaggaaggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagcggaggaatggtggacaccca aatatggcgacggttcctcacccgtcgccatatttgggtgtccgccctcg gccggggccataaatacccgctctggtatttggggttctcctctataaat acccgctctggtatttggggttggcagctgttgcgggatcttgcagctgt caggggaggggaggcgggggctgatgtcaggagggatacaaatagtgccg acggctgggggccctgtctcccctcgccgcatccactctccggccggccg cctgcccgccgcctcctccgtgcgcccgccagcctcgcccgcgccgtcac cgcggccgccacc (SEQ ID NO: 77) SP0324 Agactggggcaggtgcaggctggattgggtttccagaggctatatatata 407 aaggctgccgggagccccagggccgctccctgagggcacaacactgtggg ggcccagccaggcccacattcctttccagaggccagctctccatttatag cccctgggcagagcagcttctcctctataaatacccgctctggtatttgg ggttggcagctgttgctgccagggagatggttgggttgacgggatcttgc agctgtcaggggaggggaggcgggggctgatgtcaggagggatacaaata gtgccgacggctgggggccctgtctcccctcgccgcatccactctccggc cggccgcctgcccgccgcctcctccgtgcgcccgccagcctcgcccgcgc cgtcacc (SEQ ID NO: 78) SP0325 Agactggggcaggtgcaggctggattgggtttccagaggctatatatata 409 aaggctgccgggagccccagggccgctccctgagggcacaacactgtggg ggcccagccaggcccacattcctttccagaggccagctctccatttatag cccctgggcagagcagcataaatacccgctctggtatttggggttctcct ctataaatacccgctctggtatttggggttggcagctgttgcgggatctt gcagctgtcaggggaggggaggcgggggctgatgtcaggagggatacaaa tagtgccgacggctgggggccctgtctcccctcgccgcatccactctccg gccggccgcctgcccgccgcctcctccgtgcgcccgccagcctcgcccgc gccgtcacc (SEQ ID NO: 79) SP0326 Caccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaaa 483 tatggcgacgggtgaggaatggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacacccaaatatggcgacggttcctc acccgtcgccatatttgggtgtccgccctataaatacccgctctggtatt tggggttctcctctataaatacccgctctggtatttggggttggcagctg ttgcgggatcttgcagctgtcaggggaggggaggcgggggctgatgtcag gagggatacaaatagtgccgacggctgggggccctgtctcccctcgccgc atccactctccggccggccgcctgcccgccgcctcctccgtgcgcccgcc agcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 80) SP0327 Agactggggcaggtgcaggctggattgggtttccagaggctatatatata 538 aaggctgccgggagccccagggccgctccctgagggcacaacactgtggg ggcccagccaggcccacattcctttccagaggccagctctccatttatag cccctgggcagagcagccaccgcggtggcggccgtccgccctcggcacca tcctcacgacacccaaatatggcgacgggtgaggaatggtggggagttat ttttagagcggtgaggaaggtgggcaggcagcaggtgttggcgctctaaa aataactcccgggagttatttttagagcggaggaatggtggacacccaaa tatggcgacggttcctcacccgtcgccatatttgggtgtccgccctcggc cggggccgcattcctgggggccgggcggtgctcccgcccgcctcgataaa aggctccggggccggcggcggcccacgagctacccggaggagcgggaggc gccaagctctagaactagtggatcccgcggccgccacc (SEQ ID NO: 81) SP0328 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 822 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtagactggggcaggtgc aggctggattgggtttccagaggctatatatataaaggctgccgggagcc ccagggccgctccctgagggcacaacactgtgggggcccagccaggccca cattcctttccagaggccagctctccatttatagcccctgggcagagcag ccaccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaa atatggcgacgggtgaggaatggtggggagttatttttagagcggtgagg aaggtgggcaggcagcaggtgttggcgctctaaaaataactcccgggagt tatttttagagcggaggaatggtggacacccaaatatggcgacggttcct cacccgtcgccatatttgggtgtccgccctcggccggggccgcattcctg ggggccgggcggtgctcccgcccgcctcgataaaaggctccggggccggc ggcggcccacgagctacccggaggagcgggaggcgccaagctctagaact agtggatcccgcggccgccacc (SEQ ID NO: 82) SP0329 Acacccaaatatggcgacgggtgaggaatggtggggagttatttttagag 324 cggtgaggaaggtgggcaggcagcaggtgttggcgctctaaaaataactc ccgggagttatttttagagcggaggaatggtggacacccaaatatggcga cggttcctcacccgtcgccatatttgggtgtccgccctcggccggggccg cattcctgggggccgggcggtgctcccgcccgcctcgataaaaggctccg gggccggcggcggcccacgagctacccggaggagcgggaggcgccaagct ctagaactagtggatcccgccacc (SEQ ID NO: 83) SP0330 Caccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaaa 365 tatggcgacgggtgaggaatggtggggagttatttttagagcgtaaacga gctattagttgcagcaggtgttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacacccaaatatggcgacggttcctc acccgtcgccatatttgggtgtccgccctcggccggggccgcattcctgg gggccgggcggtgctcccgcccgcctcgataaaaggctccggggccggcg gcggcccacgagctacccggaggagcgggaggcgccaagctctagaacta gtggatcccgccacc (SEQ ID NO: 84) SP0331 Caccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaaa 365 tatggcgacgggtgaggaatggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctctaaaaataactcccgggagtt atttttagagcgaggtaaacgagctattagttatgaggtccgtagattga acccgtcgccatatttgggtgtccgccctcggccggggccgcattcctgg gggccgggcggtgctcccgcccgcctcgataaaaggctccggggccggcg gcggcccacgagctacccggaggagcgggaggcgccaagctctagaacta gtggatcccgccacc (SEQ ID NO: 85) SP0332 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 565 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgcaccgc ggtggcggccgtccgccctcggcaccatcctcacgacacccaaatatggc gacgggtgaggaatggtggggagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaataactcccgggagttattttt agagcggaggaatggtggacacccaaatatggcgacggttcctcacccgt cgccatatttgggtgtccgccctcggccggggccgcattcctgggggccg ggcggtgctcccgcccgcctcgataaaaggctccggggccggcggcggcc cacgagctacccggaggagcgggaggcgccaagctctagaactagtggat cccgcggccgccacc (SEQ ID NO: 86) SP0333 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 543 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctggtttct tagcagctgctgctgtgtccaaggcttggaattgctgtggtgaatctaaa actgtctcagtagtggtgagctgacctcacccaagttcaaagccctactc tgcctgatccttttttcctgagcctcagagctaaaatgcccccgagctct ttcctattggctggaaagacgaattgaagttcccttgcccatgttaggag gtgtacgcctcctgaactaaagatagaaacagctggcccttccaggcagc taaaagcctccagactaagaggtgttccccattcggcagccagactcctt gaaataccctttcagtaatcattcaaccaacgcttccgccacc (SEQ ID NO: 87) SP0334 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 362 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgcgggat cttgcagctgtcaggggaggggaggcgggggctgatgtcaggagggatac aaatagtgccgacggctgggggccctgtctcccctcgccgcatccactct ccggccggccgcctgcccgccgcctcctccgtgcgcccgccagcctcgcc cgcgccgtcacc (SEQ ID NO: 88) SP0335 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 715 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgtcaaag ccctactctgcctgatccttttttcctgagcctcagagctaaaatgcccc cgagctctttcctattggctggaaagacgaattgaagttcccttgcccat gttaggaggtgtacgcctcctgaactaaagatagaaacagctggcccttc caggcagctaaaagcctccagactaagaggtgttccccattcggccatgt tcccggcgaagggccagctgtcccccgccagctagactcagcacttagtt taggaaccagtgagcaagtcagcccttggggcagcccatacaaggccatg gggctgggcaagctgcacgcctgggtccggggtgggcacggtgcccgggc aacgagctgaaagctcatctactctcaggggcccctccctggggacagcc cctcctggctagtcacaccctgtaggctcctctatataacccaggggcac aggggctgcccccgggtcaccaccacctccacagcacagacagacactca ggagccagcgccacc (SEQ ID NO: 89) SP0336 Tcaaagccctactctgcctgatccttttttcctgagcctcagagctaaaa 521 tgcccccgagctctttcctattggctggaaagacgaattgaagttccctt gcccatgttaggaggtgtacgcctcctgaactaaagatagaaacagctgg cccttccaggcagctaaaagcctccagactaagaggtgttccccattcgg ccatgttcccggcgaagggccagctgtcccccgccagctagactcagcac ttagtttaggaaccagtgagcaagtcagcccttggggcagcccatacaag gccatggggctgggcaagctgcacgcctgggtccggggtgggcacggtgc ccgggcaacgagctgaaagctcatctactctcaggggcccctccctgggg acagcccctcctggctagtcacaccctgtaggctcctctatataacccag gggcacaggggctgcccccgggtcaccaccacctccacagcacagacaga cactcaggagccagcgccacc (SEQ ID NO: 90) SP0337 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 618 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgtcaaag ccctactctgcctgatccttttttcctgagcctcagagctaaaatgcccc cgagctctttcctattggctggaaagacgaattgaagttcccttgcccat gttaggaggtgtacgcctcctgaactaaagatagaaacagctggcccttc caggcagctaaaagcctccagactaagaggtgttccccattcggcccggc agacgctccttatacggcccggcctcgctcacctgggccgcggccaggag cgccttctttgggcagcgccgggccggggccgcgccgggcccgacaccca aatatggcgacggccggggccgcattcctgggggccgggcggcgctcccg cccgcctcgataaaaggctccggggccggcggcggcccacgagctacccg gaggagcgggaggccacc (SEQ ID NO: 91) SP0338 Agactggggcaggtgcaggctggattgggtttccagaggctatatatata 729 aaggctgccgggagccccagggccgctccctgagggcacaacactgtggg ggcccagccaggcccacattcctttccagaggccagctctccatttatag cccctgggcagagcagcgccactacgggtctaggctgcccatgtaaggag gcaaggcctggggacacccgagatgcctggttataattaacccagacatg tggctgccccccccccccaacacctgctgcctgagcctcacccccacccc ggtgcctgggtcttaggctctgtacaccatggaggagaagctcgctctaa aaataaccctgtcaaagccctactctgcctgatccttttttcctgagcct cagagctaaaatgcccccgagctctttcctattggctggaaagacgaatt gaagttcccttgcccatgttaggaggtgtacgcctcctgaactaaagata gaaacagctggcccttccaggcagctaaaagcctccagactaagaggtgt tccccattcggcgggatcttgcagctgtcaggggaggggaggcgggggct gatgtcaggagggatacaaatagtgccgacggctgggggccctgtctccc ctcgccgcatccactctccggccggccgcctgcccgccgcctcctccgtg cgcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 92) SP0339 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 610 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgttctcc tctataaatacccgctctggtatttggggttggcagctgttgtcaaagcc ctactctgcctgatccttttttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaattgaagttcccttgcccatgt taggaggtgtacgcctcctgaactaaagatagaaacagctggcccttcca ggcagctaaaagcctccagactaagaggtgttccccattcggcgggatct tgcagctgtcaggggaggggaggcgggggctgatgtcaggagggatacaa atagtgccgacggctgggggccctgtctcccctcgccgcatccactctcc ggccggccgcctgcccgccgcctcctccgtgcgcccgccagcctcgcccg cgccgtcacc (SEQ ID NO: 93) SP0340 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 654 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgcccggc agacgctccttatacggcccggcctcgctcacctgggccgcggccaggag cgccttctttgggcagcgccgggccggggccgcgccgggcccgacaccca aatatggcgacggccggggccgcattcctgggggccgggcggcgctcccg cccgcctcgataaaaggctccggggccggcggcggcccacgagctacccg gaggagcgggagataaatacccgctctggtatttggggttctcctctata aatacccgctctggtatttggggttggcagctgttgcgggatcttgcagc tgtcaggggaggggaggcgggggctgatgtcaggagggatacaaatagtg ccgacggctgggggccctgtctcccctcgccgcatccactctccggccgg ccgcctgcccgccgcctcctccgtgcgcccgccagcctcgcccgcgccgt cacc (SEQ ID NO: 94) SP0341 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 924 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgtcaaag ccctactctgcctgatccttttttcctgagcctcagagctaaaatgcccc cgagctctttcctattggctggaaagacgaattgaagttcccttgcccat gttaggaggtgtacgcctcctgaactaaagatagaaacagctggcccttc caggcagctaaaagcctccagactaagaggtgttccccattcgggccgcg aagaccggaagctggggcggccccgggccgcgcgcgctgggcctgggagg cgaaactcagcttccttcgtttccgacttttccatccgcgtcctccactt ccccgttccgccctcccccattgccaacattctggctgagtcacggcgcc ccagagcgcgccaggctgggggaaaggagcagaagggagggccctagcga cccgcgggatgtggtccgagtcacgtccgaggggggtggggagggatcgt gttctcggcgcccgccccttcctagcgcggcctctgggctgcgcctctcg ggggcggcccgtagcccagtccgtcgcctgccattggacgccgcccgctc ctcgtaaaggaaaaagctcggcggagggcggagtggtgcctttaaaaggc cgggcgccgccttccgcctgcccgcctcctgcgccgccccttccgaggct aaatcggctgcgttcctctcggaacgcgccgcagaaggggtcctggtgac gagtcccgcgttctctccgccacc (SEQ ID NO: 95) SP0342 Agactggggcaggtgcaggctggattgggtttccagaggctatatatata 488 aaggctgccgggagccccagggccgctccctgagggcacaacactgtggg ggcccagccaggcccacattcctttccagaggccagctctccatttatag cccctgggcagagcagcccatgttcccggcgaagggccagctgtcccccg ccagctagactcagcacttagtttaggaaccagtgagcaagtcagccctt ggggcagcccatacaaggccatggggctgggcaagctgcacgcctgggtc cggggtgggcacggtgcccgggcaacgagctgaaagctcatctactctca ggggcccctccctggggacagcccctcctggctagtcacaccctgtaggc tcctctatataacccaggggcacaggggctgcccccgggtcaccaccacc tccacagcacagacagacactcaggagccagcgccacc (SEQ ID NO: 96) SP0343 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 652 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgataaat acccgctctggtatttggggttctcctctataaatacccgctctggtatt tggggttggcagctgttgcgggatcttgcagctgtcaggggaggggaggc gggggctgatgtcaggagggatacaaatagtgccgacggctgggggccct gtctcccctcgctcagatcgcctggagacgccatccacgctgttttgacc tccatagaagacaccgggaccgatccagcctccgcggccgggaacggtgc attggaacgcggattccccgtgccaagagtgacgtaagtaccgcctatag actctataggcacacccctttggctcttatgcatgaacggtggagggcag tgtagtctgagcagtactcgttgctgccgcgcgcgccaccagacataata gctgacagactaacagactgttcctttccatgggtcttttctgcaggcca cc (SEQ ID NO: 97) SP0345 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 693 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacccaaatatggcgacgggtgag gaatggtggggagttatttttagagcggtgaggaaggtgggcaggcagca ggtgttggcgctctaaaaataactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggttcctcacccgtcgccatattt gggtgtccgccctcgggatcttgcagctgtcaggggaggggaggcggggg ctgatgtcaggagggatacaaatagtgccgacggctgggggccctgtctc ccctcgccgcatccactctccggccggccgcctgcccgccgcctcctccg tgcgcccgccagcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 98) SP0346 Agactggggcaggtgcaggctggattgggtttccagaggctatatatata 576 aaggctgccgggagccccagggccgctccctgagggcacaacactgtggg ggcccagccaggcccacattcctttccagaggccagctctccatttatag cccctgggcagagcagccaccgcggtggcggccgtccgccctcggcacca tcctcacgacacccaaatatggcgacgggtgaggaatggtggggagttat ttttagagcggtgaggaaggtgggcaggcagcaggtgttggcgctctaaa aataactcccgggagttatttttagagcggaggaatggtggacacccaaa tatggcgacggttcctcacccgtcgccatatttgggtgtccgccctcggg atcttgcagctgtcaggggaggggaggcgggggctgatgtcaggagggat acaaatagtgccgacggctgggggccctgtctcccctcgccgcatccact ctccggccggccgcctgcccgccgcctcctccgtgcgcccgccagcctcg cccgcgccgtcaccgcggccgccacc (SEQ ID NO: 99) SP0347 Ctctgtctcctcaggtgcctggctcccagtccccagaacgcctctcctgt 606 accttgcttcctagctgggcctttccttctcctctataaataccagctct ggtatttcgccttggcagctgttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtggtgtgagtgggtgtgggcggt gtgagtagggggatgaatcagagagggggcctagactagcatgctgccca tgtaaggaggcaaggcctggggacacccgagatgcctggttataattaac ccagacatgtggctgcccccccccccccaacacctgctgcctctaaaaat aaccctgcataaatacccgctctggtatttggggttctcctctataaata cccgctctggtatttggggttggcagctgttgcgggatcttgcagctgtc aggggaggggaggcgggggctgatgtcaggagggatacaaatagtgccga cggctgggggccctgtctcccctcgccgcatccactctccggccggccgc ctgcccgccgcctcctccgtgcgcccgccagcctcgcccgcgccgtcacc gccacc (SEQ ID NO: 100) SP0348 Ctctgtctcctcaggtgcctggctgcttcctagctgggcctttccttctc 575 ctctataaataccagctctggtatttcgccttggcagctgttgctgctag ggagacggctggcttgacatgcatctcctgacaaaacacaaacccgtggt gtgagtgggtgtgggcggtgtgagtagggggatgaatcagagagggggcc tagactagcatgctgcccatgtaaggaggcaaggcctggggacacccgag atgcctggttataattaacccagacatgtggctgcccccccccccccaac acctgctgcctctaaaaataaccctgcataaatacccgctctggtatttg gggttctcctctataaatacccgctctggtatttggggttggcagctgtt gcgggatcttgcagctgtcaggggaggggaggcgggggctgatgtcagga gggatacaaatagtgccgacggctgggggccctgtctcccctcgccgcat ccactctccggccggccgcctgcccgccgcctcctccgtgcgcccgccag cctcgcccgcgccgtcaccgccacc (SEQ ID NO: 101) SP0349 Ctctgtctcctcaggtgcctggctcccagtccccagaacgcctctcctgt 907 accttgcttcctagctgggcctttccttctcctctataaataccagctct ggtatttcgccttggcagctgttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtggtgtgagtgggtgtgggcggt gtgagtagggggatgaatcagagagggggcgccactacgggtctaggctg cccatgtaaggaggcaaggcctggggacacccgagatgcctggttataat taacccagacatgtggctgccccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttaggctctgtacaccatggaggag aagctcgctctaaaaataaccctgcaccgcggtggcggccgtccgccctc ggcaccatcctcacgacacccaaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgggcaggcagcaggtgttggcg ctctaaaaataactcccgggagttatttttagagcggaggaatggtggac acccaaatatggcgacggttcctcacccgtcgccatatttgggtgtccgc cctataaatacccgctctggtatttggggttctcctctataaatacccgc tctggtatttggggttggcagctgttgcgggatcttgcagctgtcagggg aggggaggcgggggctgatgtcaggagggatacaaatagtgccgacggct gggggccctgtctcccctcgccgcatccactctccggccggccgcctgcc cgccgcctcctccgtgcgcccgccagcctcgcccgcgccgtcaccgcggc cgccacc (SEQ ID NO: 102) SP0350 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 727 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtttctcctctataaata cccgctctggtatttggggttggcagctgttgctgccagggagatggttg ggttgacaccgcggtggcggccgtccgccctcggcaccatcctcacgaca cccaaatatggcgacgggtgaggaatggtggggagttatttttagagcgg tgaggaaggtgggcaggcagcaggtgttggcgctctaaaaataactcccg ggagttatttttagagcggaggaatggtggacacccaaatatggcgacgg ttcctcacccgtcgccatatttgggtgtccgccctcggccggggccgcat tcctgggggccgggcggtgctcccgcccgcctcgataaaaggctccgggg ccggcggcggcccacgagctacccggaggagcgggaggcgccaagctcta gaactagtggatcccgcggccgccacc (SEQ ID NO: 103) SP0351 Caccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaaa 365 tatggcgacgggtgaggaatggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctctaaaaataactcccgggagtt atttttagagcgagctctataaatacccgctctggtatttggggttttga acccgtcgccatatttgggtgtccgccctcggccggggccgcattcctgg gggccgggcggtgctcccgcccgcctcgataaaaggctccggggccggcg gcggcccacgagctacccggaggagcgggaggcgccaagctctagaacta gtggatcccgccacc (SEQ ID NO: 104) SP0352 Caccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaaa 365 tatggcgacgggtgaggaatggtggggagctatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctctaaaaatagctcccgggagct atttttagagcggaggaatggtggacacccaaatatggcgacggttcctc acccgtcgccatatttgggtgtccgccctcggccggggccgcattcctgg gggccgggcggtgctcccgcccgcctcgataaaaggctccggggccggcg gcggcccacgagctacccggaggagcgggaggcgccaagctctagaacta gtggatcccgccacc (SEQ ID NO: 105) SP0353 Tccctaacctcctgcttgcgaggcctctctctggcctctgagagggtcag 568 tgtcctgccccaacccatgagatgacagactataatagccacaggattaa catagcaggcattgtctttctctgactatagggtgggtattatgtgttca tcaaccatcctaaaaatacccggtaaacaggtgcagcccctgtggctcca gtcccctgggatctgttggcttctggctggagatgaagattagggcagag gagaggtgaattagtctcactgagttccaggcatgagactcgggtgtcct ttggaacctgggaaatctagattccaggaaacccatctggagggcccggc agacgctccttatacggcccggcctcgctcacctgggccgcggccaggag cgccttctttgggcagcgccgggccggggccgcgccgggcccgacaccca aatatggcgacggccggggccgcattcctgggggccgggcggcgctcccg cccgcctcgataaaaggctccggggccggcggcggcccacgagctacccg gaggagcgggaggccacc (SEQ ID NO: 106) SP0354 Ccatcctaaaaatacccggtaaacaggtgcagcccctgtggctccagtcc 376 cctgggatctgttggcttctggctggagatgaagattagggcagaggaga ggtgaattagtctcactgagttccaggcatgagactcgggtgtcctttgg aacccggcagacgctccttatacggcccggcctcgctcacctgggccgcg gccaggagcgccttctttgggcagcgccgggccggggccgcgccgggccc gacacccaaatatggcgacggccggggccgcattcctgggggccgggcgg cgctcccgcccgcctcgataaaaggctccggggccggcggcggcccacga gctacccggaggagcgggaggccacc (SEQ ID NO: 107) SP0355 Agggtcagtgtcctgccccaacccatgagatgacagactataatagccac 296 aggattaacatagcaggcattgcccggcagacgctccttatacggcccgg cctcgctcacctgggccgcggccaggagcgccttctttgggcagcgccgg gccggggccgcgccgggcccgacacccaaatatggcgacggccggggccg cattcctgggggccgggcggcgctcccgcccgcctcgataaaaggctccg gggccggcggcggcccacgagctacccggaggagcgggaggccacc (SEQ ID NO: 108) SP0356 Ctgaggggtgtcagagcacaggctgaggcctcttgcctgacgtgggaccc 654 cttggtctggcatttgtcagtgaggcaggctgggggcaggccccggagct tggcaggaggtgtaaaccggccttggaaggtagggccccacaatggggac agttggatctctgagggagacagggaggcatgatcactgccaaatgccca ccaaggacaaggcacatcccagggagacagacgcagacctggtgccctct ggacactggcattcctggaggctgatgatggacagatgggcctggaggtg gctcttcgccagctggtgtttcctttggacttcctcagtgtctttggaga agcagagccctaagaataagcagctgcccataaaatctaataccagccaa gcatctcaggaattcatggattgtctccatcccggcagacgctccttata cggcccggcctcgctcacctgggccgcggccaggagcgccttctttgggc agcgccgggccggggccgcgccgggcccgacacccaaatatggcgacggc cggggccgcattcctgggggccgggcggcgctcccgcccgcctcgataaa aggctccggggccggcggcggcccacgagctacccggaggagcgggaggc cacc (SEQ ID NO: 109) SP0358 ttctgagtcctctaaggtccctcactcccaactcagccccatgtcctgtc 659 aattcccactcagtgtctgatctccttctcctcacctttcccatctcccg tttgacccaagcttcctgagctctcctcccattcccctttttggagtcct cctcctctcccagaacccagtaataagtgggctcctccctggcctggacc cccgtggtaaccctataaggcgaggcagctgctgtctgaggcagggaggg gctggtgtgggaggctaagggcagctgctaagtttagggtggctccttct ctcttcttagagacaacaggtggctggggcctcagtgcccagaaaagaaa atgtcttagaggtatcggcatgggcctggaggaggggggacagggcaggg ggaggcatcttcctcaggacatcgggtcctagaggcccggcagacgctcc ttatacggcccggcctcgctcacctgggccgcggccaggagcgccttctt tgggcagcgccgggccggggccgcgccgggcccgacacccaaatatggcg acggccggggccgcattcctgggggccgggcggcgctcccgcccgcctcg ataaaaggctccggggccggcggcggcccacgagctacccggaggagcgg gaggccacc (SEQ ID NO: 110) SP0359 Cctccctggcctggacccccgtggtaaccctataaggcgaggcagctgct 332 gtctgaggcagggaggggctggtgtgggaggctaagggcagctgctaagt ttagggtgcccggcagacgctccttatacggcccggcctcgctcacctgg gccgcggccaggagcgccttctttgggcagcgccgggccggggccgcgcc gggcccgacacccaaatatggcgacggccggggccgcattcctgggggcc gggcggcgctcccgcccgcctcgataaaaggctccggggccggcggcggc ccacgagctacccggaggagcgggaggccacc (SEQ ID NO: 111) SP0361 Caccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaaa 483 tatggcgacgggtgaggaatggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctctaaaaataactcccgggagtt atttttagagcgagctctataaatacccgctctggtatttggggttttga acccgtcgccatatttgggtgtccgccctataaatacccgctctggtatt tggggttctcctctataaatacccgctctggtatttggggttggcagctg ttgcgggatcttgcagctgtcaggggaggggaggcgggggctgatgtcag gagggatacaaatagtgccgacggctgggggccctgtctcccctcgccgc atccactctccggccggccgcctgcccgccgcctcctccgtgcgcccgcc agcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 112) SP0362 Agactggggcaggtgcaggctggattgggtttccagaggctatatatata 535 aaggctgccgggagccccagggccgctccctgagggcacaacactgtggg ggcccagccaggcccacattcctttccagaggccagctctccatttatag cccctgggcagagcagcacacccaaatatggcgacgggtgaggaatggtg gggagttatttttagagcggtgaggaaggtgggcaggcagcaggtgttgg cgctctaaaaataactcccgggagttatttttagagcgagctctataaat acccgctctggtatttggggttttgaacccgtcgccatatttgggtgtcc gccctcgggatcttgcagctgtcaggggaggggaggcgggggctgatgtc aggagggatacaaatagtgccgacggctgggggccctgtctcccctcgcc gcatccactctccggccggccgcctgcccgccgcctcctccgtgcgcccg ccagcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 113) SP0363 Ctctgtctcctcaggtgcctggctcccagtccccagaacgcctctcctgt 598 accttgcttcctagctgggcctttccttctcctctataaataccagctct ggtatttcgccttggcagctgttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtggtgtgagtgggtgtgggcggt gtgagtagggggatgaatcagagagggggcacacccaaatatggcgacgg gtgaggaatggtggggagttatttttagagcggtgaggaaggtgggcagg cagcaggtgttggcgctctaaaaataactcccgggagttatttttagagc gagctctataaatacccgctctggtatttggggttttgaacccgtcgcca tatttgggtgtccgccctcgggatcttgcagctgtcaggggaggggaggc gggggctgatgtcaggagggatacaaatagtgccgacggctgggggccct gtctcccctcgccgcatccactctccggccggccgcctgcccgccgcctc ctccgtgcgcccgccagcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 114) SP0364 Ctctgtctcctcaggtgcctggctcccagtccccagaacgcctctcctgt 683 accttgcttcctagctgggcctttccttctcctctataaataccagctct ggtatttcgccttggcagctgttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtggtgtgagtgggtgtgggcggt gtgagtagggggatgaatcagagagggggccaccgcggtggcggccgtcc gccctcggcaccatcctcacgacacccaaatatggcgacgggtgaggaat ggtggggagttatttttagagcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagttatttttagagcggaggaatg gtggacacccaaatatggcgacggttcctcacccgtcgccatatttgggt gtccgccctcccggcagacgctccttatacggcccggcctcgctcacctg ggccgcggccaggagcgccttctttgggcagcgccgggccggggccgcgc cgggcccgacacccaaatatggcgacggccggggccgcattcctgggggc cgggcggcgctcccgcccgcctcgataaaaggctccggggccggcggcgg cccacgagctacccggaggagcgggaggccacc (SEQ ID NO: 115) SP0365 Caccgcggtggcggccgtccgccctcggcaccatcctcacgacacccaaa 453 tatggcgacgggtgaggaatggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacacccaaatatggcgacggttcctc acccgtcgccatatttgggtgtccgccctcccggcagacgctccttatac ggcccggcctcgctcacctgggccgcggccaggagcgccttctttgggca gcgccgggccggggccgcgccgggcccgacacccaaatatggcgacggcc ggggccgcattcctgggggccgggcggcgctcccgcccgcctcgataaaa ggctccggggccggcggcggcccacgagctacccggaggagcgggaggcc acc (SEQ ID NO: 116) SP0366 Cctccctggcctggacccccgtggtaaccctataaggcgaggcagctgct 591 gtctgaggcagggaggggctggtgtgggaggctaagggcagctgctaagt ttagggtgcaccgcggtggcggccgtccgccctcggcaccatcctcacga cacccaaatatggcgacgggtgaggaatggtggggagttatttttagagc ggtgaggaaggtgggcaggcagcaggtgttggcgctctaaaaataactcc cgggagttatttttagagcggaggaatggtggacacccaaatatggcgac ggttcctcacccgtcgccatatttgggtgtccgccctataaatacccgct ctggtatttggggttctcctctataaatacccgctctggtatttggggtt ggcagctgttgcgggatcttgcagctgtcaggggaggggaggcgggggct gatgtcaggagggatacaaatagtgccgacggctgggggccctgtctccc ctcgccgcatccactctccggccggccgcctgcccgccgcctcctccgtg cgcccgccagcctcgcccgcgccgtcaccgcggccgccacc (SEQ ID NO: 117) SP0367 Cctccctggcctggacccccgtggtaaccctataaggcgaggcagctgct 429 gtctgaggcagggaggggctggtgtgggaggctaagggcagctgctaagt ttagggtgccatgttcccggcgaagggccagctgtcccccgccagctaga ctcagcacttagtttaggaaccagtgagcaagtcagcccttggggcagcc catacaaggccatggggctgggcaagctgcacgcctgggtccggggtggg cacggtgcccgggcaacgagctgaaagctcatctactctcaggggcccct ccctggggacagcccctcctggctagtcacaccctgtaggctcctctata taacccaggggcacaggggctgcccccgggtcaccaccacctccacagca cagacagacactcaggagccagcgccacc (SEQ ID NO: 118) SP0368 Cctccctggcctggacccccgtggtaaccctataaggcgaggcagctgct 550 gtctgaggcagggaggggctggtgtgggaggctaagggcagctgctaagt ttagggtggccactacgggtctaggctgcccatgtaaggaggcaaggcct ggggacacccgagatgcctggttataattaacccagacatgtggctgccc cccccccccaacacctgctgcctgagcctcacccccaccccggtgcctgg gtcttaggctctgtacaccatggaggagaagctcgctctaaaaataaccc tgataaatacccgctctggtatttggggttctcctctataaatacccgct ctggtatttggggttggcagctgttgcgggatcttgcagctgtcagggga ggggaggcgggggctgatgtcaggagggatacaaatagtgccgacggctg ggggccctgtctcccctcgccgcatccactctccggccggccgcctgccc gccgcctcctccgtgcgcccgccagcctcgcccgcgccgtcaccgccacc (SEQ ID NO: 119) SP0369 Cgacacccaaatatggcgacgggtgaggaatggtggggagttatttttag 388 agcggtgaggaaggtgggcaggcagcaggtgttggcgctctaaaaataac tcccgggagttatttttagagcggagcgacacccaaatatggcgacgggt gaggaatggtggggagttatttttagagcggtgaggaaggtgggcaggca gcaggtgttggcgctctaaaaataactcccgggagttatttttagagcgg agcggccggggccgcattcctgggggccgggcggtgctcccgcccgcctc gataaaaggctccggggccggcggcggcccacgagctacccggaggagcg ggaggcgccaagctctagaactagtggatcccgccacc (SEQ ID NO: 120) SP0370 Cgacacccaaatatggcgacgggtgaggaatggtggggagttatttttag 514 agcggtgaggaaggtgggcaggcagcaggtgttggcgctctaaaaataac tcccgggagttatttttagagcggagcgacacccaaatatggcgacgggt gaggaatggtggggagttatttttagagcggtgaggaaggtgggcaggca gcaggtgttggcgctctaaaaataactcccgggagttatttttagagcgg agcgacacccaaatatggcgacgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcaggtgttggcgctctaaaaata actcccgggagttatttttagagcggagcggccggggccgcattcctggg ggccgggcggtgctcccgcccgcctcgataaaaggctccggggccggcgg cggcccacgagctacccggaggagcgggaggcgccaagctctagaactag tggatcccgccacc (SEQ ID NO: 121) SP0371 Taaggcgaggcagctgctgtctgaggcaggacacccaaatatggcgacgg 354 gtgaggaatggtggggagttatttttagagcggtgaggaaggtgggcagg cagcaggtgttggcgctctaaaaataactcccgggagttatttttagagc ggaggaatggtggacacccaaatatggcgacggttcctcacccgtcgcca tatttgggtgtccgccctcggccggggccgcattcctgggggccgggcgg tgctcccgcccgcctcgataaaaggctccggggccggcggcggcccacga gctacccggaggagcgggaggcgccaagctctagaactagtggatcccgc cacc (SEQ ID NO: 122) SP0372 Aggctaagggcagctgctaagtttagggtgacacccaaatatggcgacgg 354 gtgaggaatggtggggagttatttttagagcggtgaggaaggtgggcagg cagcaggtgttggcgctctaaaaataactcccgggagttatttttagagc ggaggaatggtggacacccaaatatggcgacggttcctcacccgtcgcca tatttgggtgtccgccctcggccggggccgcattcctgggggccgggcgg tgctcccgcccgcctcgataaaaggctccggggccggcggcggcccacga gctacccggaggagcgggaggcgccaagctctagaactagtggatcccgc cacc (SEQ ID NO: 123) SP0373 Taaggcgaggcagctgctgtctgaggcaggacacccaaatatggcgacgg 362 gtgaggaatggtggggagttatttttagagcggtgaggaaggtgggcagg cagcaggtgttggcgctctaaaaataactcccgggagttatttttagagc gctctaaggtccctcactcccaactcagccccatgtcctgtcaattcacc cgtcgccatatttgggtgtccgccctcggccggggccgcattcctggggg ccgggcggtgctcccgcccgcctcgataaaaggctccggggccggcggcg gcccacgagctacccggaggagcgggaggcgccaagctctagaactagtg gatcccgccacc (SEQ ID NO: 124) SP0374 Ctctaaggtccctcactcccaactcagccccatgtcctgtcaattcgaca 362 cccaaatatggcgacgggtgaggaatggtggggagttatttttagagcgg tgaggaaggtgggcaggcagcaggtgttggcgctctaaaaataactcccg ggagttatttttagagcgtaaggcgaggcagctgctgtctgaggcagacc cgtcgccatatttgggtgtccgccctcggccggggccgcattcctggggg ccgggcggtgctcccgcccgcctcgataaaaggctccggggccggcggcg gcccacgagctacccggaggagcgggaggcgccaagctctagaactagtg gatcccgccacc (SEQ ID NO: 125) SP0375 Taaggcgaggcagctgctgtctgaggcagaggctaagggcagctgctaag 376 tttagggtctctaaggtccctcactcccaactcagccccatgtcctgtca attccgacacccaaatatggcgacgggtgaggaatggtggggagttattt ttagagcaggcagcaggtgttggcgctctaaaaataactcccgggagtta tttttagagcgacccgtcgccatatttgggtgtccgccctcggccggggc cgcattcctgggggccgggcggtgctcccgcccgcctcgataaaaggctc cggggccggcggcggcccacgagctacccggaggagcgggaggcgccaag ctctagaactagtggatcccgccacc (SEQ ID NO: 126) SP0376 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 434 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgataaat acccgctctggtatttggggtactaaaaatagaacgactatttttaggct tttctggcagctggcccgggatcttgcagctgtcaggggaggggaggcgg gggctgatgtcaggagggatacaaatagtgccgacggctgggggccctgt ctcccctcgccgcatccactctccggccggccgcctgcccgccgcctcct ccgtgcgcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 127) SP0377 Gccactacgggtctaggctgcccatgtaaggaggcaaggcctggggacac 436 ccgagatgcctggttataattaacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctctaaaaataaccctgataaat acccgctctggtatttggggcgaggtactataaatacccttagaggtatt ttatcttggcagctaggtcgggatcttgcagctgtcaggggaggggaggc gggggctgatgtcaggagggatacaaatagtgccgacggctgggggccct gtctcccctcgccgcatccactctccggccggccgcctgcccgccgcctc ctccgtgcgcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 128) SP0378 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 522 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagttactaaaaatagaacg actatttttaggcttttctggcagctggccctgccagacagagttcctca gtaacgggatcttgcagctgtcaggggaggggaggcgggggctgatgtca ggagggatacaaatagtgccgacggctgggggccctgtctcccctcgccg catccactctccggccggccgcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcacc (SEQ ID NO: 129) SP0379 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 524 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtcgaggtactataaata cccttagaggtattttatcttggcagctaggtctgccagacagagttcct cagtaacgggatcttgcagctgtcaggggaggggaggcgggggctgatgt caggagggatacaaatagtgccgacggctgggggccctgtctcccctcgc cgcatccactctccggccggccgcctgcccgccgcctcctccgtgcgccc gccagcctcgcccgcgccgtcacc (SEQ ID NO: 130) SP0380 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 522 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagttactaaaaatagaacg actatttttaggcttttctggcagctggccctgccagacagataaacgag ctatcgggatcttgcagctgtcaggggaggggaggcgggggctgatgtca ggagggatacaaatagtgccgacggctgggggccctgtctcccctcgccg catccactctccggccggccgcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcacc (SEQ ID NO: 131) SP0381 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 524 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtcgaggtactataaata cccttagaggtattttatcttggcagctaggtctgccagacagataaacg agctatcgggatcttgcagctgtcaggggaggggaggcgggggctgatgt caggagggatacaaatagtgccgacggctgggggccctgtctcccctcgc cgcatccactctccggccggccgcctgcccgccgcctcctccgtgcgccc gccagcctcgcccgcgccgtcacc (SEQ ID NO: 132) SP0382 Gggccccacagcagctgggggcatttatgggccttcctataaacttctga 524 gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagttaaacgagctattagt tatgaggtccgtagattgaataaacgagctattagttatgaggtccgtag attgaacgggatcttgcagctgtcaggggaggggaggcgggggctgatgt caggagggatacaaatagtgccgacggctgggggccctgtctcccctcgc cgcatccactctccggccggccgcctgcccgccgcctcctccgtgcgccc gccagcctcgcccgcgccgtcacc (SEQ ID NO: 133) SKM_14 Ttctcctctataaatacccgctctggtatttggggttggcagctgttgct 240 gccagggagatggttgggttgacgggatcttgcagctgtcaggggagggg aggcgggggctgatgtcaggagggatacaaatagtgccgacggctggggg ccctgtctcccctcgccgcatccactctccggccggccgcctgcccgccg cctcctccgtgcgcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 134) SKM_18 Ataaatacccgctctggtatttggggttctcctctataaatacccgctct 242 ggtatttggggttggcagctgttgcgggatcttgcagctgtcaggggagg ggaggcgggggctgatgtcaggagggatacaaatagtgccgacggctggg ggccctgtctcccctcgccgcatccactctccggccggccgcctgcccgc cgcctcctccgtgcgcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 135) SKM_20 Atttttaaagactgaggaattaggcacctgtcatttttgccagctggtgt 232 agatgttaaaaattactgtcactcttccgcctgctactttattttgcacc tgctgttacttgagttacaggcatttcacacatggtaatttaataaggtt agttcccatgacacaccgcctgctgccacggccggccgtataaatagagg cgaggagcagctgggctctcttggcagtcacc (SEQ ID NO: 136) SP0357 Tctgagggagacagggaggcatgatcactgccaaatgcccaccaaggaca 335 aggcacatcccagggagacagacgcagacctggtgccctctggacactgg cattcctggagcccggcagacgctccttatacggcccggcctcgctcacc tgggccgcggccaggagcgccttctttgggcagcgccgggccggggccgc gccgggcccgacacccaaatatggcgacggccggggccgcattcctgggg gccgggcggcgctcccgcccgcctcgataaaaggctccggggccggcggc ggcccacgagctacccggaggagcgggaggccacc (SEQ ID NO: 137) SP0229 gggccccacagcagctgggggcatttatgggccttcctataaacttctga 997 A gagggtaactttatcctgcttctttcagccaagtatcctcctccagcagc tggtcacaaagctggttaatctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttctctggtttctccaactgagtc ctgaggtttggggccttgtcttccttcctggagtctctgtctcctcaggt gcctggctcccagtccccagaacgcctctcctgtaccttgcttcctagct gggcctttccttctcctctataaataccagctctggtatttcgccttggc agctgttgctgctagggagacggctggcttgacatgcatctcctgacaaa acacaaacccgtggtgtgagtgggtgtgggcggtgtgagtagggggatga atcagagagggggccaccgcggtggcggccgtccgccctcggcaccatcc tcacgacacccaaatatggcgacgggtgaggaatggtggggagttatttt tagagcggtgaggaaggtgggcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggaggaatggtggacacccaaatat ggcgacggttcctcacccgtcgccatatttgggtgtccgccctcggccga ccctgataaatacccgctctggtatttggggttctcctctataaataccc gctctggtatttggggttggcagctgttgcgggatcttgcagctgtcagg ggaggggaggcgggggctgatgtcaggagggatacaaatagtgccgacgg ctgggggccctgtctcccctcgccgcatccactctccggccggccgcctg cccgccgcctcctccgtgcgcccgccagcctcgcccgcgccgtcacc (SEQ ID NO: 548)
TABLE-US-00010 TABLE 1A Further Muscle-Specific Promoters NAME SEQUENCE LENGTH SP0407 Agctttgaggctgtgggcagctcagctgtc 388 atgcgggcacacaggtgatgtaagacaata gctgtggagtcagctggcttccaaggtgcc tgggatcttttcgttctgcccttggctcct gccctaactggcaaaccccaataaataccc gctctggtatttggggttctcctctataaa tacccgctctggtatttggggttggcagct gttgcgggatcttgcagctgtcaggggagg ggaggcgggggctgatgtcaggagggatac aaatagtgccgacggctgggggccctgtct cccctcgccgcatccactctccggccggcc gcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcaccgccacc (SEQ ID NO: 342) SP0408 Agctttgaggctgtgggcagctcagctgtc 306 atgcgggcacacaggtgatgtaagacaata gctgtggagtcagctggcttccaaggtgac aatccctgcctgggatcttttcgttctgcc cttggctcctgccctaactggcaaacccca ccccctcatcaccagctttcaagtatcaga ttgcgtttccggcctcttctttccaaaccc ctaaaccaccagcacctgtccccttgcttg cctcattccacagccaacaggctgaaggga agacaaaccctagtcagtcagaggtggggg gccacc (SEQ ID NO: 343) SP0409 Ccagcccacctgtcccaatgctgacttagt 344 gcaaggcgagccagcaaggagggaggacag gtggcagtggggggtgaggagcatctaaaa atagccataaatacccgctctggtatttgg ggttctcctctataaatacccgctctggta tttggggttggcagctgttgcgggatcttg cagctgtcaggggaggggaggcgggggctg atgtcaggagggatacaaatagtgccgacg gctgggggccctgtctcccctcgccgcatc cactctccggccggccgcctgcccgccgcc tcctccgtgcgcccgccagcctcgcccgcg ccgtcaccgccacc (SEQ ID NO: 344) SP0410 Agtgattctccctcaagaccttataaaacc 588 actttaaccctcaatgggataatatctagt acattgtcatgggaactaaccttattaaat taccatgtgtgaaatgcctgtaactcaagt aacagcaggtgcaaaataaagtagcaggcg gaagagtgacagtaatttttaacatctaca ccagctggcaaaaatgacaggtgcctaatt cctcagtctttaaaaataacttttgagaag cctacacagcataagcaaatattttcaagt ttattttttagctatcttcgagttaccttc ctgacaaaatgtaataatatacactgattt ttgcagaaaaataaatacccgctctggtat ttggggttctcctctataaatacccgctct ggtatttggggttggcagctgttgcgggat cttgcagctgtcaggggaggggaggcgggg gctgatgtcaggagggatacaaatagtgcc gacggctgggggccctgtctcccctcgccg catccactctccggccggccgcctgcccgc cgcctcctccgtgcgcccgccagcctcgcc cgcgccgtcaccgccacc (SEQ ID NO: 345) SP0411 Ataacttcagcacactgtcatgggacctaa 505 ccttattaaattaccatgtgtgaagcgtcc ataactcaagtaacagcaggtgcaaaaatg gagctgcaggcagaagagtggtagtcattt ttacaaatccccaccagctggcgaaacaac aggtgcctaattcctcagcttttaaaaata acttttaaaaagcctgtgctgcataagcaa atattttcaagtttgtttttaaaccatctt caagttaccttggtcacataaatacccgct ctggtatttggggttctcctctataaatac ccgctctggtatttggggttggcagctgtt gcgggatcttgcagctgtcaggggagggga ggcgggggctgatgtcaggagggatacaaa tagtgccgacggctgggggccctgtctccc ctcgccgcatccactctccggccggccgcc tgcccgccgcctcctccgtgcgcccgccag cctcgcccgcgccgtcaccgccacc (SEQ ID NO: 346) SP0412 Agggcaccatccggatgcctgcctagttcc 528 cttccggccctgatggaggcatgagcctcc cccaccgcctgctcactgctcactcctcgg ccgccagcccagcagctgttgcctcagatc agtgtggaccatctaatcccctctccagag ccctggccccctcctcaggcagtaaattaa ggaggatgtaagaacagagggcaccagcgt cagcagagcggcatccaaaacatcctcccc aacccgcgcctgagtcacagggccctgaat tggcccctctataaatacccgctctggtat ttggggttctcctctataaatacccgctct ggtatttggggttggcagctgttgcgggat cttgcagctgtcaggggaggggaggcgggg gctgatgtcaggagggatacaaatagtgcc gacggctgggggccctgtctcccctcgccg catccactctccggccggccgcctgcccgc cgcctcctccgtgcgcccgccagcctcgcc cgcgccgtcaccgccacc (SEQ ID NO: 347) SP0413 Agggcaccatccggatgcctgcctagttcc 554 cttccggccctgatggaggcatgagcctcc cccaccgcctgctcactgctcactcctcgg ccgccagcccagcagctgttgcctcagatc agtgtggaccatctaatcccctctccagag ccctggccccctcctcaggcagtaaattaa ggaggatgtaagaacagagggcaccagcgt cagcagagcggcatccaaaacatcctcccc aacccgcgcctgagtcacagggccctgaat tggcccctctattattcacctgttcgcctt agatgaagaatcaaggaacagcagctctag ggggttgggaggagttagggtccggccctg ccccagacctctcagtgtccaatttctctg tgtcagctgtgtttctcagctgtccacttt cctccagccctgtcatttcagccctgacac caaggcaggaggctaggaggtctacaaata gcgactgggtagctggtgtgaacacagggg gtactgggggggcttagcccccaaggaaga ggaccagtgccacc (SEQ ID NO: 348) SP0414 Agggcaccatccggatgcctgcctagttcc 621 cttccggccctgatggaggcatgagcctcc cccaccgcctgctcactgctcactcctcgg ccgccagcccagcagctgttgcctcagatc agtgtggaccatctaatcccctctccagag ccctggccccctcctcaggcagtaaattaa ggaggatgtaagaacagagggcaccagcgt cagcagagcggcatccaaaacatcctcccc aacccgcgcctgagtcacagggccctgaat tggcccctctagactggggcaggtgcaggc tggattgggtttccagaggctatatatata aaggctgccgggagccccagggccgctccc tgagggcacaacactgtgggggcccagcca ggcccacattcctttccagaggccagctct ccatttatagcccctgggcagagcagccgg gatcttgcagctgtcaggggaggggaggcg ggggctgatgtcaggagggatacaaatagt gccgacggctgggggccctgtctcccctcg ccgcatccactctccggccggccgcctgcc cgccgcctcctccgtgcgcccgccagcctc gcccgcgccgtcaccgccacc (SEQ ID NO: 349) SP0415 Atggtgcttccaagtctgctcccgggacgt 497 ttcctgttcttggaacagctgcaccagcct ggggtaccctcctgctacttgatcctatag ggaggtgtccagtggctgtgggcaattttc agatgaccttgttcgtctgacgtcattaga tcgctatttttggctttgctgtttatgctg cagaagttgggctggaatgggagaggagga atgaaggaggggctgctcttggtttcccat tgttccagggataaatacccgctctggtat ttggggttctcctctataaatacccgctct ggtatttggggttggcagctgttgcgggat cttgcagctgtcaggggaggggaggcgggg gctgatgtcaggagggatacaaatagtgcc gacggctgggggccctgtctcccctcgccg catccactctccggccggccgcctgcccgc cgcctcctccgtgcgcccgccagcctcgcc cgcgccgtcaccgccacc (SEQ ID NO: 350) SP0416 Actgatgtggaaggggttatatataggaag 618 atgtgtaggaagaaaaaggtagagagctct cctcagagggtgggggattatgggtagcca gagggagcctgggttagtggagttgaagcc ctagtcttgggtgctttgtagcatcagaag cctctggagcctttgctgacacctgcctga tgtacggagccatctgtgggtgtctgtgtg ctggaggattgcccacagctatgattcaga gatgctcatgttgttgcccaagcaattgac agatgatgtttcaggcttggagatggcagg atgggagcaaagagaagccaggtcaggaaa gaacgtgccgttctggccctagtggggaat tctgggccttataaatacccgctctggtat ttggggttctcctctataaatacccgctct ggtatttggggttggcagctgttgcgggat cttgcagctgtcaggggaggggaggcgggg gctgatgtcaggagggatacaaatagtgcc gacggctgggggccctgtctcccctcgccg catccactctccggccggccgcctgcccgc cgcctcctccgtgcgcccgccagcctcgcc cgcgccgtcaccgccacc (SEQ ID NO: 351) SP0417 Gggagagccaggacattggctgcctgtggt 498 cttggtggtcgtggtcagttccctctcctg ccagctgtggaatgtgaggcctggcctggg agatatttttgctgcactttgagccacccc gccccctggaactcagaccctgcacagtcc atgccataacaatgacgaccacttccaatt gtttcctagctggagaggcggggaggggag cactgtttgggaagggggggagcctggggg aaatgcttctataaatacccgctctggtat ttggggttctcctctataaatacccgctct ggtatttggggttggcagctgttgcgggat cttgcagctgtcaggggaggggaggcgggg gctgatgtcaggagggatacaaatagtgcc gacggctgggggccctgtctcccctcgccg catccactctccggccggccgcctgcccgc cgcctcctccgtgcgcccgccagcctcgcc cgcgccgtcaccgccacc (SEQ ID NO: 352) SP0418 Ccagcccacctgtcccaatgctgacttagt 594 gcaaggcgagccagcaaggagggaggacag gtggcagtggggggtgaggagcatctaaaa atagccgggagagccaggacattggctgcc tgtggtcttggtggtcgtggtcagttccct ctcctgccagctgtggaatgtgaggcctgg cctgggagatatttttgctgcactttgagc caccccgccccctggaactcagaccctgca cagtccatgccataacaatgacgaccactt ccaattgtttcctagctggagaggcgggga ggggagcactgtttgggaagggggggagcc tgggggaaatgcttctataaatacccgctc tggtatttggggttctcctctataaatacc cgctctggtatttggggttggcagctgttg cgggatcttgcagctgtcaggggaggggag gcgggggctgatgtcaggagggatacaaat agtgccgacggctgggggccctgtctcccc tcgccgcatccactctccggccggccgcct gcccgccgcctcctccgtgcgcccgccagc ctcgcccgcgccgtcaccgccacc (SEQ ID NO: 353) SP0419 Gggccccacagcagctgggggcatttatgg 657 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagttccatgccataacaat gacgaccacttccaattgtttcctagctgg ccatgttcccggcgaagggccagctgtccc ccgccagctagactcagcacttagtttagg aaccagtgagcaagtcagcccttggggcag cccatacaaggccatggggctgggcaagct gcacgcctgggtccggggtgggcacggtgc ccgggcaacgagctgaaagctcatctactc tcaggggcccctccctggggacagcccctc ctggctagtcacaccctgtaggctcctcta tataacccaggggcacaggggctgcccccg ggtcaccaccacctccacagcacagacaga cactcaggagccagcgcggccgccacc (SEQ ID NO: 354) SP0420 Ccttgcctgactattggcaggcggacctgg 564 tggtcagacctcagtgatcctcagggacca gtgaatatttcaggctggggctgagcatca cctgctcccttggccccacttatagggcaa aggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgct ctggccccacctcgccctctcccctacttg gaagttcctttcctgaaccactgactgcca aagcttgagggattaaataaatcatctggc ccaatccatgccataacaatgacgaccact tccaattgtttcctagctggatttttaaag actgaggaattaggcacctgtcatttttgc cagctggtgtagatgttaaaaattactgtc actcttccgcctgctactttattttgcacc tgctgttacttgagttacaggcatttcaca catggtaatttaataaggttagttcccatg acacaccgcctgctgccacggccggccgta taaatagaggcgaggagcagctgggctctc ttggcagtcaccgcggccgccacc (SEQ ID NO: 355) SP0421 Ccacagcagctgggggcatttatgggcctt 577 cctataaacttctgagagggtaactttatc ctgcttctttcagccaagtatcctcctcca gcagctggtcacaaagctggttaatctccc agagtgctcagcttaaaacccgtgactcac agcacagccagtgtgggggagggggtggct gcctccaatacgtggcgcccagagtcagct gttctggggccttctctggtttctccaact gagtcctgaggtttggccatgttcccggcg aagggccagctgtcccccgccagctagact cagcacttagtttaggaaccagtgagcaag tcagcccttggggcagcccatacaaggcca tggggctgggcaagctgcacgcctgggtcc ggggtgggcacggtgcccgggcaacgagct gaaagctcatctactctcaggggcccctcc ctggggacagcccctcctggctagtcacac cctgtaggctcctctatataacccaggggc acaggggctgcccccgggtcaccaccacct ccacagcacagacagacactcaggagccag cgccacc (SEQ ID NO: 356) SP0422 Ccacagcagctgggggcatttatgggcctt 532 cctataaacttctgagagggtaactttatc ctgcttctttcagccaagtatcctcctcca aaacccgtgactcacagcacagccagtgtg ggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttct ctggtttctccaactgagtcctgaggtttg gccatgttcccggcgaagggccagctgtcc cccgccagctagactcagcacttagtttag gaaccagtgagcaagtcagcccttggggca gcccatacaaggccatggggctgggcaagc tgcacgcctgggtccggggtgggcacggtg cccgggcaacgagctgaaagctcatctact ctcaggggcccctccctggggacagcccct cctggctagtcacaccctgtaggctcctct atataacccaggggcacaggggctgccccc gggtcaccaccacctccacagcacagacag acactcaggagccagcgccacc (SEQ ID NO: 357) SP0423 Ggcaggcggacctggtggtcagacctcagt 461 gatcctcagggaccagtgaatatttcaggc tggggctgagcatcacctgctcccttggcc ccacttatagggcaaaggggagtctaccag cctactcactgatgacaaactggaaaagtt tgtcctgtctctgctctggccccacctcgc cctctcccctacttggaagttcctttcctg aaccactgactgcatttttaaagactgagg aattaggcacctgtcatttttgccagctgg tgtagatgttaaaaattactgtcactcttc cgcctgctactttattttgcacctgctgtt acttgagttacaggcatttcacacatggta atttaataaggttagttcccatgacacacc gcctgctgccacggccggccgtataaatag aggcgaggagcagctgggctctcttggcag tcaccgccacc (SEQ ID NO: 358) SP0424 Ttctgactgggtcccttaccactgtctttg 765 caaatggcatttccattaacatttctattt ctggccattaggggcacctaaagatttccc accaagattgacagccactattttaagaaa gtgcttttaaaaagccagtgcttttgctaa gtttaaatctgactttctcaggggatgctt aaaagaaatacacagtttgtttgttttttt tttaagaacctttgcaagttcaaaataaca ttccagaaggagtcactagaaaaacattca agggaagagaaaaaaattgttttcgtttgt agcagacctggcttcatccaaatgttctat ttgttttttactgcagggataaaagcagtc tgggctttcacatgacagcatctggggctg cggcagagggtcgggtccgaagcgctgcct tatcagcgtccccagccctgggaggtgaca gctggctggcttgtgtcagcccctcgggca ctcacgtatctccgtccgacgggtttaaaa tagcaaaactctgaggccacacaatagctt gggcttatatgggctcctgtgggggaaggg ggagcacggagggggccggggccgctgctg ccaaaatagcagctcacaagtgttgcattc ctctctgggcgccgggcacattcctgctgg ctctgcccgccccggggtgggcgccggggg gaccttaaagcctctgccccccaaggagcc cttcccagacagccgccggcacccaccgct ccgtgggacgccacc (SEQ ID NO: 359) SP0425 Taagtgtgatgcacagtgcttgcattttct 631 tgatacgttagtcatatgagagctgacaaa gaaggaaaaagagcagcgatgtggtgcaat attaacaggcagctgtcccctggcttcccg atacgtgggatgactcgcattgctgagcgg tgtggtcactgccaaaggaatgaccctctc acatttcttcctgattcgcatacgccgcgg cgggataaaagcagtctgggctttcacatg acagcatctggggctgcggcagagggtcgg gtccgaagcgctgccttatcagcgtcccca gccctgggaggtgacagctggctggcttgt gtcagcccctcgggcactcacgtatctccg tccgacgggtttaaaatagcaaaactctga ggccacacaatagcttgggcttatatgggc tcctgtgggggaagggggagcacggagggg gccggggccgctgctgccaaaatagcagct cacaagtgttgcattcctctctgggcgccg ggcacattcctgctggctctgcccgccccg gggtgggcgccggggggaccttaaagcctc tgccccccaaggagcccttcccagacagcc gccggcacccaccgctccgtgggacgccac c (SEQ ID NO: 360) SP0426 Ccttgcctgactattggcaggcggacctgg 525 tggtcagacctcagtgatcctcagggacca gtgaatatttcaggctggggctgagcatca cctgctcccttggccccacttatagggcaa aggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgct ctggccccacctcgccctctcccctacttg gaagttcctttcctgaaccactgactgcca aagcttgagggattaaataaatcatctggc ccaaactcgggggccaggcactggcgctga cgcaggctagcagggcgccactggctggtc cccacccacctcggtgggttgggggatggg cgcaccagcccctcctgggtgagccctagc ctggggcttcctatttcgggagccgggggc gtgggccacgtctcctcatgtgatgcgagg gctatttaaagcggcagcccgggcagggag ccgccgtcggagcccttgcacgcctgctct cttgtagctgccacc (SEQ ID NO: 361) SP0427 Ttctcctctataaatacccgctctggtatt 422 tggggttggcagctgttgcccctgcccccc acagctcctctcctgtgccttgtttcccag ccatgcgttctcctctataaatacccgctc tggtatttggggttggcagctgttgctgcc agggagatggttgggttgacatggactcag gggcgcaggcctcttgcgggggagctggcc tccccgcccccacggccacgggccgccctt tcctggcaggacagcgggatcttgcagctg tcaggggaggggaggcgggggctgatgtca ggagggatacaaatagtgccgacggctggg ggccctgtctcccctcgccgcatccactct ccggccggccgcctgcccgccgcctcctcc gtgcgcccgccagcctcgcccgcgccgcca cc (SEQ ID NO: 362) SP0428 Gccactacgggtctaggctgcccatgtaag 616 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgttctcctctataaata cccgctctggtatttggggttggcagctgt tgcccctgccccccacagctcctctcctgt gccttgtttcccagccatgcgttctcctct ataaatacccgctctggtatttggggttgg cagctgttgctgccagggagatggttgggt tgacatggactcaggggcgcaggcctcttg cgggggagctggcctccccgcccccacggc cacgggccgccctttcctggcaggacagcg ggatcttgcagctgtcaggggaggggaggc gggggctgatgtcaggagggatacaaatag tgccgacggctgggggccctgtctcccctc gccgcatccactctccggccggccgcctgc ccgccgcctcctccgtgcgcccgccagcct cgcccgcgccgccacc (SEQ ID NO: 363) SP0429 Aaactttaaagattagctattaaaaatgcc 806 attttacataaattaattggtttttatcag agtagtataatagtaaactactttttgtct aatgacttctgttcacaggtgaagtggtat aatctgcccttgtttatatttttggttgtc tgaataagatgggaaatatttttaatatgc aggggcagtagtgaggcaccaagattccat gcacttcctgtcagcaaaggtatcaactgc caggaacccctgataagtcctattttgagc aagcagtgtcaggataacagaagacagaca cagtttactgctgtgaggctggcagcagag ccaactgcactaccatcctaatcacaacag acactctggagttagacaaagccaagggga taaaagcagtctgggctttcacatgacagc atctggggctgcggcagagggtcgggtccg aagcgctgccttatcagcgtccccagccct gggaggtgacagctggctggcttgtgtcag cccctcgggcactcacgtatctccgtccga cgggtttaaaatagcaaaactctgaggcca cacaatagcttgggcttatatgggctcctg tgggggaagggggagcacggagggggccgg ggccgctgctgccaaaatagcagctcacaa gtgttgcattcctctctgggcgccgggcac attcctgctggctctgcccgccccggggtg ggcgccggggggaccttaaagcctctgccc cccaaggagcccttcccagacagccgccgg cacccaccgctccgtgggacgccacc (SEQ ID NO: 364) SP0430 Gaagcaacacatgccccttcccaaaaatat 842 ctagccagtgcctaatgccagattgtcaag tagaaagtctgtccagcagtgagacggagg tcgttctcctaatctgtcctgcattcccct gcactctaaaaggagatccaccaggccagg acaggcaagttggctctacacgtagctgca aatagaagcagggctcaagccatccatagc tcgactcacttactaaataaggatgaaaca ataccgggttcacttctctgacacattccc ctgtctacgacgagggctgggtggagagag cagggaagtccacagtgcactattgttagc ctttatcaagaaacatgacaaatgaccctg aaatggagcctcttatcacccaaacctctc cacagcctgcacaaggagcagctgcagtcc atgggataaaagcagtctgggctttcacat gacagcatctggggctgcggcagagggtcg ggtccgaagcgctgccttatcagcgtcccc agccctgggaggtgacagctggctggcttg tgtcagcccctcgggcactcacgtatctcc gtccgacgggtttaaaatagcaaaactctg aggccacacaatagcttgggcttatatggg ctcctgtgggggaagggggagcacggaggg ggccggggccgctgctgccaaaatagcagc tcacaagtgttgcattcctctctgggcgcc gggcacattcctgctggctctgcccgcccc ggggtgggcgccggggggaccttaaagcct ctgccccccaaggagcccttcccagacagc cgccggcacccaccgctccgtgggacgcca cc (SEQ ID NO: 365) SP0431 Gatcctctgcctggcaggggggtggcctta 648 tttagcctggcctggctcctctgagctttc ttgggaatgtctatatataggggaagagcg cagcccagttgccactgtccatctgccttc cttggactctggtccacccctccctgaccc tgggctccattttctttctgtgccactttc ttctgcgtacccctcctacttgacttgaag aagtaattggactccagagaccagctgcca ttgcccatgcccaactaaaaatagcctatc ctcctggatcaggccaagggccggaggagg gaaggaggaactgggccagctggctgaagg atgtcttgggactcgtcaccccttcttcac catcccgagtccaaagccctgacccagatg gcctggcttgataaatacccgctctggtat ttggggttctcctctataaatacccgctct ggtatttggggttggcagctgttgcgggat cttgcagctgtcaggggaggggaggcgggg gctgatgtcaggagggatacaaatagtgcc gacggctgggggccctgtctcccctcgccg catccactctccggccggccgcctgcccgc cgcctcctccgtgcgcccgccagcctcgcc cgcgccgtcaccgccacc (SEQ ID NO: 366) SP0432 Tgccactttcttctgcgtacccctcctact 478 tgacttgaagaagtaattggactccagaga ccagctgccattgcccatgcccaactaaaa atagcctatcctcctggatcaggccaaggg ccggaggagggaaggaggaactgggccagc tggctgaaggatgtcttgggactcgtcacc ccttcttcaccatcccgagtccaaagccct gacccagatggcctggcttgataaataccc gctctggtatttggggttctcctctataaa tacccgctctggtatttggggttggcagct gttgcgggatcttgcagctgtcaggggagg ggaggcgggggctgatgtcaggagggatac aaatagtgccgacggctgggggccctgtct cccctcgccgcatccactctccggccggcc gcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcaccgccacc (SEQ ID NO: 367)
TABLE-US-00011 TABLE 1B Further Cardiac Muscle-Specific Promoters NAME SEQUENCE LENGTH SP0344 cccttcagattaaaaataactgaggtaagg 460 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 424) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctgggccccagccactgtctcttt aaccttgaaggcatttttgggtctcacgtg tccacccaggcgggtgtcggactttgaacg gctcttacttcagaagaacggcatggggtg ggggggcttaggtggcctctgcctcaccta caactgccaaaagtggtcatggggttattt ttaaccccagggaagaggtatttattgttc cacagcaggggccggccagcaggctccttg aattcttcagaggcagcagccagcctcaga cagccacc SP0433 Cccttcagattaaaaataactgaggtaagg 554 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 425) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctgcaccgcggtggcggccgtccg ccctcggcaccatcctcacgacacccaaat atggcgacgggtgaggaatggtggggagtt atttttagagcgtaaacgagctattagttg cagcaggtgttggcgctctaaaaataactc ccgggagttatttttagagcggaggaatgg tggacacccaaatatggcgacggttcctca cccgtcgccatatttgggtgtccgccctcg gccggggccgcattcctgggggccgggcgg tgctcccgcccgcctcgataaaaggctccg gggccggcggcggcccacgagctacccgga ggagcgggaggcgccaagctctagaactag tggatcccgccacc SP0435 cccttcagattaaaaataactgaggtaagg 609 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 426) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctggggataaaagcagtctgggct ttcacatgacagcatctggggctgcggcag agggtcgggtccgaagcgctgccttatcag cgtccccagccctgggaggtgacagctggc tggcttgtgtcagcccctcgggcactcacg tatctccgtccgacgggtttaaaatagcaa aactctgaggccacacaatagcttgggctt atatgggctcctgtgggggaagggggagca cggagggggccggggccgctgctgccaaaa tagcagctcacaagtgttgcattcctctct gggcgccgggcacattcctgctggctctgc ccgccccggggtgggcgccggggggacctt aaagcctctgccccccaaggagcccttccc agacagccgccggcacccaccgctccgtgg gacgccacc SP0436 cccttcagattaaaaataactgaggtaagg 632 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 427) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctgcccttcagattaaaaataact gaggtaagggcctgggtaggggaggtggtg tgagacgctcctgtctctcctctatctgcc catcggccctttggggaggaggaatgtgcc caaggactaaaaaaaggccatggagccaga ggggcgagggcaacagacctttcatgggca aaccttggggccctgctgataaatacccgc tctggtatttggggttctcctctataaata cccgctctggtatttggggttggcagctgt tgcgggatcttgcagctgtcaggggagggg aggcgggggctgatgtcaggagggatacaa atagtgccgacggctgggggccctgtctcc cctcgccgcatccactctccggccggccgc ctgcccgccgcctcctccgtgcgcccgcca gcctcgcccgcgccgtcaccgcggccgcca cc SP0449 ttctgactgggtcccttaccactgtctttg 782 (SEQ ID caaatggcatttccattaacatttctattt NO: 428) ctggccattaggggcacctaaagatttccc accaagattgacagccactattttaagaaa gtgcttttaaaaagccagtgcttttgctaa gtttaaatctgactttctcaggggatgctt aaaagaaatacacagtttgtttgttttttt tttaagaacctttgcaagttcaaaataaca ttccagaaggagtcactagaaaaacattca agggaagagaaaaaaattgttttcgtttgt agcagacctggcttcatccaaatgttctat ttgttttttactgcacccttcagattaaaa ataactgaggtaagggcctgggtaggggag gtggtgtgagacgctcctgtctctcctcta tctgcccatcggccctttggggaggaggaa tgtgcccaaggactaaaaaaaggccatgga gccagaggggcgagggcaacagacctttca tgggcaaaccttggggccctgctgataaat acccgctctggtatttggggttctcctcta taaatacccgctctggtatttggggttggc agctgttgcgggatcttgcagctgtcaggg gaggggaggcgggggctgatgtcaggaggg atacaaatagtgccgacggctgggggccct gtctcccctcgccgcatccactctccggcc ggccgcctgcccgccgcctcctccgtgcgc ccgccagcctcgcccgcgccgtcaccgcca cc SP0450 aaactttaaagattagctattaaaaatgcc 823 (SEQ ID attttacataaattaattggtttttatcag NO: 429) agtagtataatagtaaactactttttgtct aatgacttctgttcacaggtgaagtggtat aatctgcccttgtttatatttttggttgtc tgaataagatgggaaatatttttaatatgc aggggcagtagtgaggcaccaagattccat gcacttcctgtcagcaaaggtatcaactgc caggaacccctgataagtcctattttgagc aagcagtgtcaggataacagaagacagaca cagtttactgctgtgaggctggcagcagag ccaactgcactaccatcctaatcacaacag acactctggagttagacaaagccaagccct tcagattaaaaataactgaggtaagggcct gggtaggggaggtggtgtgagacgctcctg tctctcctctatctgcccatcggccctttg gggaggaggaatgtgcccaaggactaaaaa aaggccatggagccagaggggcgagggcaa cagacctttcatgggcaaaccttggggccc tgctgataaatacccgctctggtatttggg gttctcctctataaatacccgctctggtat ttggggttggcagctgttgcgggatcttgc agctgtcaggggaggggaggcgggggctga tgtcaggagggatacaaatagtgccgacgg ctgggggccctgtctcccctcgccgcatcc actctccggccggccgcctgcccgccgcct cctccgtgcgcccgccagcctcgcccgcgc cgtcaccgccacc SP0451 gaagcaacacatgccccttcccaaaaatat 859 (SEQ ID ctagccagtgcctaatgccagattgtcaag NO: 430) tagaaagtctgtccagcagtgagacggagg tcgttctcctaatctgtcctgcattcccct gcactctaaaaggagatccaccaggccagg acaggcaagttggctctacacgtagctgca aatagaagcagggctcaagccatccatagc tcgactcacttactaaataaggatgaaaca ataccgggttcacttctctgacacattccc ctgtctacgacgagggctgggtggagagag cagggaagtccacagtgcactattgttagc ctttatcaagaaacatgacaaatgaccctg aaatggagcctcttatcacccaaacctctc cacagcctgcacaaggagcagctgcagtcc atcccttcagattaaaaataactgaggtaa gggcctgggtaggggaggtggtgtgagacg ctcctgtctctcctctatctgcccatcggc cctttggggaggaggaatgtgcccaaggac taaaaaaaggccatggagccagaggggcga gggcaacagacctttcatgggcaaaccttg gggccctgctgataaatacccgctctggta tttggggttctcctctataaatacccgctc tggtatttggggttggcagctgttgcggga tcttgcagctgtcaggggaggggaggcggg ggctgatgtcaggagggatacaaatagtgc cgacggctgggggccctgtctcccctcgcc gcatccactctccggccggccgcctgcccg ccgcctcctccgtgcgcccgccagcctcgc ccgcgccgtcaccgccacc SP0452 gggataaaagcagtctgggctttcacatga 851 (SEQ ID cagcatctggggctgcggcagagggtcggg NO: 431) tccgaagcgctgccttatcagcgtccccag ccctgggaggtgacagctggctggcttgtg tcagcccctcgggcactcacgtatctccgt ccgacgggtttaaaatagcaaaactctgag gccacacaatagcttgggcttatatgggct cctgtgggggaagggggagcacggaggggg ccggggccgctgctgccaaaatagcagctc acaagtgttgcattcctctctgggcgccgg gcacattcctgctggctctgcccgccccgg ggtgggcgccggggggaccttaaagcctct gccccccaaggagcccttcccagacagccg ccggcacccaccgctccgtgggaccccttc agattaaaaataactgaggtaagggcctgg gtaggggaggtggtgtgagacgctcctgtc tctcctctatctgcccatcggccctttggg gaggaggaatgtgcccaaggactaaaaaaa ggccatggagccagaggggcgagggcaaca gacctttcatgggcaaaccttggggccctg ctgataaatacccgctctggtatttggggt tctcctctataaatacccgctctggtattt ggggttggcagctgttgcgggatcttgcag ctgtcaggggaggggaggcgggggctgatg tcaggagggatacaaatagtgccgacggct gggggccctgtctcccctcgccgcatccac tctccggccggccgcctgcccgccgcctcc tccgtgcgcccgccagcctcgcccgcgccg tcaccgccacc SP0475 cccttcagattaaaaataactgaggtaagg 647 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 432) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctgataaatacccgctctggtatt tggggttctcctctataaatacccgctctg gtatttggggttggcagctgttgcgggatc ttgcagctgtcaggggaggggaggcggggg ctgatgtcaggagggatacaaatagtgccg acggctgggggccctgtctcccctcgctca gatcgcctggagacgccatccacgctgttt tgacctccatagaagacaccgggaccgatc cagcctccgcggccgggaacggtgcattgg aacgcggattccccgtgccaagagtgacgt aagtaccgcctatagactctataggcacac ccctttggctcttatgcatgaacggtggag ggcagtgtagtctgagcagtactcgttgct gccgcgcgcgccaccagacataatagctga cagactaacagactgttcctttccatgggt cttttctgcaggccacc SP0476 ccagcagtttcatccctagaccatcccaaa 501 (SEQ ID catggttgagaagctctgaggggaggaccc NO: 433) agcactgcccggcccctgaagtatctaatc agcagtcctgctcagcatatcaatccaagc ccactctagacagagatgccggtgcccagt tttctatttttaactggtgtgaactgaagg aaaagcacagcattagaagtccaagcacta gtcaagaaccaagaatacagggcaccccag ggcaagcataaatacccgctctggtatttg gggttctcctctataaatacccgctctggt atttggggttggcagctgttgcgggatctt gcagctgtcaggggaggggaggcgggggct gatgtcaggagggatacaaatagtgccgac ggctgggggccctgtctcccctcgccgcat ccactctccggccggccgcctgcccgccgc ctcctccgtgcgcccgccagcctcgcccgc gccgtcaccgcggccgccacc SP0477 gtcaccctctgcttccctgcatgggtcctg 484 (SEQ ID ttgccagggagaaagaatcctgaggcgagc NO: 434) gcccaggaagataaccaaggactcttttct gctcctctcacacctttgaagtgggggcct cttgaggcaaatcagcaagaatgtgactct tgcagctgagggtctgggggaggggggtga gtggagctgctcaaggcaaaggggccgtga caagctttgccgaactgataataaataccc gctctggtatttggggttctcctctataaa tacccgctctggtatttggggttggcagct gttgcgggatcttgcagctgtcaggggagg ggaggcgggggctgatgtcaggagggatac aaatagtgccgacggctgggggccctgtct cccctcgccgcatccactctccggccggcc gcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcaccgcggccgc cacc SP0478 cctgggctcctggcatctgctttatcggga 465 (SEQ ID ttctcaagagggacagctggtttatgttac NO: 435) aagcctgttccctgcatatctgctctggtt ttaaatagctttatctgagcagctggagga ccacatgagcttatatggcgtggggtactt gttcttttagccctgtgccgggcacctgcc aaaatagcagccaacaccccccattgtgtt gataaatacccgctctggtatttggggttc tcctctataaatacccgctctggtatttgg ggttggcagctgttgcgggatcttgcagct gtcaggggaggggaggcgggggctgatgtc aggagggatacaaatagtgccgacggctgg gggccctgtctcccctcgccgcatccactc tccggccggccgcctgcccgccgcctcctc cgtgcgcccgccagcctcgcccgcgccgtc accgcggccgccacc SP0479 ccagttgttcaactcacccttcagattaaa 456 (SEQ ID aataactgaggtaagggcctgggtagggga NO: 436) ggtggtgtgagacgctcctgtctctcctct atctgcccatcggccctttggggaggagga atgtgcccaaggactaaaaaaaggccatgg agccagaggggcgagggcaacagacctttc atgggcaaaccttggggccctgataaatac ccgctctggtatttggggttctcctctata aatacccgctctggtatttggggttggcag ctgttgcgggatcttgcagctgtcagggga ggggaggcgggggctgatgtcaggagggat acaaatagtgccgacggctgggggccctgt ctcccctcgccgcatccactctccggccgg ccgcctgcccgccgcctcctccgtgcgccc gccagcctcgcccgcgccgtcaccgcggcc gccacc SP0480 tgctgagcccagaaaaactgaccgccctgt 496 (SEQ ID gtcctgcccacctccacactctagagctat NO: 437) attgagaggtgacagtagatagggtgggag ctggtagcagggagagtgttcctgggtgtg agggtgtaggggaaagccagagcaggggag tctggctttgcctcctgaacacaatgtcta cttagttataacaggcatgacctgctaaag acccaacatctacgacctctgaaaagacag caataaatacccgctctggtatttggggtt ctcctctataaatacccgctctggtatttg gggttggcagctgttgcgggatcttgcagc tgtcaggggaggggaggcgggggctgatgt caggagggatacaaatagtgccgacggctg ggggccctgtctcccctcgccgcatccact ctccggccggccgcctgcccgccgcctcct ccgtgcgcccgccagcctcgcccgcgccgt caccgcggccgccacc SP0481 cccttcagattaaaaataactgaggtaagg 456 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 438) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctgtatgtctatattaggtgacgc agaactgcccgtcgctcctgtcatccaggc ccctggcccaatggcaggctgaatcccccc tactccagcctgctcccgcctcttctgccc ctggtgctccgcgctacctgctgccgcgcg ccacatccagggcagagaggcgggtgcgcg ggcgggcggcgggcaccatgcggggaggct gtccccaggggtgggcagcaccactctctg ctacccacctggcgctgtgaaacctgcgtc gccacc SP0482 agcggagccgagggggcagcgcgtgacccc 517 (SEQ ID gagcggaagggccccagtctgggtcctaat NO: 439) gcgggtggcgtctctcttgacaggcagcgt ttggggacaacagcggggaagggagataag atgacataccagagcagatttggtgtgcgc gctgatactcctggcccgacaggaaactcg gagctatttaaaaaggccctatcgattact ttatcttccccggaggaaaacttcttgccg agagacaaaagatgtccccctacataaata cccgctctggtatttggggttctcctctat aaatacccgctctggtatttggggttggca gctgttgcgggatcttgcagctgtcagggg aggggaggcgggggctgatgtcaggaggga tacaaatagtgccgacggctgggggccctg tctcccctcgccgcatccactctccggccg gccgcctgcccgccgcctcctccgtgcgcc cgccagcctcgcccgcgccgtcaccgcggc cgccacc SP0483 cccttcagattaaaaataactgaggtaagg 453 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 440) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctgggccccagccactgactcttt aaccttgaaggcatttttgggtctcacgtg tccacccaggcgggtggccgcctttgagca gctcttacttcagaagaacggcatggagtg gggggtggggggcttaggtggcctccgcct cacctacaactgccaaaagtggtcatgggg ttatttttaaccccaggggagaggtattta ttgttccacagcaggggcagaggccagcag gctcctcgaactctccagaggtggcaagcc acc SP0484 cccttcagattaaaaataactgaggtaagg 348 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 441) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctggactcgctgaattaatgaatc acttttcttatctattttttgctgttatct aattctgagagggaagccgggagcagaggg agttgggagacgtagctcacaacgtctccc tcccacccggctcaaacaggctggaatctc tgggcctagagggccacc SP0485 cctctagaggcaggtgaccttgatgaaagg 442 (SEQ ID ccttcagtgtgacacaggtgtaaaaatagc NO: 442) ctctgtgctgacttaactccctggcttgag caaacggcccctcacacctgtatattgttt gcttggcatagacacactgctacctgtttg caggtgtaaatgactgtttatgtacccaga gttatgagataaatacccgctctggtattt ggggttctcctctataaatacccgctctgg tatttggggttggcagctgttgcgggatct tgcagctgtcaggggaggggaggcgggggc tgatgtcaggagggatacaaatagtgccga cggctgggggccctgtctcccctcgccgca tccactctccggccggccgcctgcccgccg cctcctccgtgcgcccgccagcctcgcccg cgccgtcaccgcggccgccacc SP0486 cccttcagattaaaaataactgaggtaagg 463 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 443) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctggggctggctgaaaggatgtct atatgtgtatttttatcacccatgtgtcgg atgagcctgagagctgccagatagctttct cgacagcttggcgttagtgttgggaacagg tccatgtatggaagcgaaagccgaaaggca cagataagctaagagccagctatgcagcca tgcttagagacactaaggacaggctccccg ggtcctttctttctggtctatctggagcag ccttcagagctggtcggtttctcatccagc ccatgcagccacc SP0487 cccttcagattaaaaataactgaggtaagg 337 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 444) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctgaagatacctcag ctggatggaatttgtctatatttagcaggt ggctagcaggaggctgataagcagggctgg ggagggggcagtcctcataaatagtgagaa cacaggacactgttcagtccctccttgggt ggcctgcttggccacc SP0488 taagtgtgatgcacagtgcttgcattttct 544 (SEQ ID tgatacgttagtcatatgagagctgacaaa NO: 445) gaaggaaaaagagcagcgatgtggtgcaat attaacaggcagctgtcccctggcttcccg atacgtgggatgactcgcattgctgagcgg tgtggtcactgccaaaggaatgaccctctc acatttcttcctgattcgcatacgccgcgg ccagcttgtcatctccctcttgggcttccc agacactaagtctggaatgaaaattcacct gcctctgaattggccactggataaataccc gctctggtatttggggttctcctctataaa tacccgctctggtatttggggttggcagct gttgcgggatcttgcagctgtcaggggagg ggaggcgggggctgatgtcaggagggatac aaatagtgccgacggctgggggccctgtct cccctcgccgcatccactctccggccggcc gcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcaccgcggccgc cacc SP0489 Cccttcagattaaaaataactgaggtaagg 553 (SEQ ID gcctgggtaggggaggtggtgtgagacgct NO: 446) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctggtctagactcttggatttgag agaagagggaccttgctccgggttttccta agtttgagggaggagggagctggggcgcta gagtcaaaggaggaggggtgtagatcctgg gcaccttggttgacccaactggagctttgc acacggctcccctcacaccctgttatcgct tatcctgggcaggggaggagacagcagtat atttagtctttgtcctcgccccttatctca gtgtcctcagtgaggcttgagcagcccaga ggaaacccaacctctagagacctccaaggt caccagggacacccttccaggaccctccag gaatctccgatcctgttctctgcctctgga gatcatcgccacc SP0490 gtcaccctctgcttccctgcatgggtcctg 497 (SEQ ID ttgccagggagaaagaatcctgaggcgagc NO: 447) gcccaggaagataaccaaggactcttttct gctcctctcacacctttgaagtgggggcct cttgaggcaaatcagcaagaatgtgactct tgcagctgagggtctgggggaggggggtga gtggagctgctcaaggcaaaggggccgtga caagctttgccgaactgatatatgtctata ttaggtgacgcagaactgcccgtcgctcct gtcatccaggcccctggcccaatggcaggc tgaatcccccctactccagcctgctcccgc ctcttctgcccctggtgctccgcgctacct gctgccgcgcgccacatccagggcagagag gcgggtgcgcgggcgggcggcgggcaccat gcggggaggctgtccccaggggtgggcagc accactctctgctacccacctggcgctgtg aaacctgcgtcgccacc SP0491 cctgggctcctggcatctgctttatcggga 478 (SEQ ID ttctcaagagggacagctggtttatgttac NO: 448) aagcctgttccctgcatatctgctctggtt ttaaatagctttatctgagcagctggagga ccacatgagcttatatggcgtggggtactt gttcttttagccctgtgccgggcacctgcc aaaatagcagccaacaccccccattgtgtt gtatgtctatattaggtgacgcagaactgc ccgtcgctcctgtcatccaggcccctggcc caatggcaggctgaatcccccctactccag cctgctcccgcctcttctgcccctggtgct ccgcgctacctgctgccgcgcgccacatcc agggcagagaggcgggtgcgcgggcgggcg gcgggcaccatgcggggaggctgtccccag gggtgggcagcaccactctctgctacccac ctggcgctgtgaaacctgcgtcgccacc SP0492 gtcaccctctgcttccctgcatgggtcctg 378 (SEQ ID ttgccagggagaaagaatcctgaggcgagc NO: 449) gcccaggaagataaccaaggactcttttct gctcctctcacacctttgaagtgggggcct cttgaggcaaatcagcaagaatgtgactct tgcagctgagggtctgggggaggggggtga gtggagctgctcaaggcaaaggggccgtga caagctttgccgaactgataaagatacctc agctggatggaatttgtctatatttagcag gtggctagcaggaggctgataagcagggct ggggagggggcagtcctcataaatagtgag aacacaggacactgttcagtccctccttgg gtggcctgcttggccacc SP0493 cctgggctcctggcatctgctttatcggga 359 (SEQ ID ttctcaagagggacagctggtttatgttac NO: 450) aagcctgttccctgcatatctgctctggtt ttaaatagctttatctgagcagctggagga ccacatgagcttatatggcgtggggtactt gttcttttagccctgtgccgggcacctgcc aaaatagcagccaacaccccccattgtgtt gaagatacctcagctggatggaatttgtct atatttagcaggtggctagcaggaggctga taagcagggctggggagggggcagtcctca taaatagtgagaacacaggacactgttcag tccctccttgggtggcctgcttggccacc SP0494 aaacttaagtgctgaagatagcacttgcct 545 (SEQ ID ggttctattttagtaggtccctggcagcca NO: 451) gtcagcaagtgcagttgctcaagtgtgctt ttggatcattgagtttcgtgtactggccat atcaggacaaggagaggccatgggaaaaaa tagtccagcatctgatagtgtcaggtagtg ttatccctgtcagggtgacagttgaagtgt ttgagtaatagcagtgtcagcagatgccca gagtttaacatgtactcacttcaaaaggga cagctgatctaagtgctggatataaatacc cgctctggtatttggggttctcctctataa atacccgctctggtatttggggttggcagc tgttgcgggatcttgcagctgtcaggggag gggaggcgggggctgatgtcaggagggata caaatagtgccgacggctgggggccctgtc tcccctcgccgcatccactctccggccggc cgcctgcccgccgcctcctccgtgcgcccg ccagcctcgcccgcgccgtcaccgcggccg ccacc SP0495 gtcaccctctgcttccctgcatgggtcctg 567 (SEQ ID ttgccagggagaaagaatcctgaggcgagc NO: 452) gcccaggaagataaccaaggactcttttct gctcctctcacacctttgaagtgggggcct cttgaggcaaatcagcaagaatgtgactct tgcagctgagggtctgggggaggggggtga gtggagctgctcaaggcaaaggggccgtga caagctttgccgaactgatacccttcagat taaaaataactgaggtaagggcctgggtag gggaggtggtgtgagacgctcctgtctctc ctctatctgcccatcggccctttggggagg aggaatgtgcccaaggactaaaaaaaggcc atggagccagaggggcgagggcaacagacc tttcatgggcaaac cttggggccctgctgaagatacctcagctg gatggaatttgtctatatttagcaggtggc tagcaggaggctgataagcagggctgggga gggggcagtcctcataaatagtgagaacac aggacactgttcagtccctccttgggtggc ctgcttggccacc SP0496 cctgggctcctggcatctgctttatcggga 548 (SEQ ID ttctcaagagggacagctggtttatgttac NO: 453) aagcctgttccctgcatatctgctctggtt ttaaatagctttatctgagcagctggagga ccacatgagcttatatggcgtggggtactt gttcttttagccctgtgccgggcacctgcc aaaatagcagccaacaccccccattgtgtt gcccttcagattaaaaataactgaggtaag ggcctgggtaggggaggtggtgtgagacgc tcctgtctctcctctatctgcccatcggcc ctttggggaggaggaatgtgcccaaggact aaaaaaaggccatggagccagaggggcgag ggcaacagacctttcatgggcaaaccttgg ggccctgctgaagatacctcagctggatgg aatttgtctatatttagcaggtggctagca ggaggctgataagcagggctggggaggggg cagtcctcataaatagtgagaacacaggac actgttcagtccctccttgggtggcctgct tggccacc
TABLE-US-00012 TABLE 1C Further muscle-specific promoters NAME SEQUENCE LENGTH SP0437 caccgcggtggcggccgtccgccctcggat 340 (SEQ ID agctcgtttagacacccaaatatggcgacg NO: 478) gtaaacgagctattgggagttatttttaga gcgtaaacgagctattagttgcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctcggccggggcc gcattcctgggggccgggcggtgctcccgc ccgcctcgataaaaggctccggggccggcg gcggcccacgagctacccggaggagcggga ggcggccacc SP0438 caccgcggtggcggccgtccgccctcggat 365 (SEQ ID agctcgtttagacacccaaatatggcgacg NO: 479) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctcggccggggcc gcattcctgggggccgggcggtgctcccgc ccgcctcgataaaaggctccggggccggcg gcggcccacgagctacccggaggagcggga ggcgccaagctctagaactagtggatcccg ccacc SP0439 caccgcggtggcggccgtccgccctcggca 365 (SEQ ID ccatcctcacgacacccaaatatggcgacg NO: 480) gtaaacgagctattgggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctcggccggggcc gcattcctgggggccgggcggtgctcccgc ccgcctcgataaaaggctccggggccggcg gcggcccacgagctacccggaggagcggga ggcgccaagctctagaactagtggatcccg ccacc SP0440 gggccccacagcagctgggggcatttatgg 585 (SEQ ID gccttcctataaacttctgagagggtaact NO: 481) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcggaggaatggtggaca cccaaatatggcgacggttcctcacccgtc gccatatttgggtgtccgccctcggccggg gccgcattcctgggggccgggcggtgctcc cgcccgcctcgataaaaggctccggggccg gcggcggcccacgagctacccggaggagcg ggaggcgccgccacc SP0441 gggccccacagcagctgggggcatttatgg 546 (SEQ ID gccttcctataaacttctgagagggtaact NO: 482) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcgcccgtcgccatattt gggtgtccgccctcggccggggccgcattc ctgggggccgggcggtgctcccgcccgcct cgataaaaggctccggggccggcggcggcc cacgagctacccggaggagcgggaggcgcc gccacc SP0442 gggccccacagcagctgggggcatttatgg 585 (SEQ ID gccttcctataaacttctgagagggtaact NO: 483) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcgagctctataaatacc cgctctggtatttggggttttgaacccgtc gccatatttgggtgtccgccctcggccggg gccgcattcctgggggccgggcggtgctcc cgcccgcctcgataaaaggctccggggccg gcggcggcccacgagctacccggaggagcg ggaggcgccgccacc SP0443 ggccgtccgccctcggcaccatcctcacga 328 (SEQ ID cacccaaatatggcgacgggtgaggaatgg NO: 484) tggggagctatttttagagcgtaaacgagc tattagttgcagcaggtgttggcgctctaa aaatagctcccgggagctatttttagagcg gaggaatggtggacacccaaatatggcgac ggttcctcacccgtcgccatatttgggtgt ccgccctcggccggggccgcattcctgggg gccgggcggtgctcccgcccgcctcgataa aaggctccggggccggcggcggcccacgag ctacccggaggagcgggaggcggccacc SP0444 ggccgtccgccctcggcaccatcctcacga 328 (SEQ ID cacccaaatatggcgacgggtgaggaatgg NO: 485) tggggagctatttttagagcgtaaacgagc tattagttgcagcaggtgttggcgctctaa aaatagctcccgggagctatttttagagcg agctctataaatacccgctctggtatttgg ggttttgaacccgtcgccatatttgggtgt ccgccctcggccggggccgcattcctgggg gccgggcggtgctcccgcccgcctcgataa aaggctccggggccggcggcggcccacgag ctacccggaggagcgggaggcggccacc SP0445 acacccaaatatggcgacgggtgaggaatg 436 (SEQ ID gtggggagttatttttagagcggtgaggaa NO: 486) ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc gagctctataaatacccgctctggtatttg gggttttgaacccgtcgccatatttgggtg tccgccctataaatacccgctctggtattt ggggttctcctctataaatacccgctctgg tatttggggttggcagctgttgcgggatct tgcagctgtcaggggaggggaggcgggggc tgatgtcaggagggatacaaatagtgccga cggctgggggccctgtctcccctcgccgca tccactctccggccggccgcctgcccgccg cctcctccgtgcgcccgccagcctcgcccg cgccgtcaccgccacc SP0446 agctttgaggctgtgggcagctcagctgtc 464 (SEQ ID atgcgggcacacaggtgatgtaagacaata NO: 487) gctgtggagtcagctggcttccaaggtgcc tgggatcttttcgttctgcccttggctcct gccctaactggcaaaccccacatgttcccg gcgaagggccagctgtcccccgccagctag actcagcacttagtttaggaaccagtgagc aagtcagcccttggggcagcccatacaagg ccatggggctgggcaagctgcacgcctggg tccggggtgggcacggtgcccgggcaacga gctgaaagctcatctgctctcaggggcccc tccctggggacagcccctcctggctagtca caccctgtaggctcctctatataacccagg ggcacaggggctgccctcattctaccacca cctccacagcacagacagacactcaggagc cagccagcgccacc SP0447 ggccgtccgccctcgggacacccaaatatg 291 (SEQ ID gcgacgggggagttatttttagagcgggca NO: 488) ggcagcaggtgttggcgctctaaaaataac tcccgggagttatttttagagcggaggaat ggtggacacccaaatatggcgacggttcct cacccgtcgccatatttgggtgtccgccct cggccggggccgcattcctgggggccgggc ggtgctcccgcccgcctcgataaaaggctc cggggccggcggcggcccacgagctacccg gaggagcgggaggcggccacc SP0453 gggccccacagcagctgggggcatttatgg 761 (SEQ ID gccttcctataaacttctgagagggtaact NO: 489) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cctataaatacccgctctggtatttggggt tctcctctataaatacccgctctggtattt ggggttggcagctgttgcgggatcttgcag ctgtcaggggaggggaggcgggggctgatg tcaggagggatacaaatagtgccgacggct gggggccctgtctcccctcgccgcatccac tctccggccggccgcctgcccgccgcctcc tccgtgcgcccgccagcctcgcccgcgccg tcaccgccacc SP0454 gggccccacagcagctgggggcatttatgg 720 (SEQ ID gccttcctataaacttctgagagggtaact NO: 490) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcgagctctataaatacc cgctctggtatttggggttttgaacccgtc gccatatttgggtgtccgccctataaatac ccgctctggtatttggggttctcctctata aatacccgctctggtatttggggttggcag ctgttgcgggatcttgcagctgtcagggga ggggaggcgggggctgatgtcaggagggat acaaatagtgccgacggctgggggccctgt ctcccctcgccgcatccactctccggccgg ccgcctgcccgccgcctcctccgtgcgccc gccagcctcgcccgcgccgtcaccgccacc SP0455 ccacagcagctgggggcatttatgggcctt 551 (SEQ ID cctataaacttctgagagggtaactttatc NO: 491) ctgcttctttcagccaagtatcctcctcca aaacccgtgactcacagcacagccagtgtg ggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttct ctggtttctccaactgagtcctgaggtttg gcaccgcggtggcggccgtccgccctcggc accatcctcacgacacccaaatatggcgac gggtgaggaatggtggggagttatttttag agcggtgaggaaggtgggcaggcagcaggt gttggcgctctaaaaataactcccgggagt tatttttagagcggaggaatggtggacacc caaatatggcgacggttcctcacccgtcgc catatttgggtgtccgccctcggccggggc cgcattcctgggggccgggcggtgctcc cgcccgcctcgataaaaggctccggggcc ggcggcggcccacgagctacccggaggag cgggaggcggccacc SP0456 ccacagcagctgggggcatttatgggcctt 688 (SEQ ID cctataaacttctgagagggtaactttatc NO: 492) ctgcttctttcagccaagtatcctcctcca aaacccgtgactcacagcacagccagtgtg ggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttct ctggtttctccaactgagtcctgaggtttg gcaccgcggtggcggccgtccgccctcggc accatcctcacgacacccaaatatggcgac gggtgaggaatggtggggagttatttttag agcggtgaggaaggtgggcaggcagcaggt gttggcgctctaaaaataactcccgggagt tatttttagagcggaggaatggtggacacc caaatatggcgacggttcctcacccgtcgc catatttgggtgtccgccctataaataccc gctctggtatttggggttctcctctataaa tacccgctctggtatttggggttggcagct gttgcgggatcttgcagctgtcaggggagg ggaggcgggggctgatgtcaggagggatac aaatagtgccgacggctgggggccctgtct cccctcgccgcatccactctccggccggcc gcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcaccgccacc SP0457 ccccacagcagctgggggcatttatgggcc 621 (SEQ ID ttcctataaacttctgagagggtaacttta NO: 493) tcctgcttctttcagccaagtatcctcctc caaggcagtgtatactcttccataaacgag ctattagttatgaggtcaaacccgtgactc acagcacagccagtgtgggggagggggtgg ctgcctccaatacgtggcgcccagagtcag ctgttctggggccttctctggtttctccaa ctgagtcctgaggtttggtgacggaattcg gccgaacgggacaccgcggtggcggccgtc cgccctcggcaccatcctcacgacacccaa atatggcgacgggtgaggaatggtggggag ttatttttagagcggtgaggaaggtgggca ggcagcaggtgttggcgctctaaaaataac tcccgggagttatttttagagcggaggaat ggtggacacccaaatatggcgacggttcct cacccgtcgccatatttgggtgtccgccct cggccggggccgcattcctgggggccgggc ggtgctcccgcccgcctcgataaaaggctc cggggccggcggcggcccacgagctacccg gaggagcgggaggcggccacc SP0458 gggccccacagcagctgggggcatttatgg 759 (SEQ ID gccttcctataaacttctgagagggtaact NO: 494) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cctttctcctctataaatacccgctctggt atttggggttggcagctgttgctgccaggg agatggttgggttgacgggatcttgcagct gtcaggggaggggaggcgggggctgatgtc aggagggatacaaatagtgccgacggctgg gggccctgtctcccctcgccgcatccactc tccggccggccgcctgcccgccgcctcctc cgtgcgcccgccagcctcgcccgcgccgtc accgccacc SP0459 gggccccacagcagctgggggcatttatgg 837 (SEQ ID gccttcctataaacttctgagagggtaact NO: 495) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cctcatgttcccggcgaagggccagctgtc ccccgccagctagactcagcacttagttta ggaaccagtgagcaagtcagcccttggggc agcccatacaaggccatggggctgggcaag ctgcacgcctgggtccggggtgggcacggt gcccgggcaacgagctgaaagctcatctgc tctcaggggcccctccctggggacagcccc tcctggctagtcacaccctgtaggctcctc tatataacccaggggcacaggggctgccct cattctaccaccacctccacagcacagaca gacactcaggagccagccagcgccacc SP0460 caccgcggtggcggccgtccgccctcggca 298 (SEQ ID ccatcctcacgacacccaaatatggcgacg NO: 496) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcgcggccggggccgcattcc tgggggccgggcggtgctcccgcccgcctc gataaaaggctccggggccggcggcggccc acgagctacccggaggagcgggaggcgcca agctctagaactagtggatcccgccacc SP0461 caccgcggtggcggccgtccgccctcggca 365 (SEQ ID ccatcctcacgacacccaaatatggcgacg NO: 497) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcgaggcagtgtatactcttc cataaacgagctattagttatgaggtccgt agattgaaaagggtgacggcggccggggcc gcattcctgggggccgggcggtgctcccgc ccgcctcgataaaaggctccggggccggcg gcggcccacgagctacccggaggagcggga ggcgccaagctctagaactagtggatcccg ccacc SP0462 ctctataaatacccgctctggtatttgggg 356 (SEQ ID ttacacccaaatatggcgacgggtgaggaa NO: 498) tggtggggagttatttttagagcggtgagg aaggtgggcaggcagcaggtgttggcgctc taaaaataactcccgggagttatttttaga gcggaggaatggtggacacccaaatatggc gacggttcctcacccgtcgccatatttggg tgtccgccctcggccggggccgcattcctg ggggccgggcggtgctcccgcccgcctcga taaaaggctccggggccggcggcggcccac gagctacccggaggagcgggaggcgccaag ctctagaactagtggatcccgccacc SP0463 gggccccacagcagctgggggcatttatgg 772 (SEQ ID gccttcctataaacttctgagagggtaact NO: 499) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cctccactacgggtctaggctgcccatgta aggaggcaaggcctggggacacccgagatg cctggttataattaacccagacatgtggct gcccccccccccccaacacctgctgcctct aaaaataaccctgtccctggtggatcccct gcatgcgaagatcttcgaacaaggctgtgg gggactgagggcaggctgtaacaggcttgg gggccagggcttatacgtgcctgggactcc caaagtattactgttcgccacc SP0464 caccgcggtggcggccgtccgccctcggca 837 (SEQ ID ccatcctcacgacacccaaatatggcgacg NO: 500) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctgggccccacag cagctgggggcatttatgggccttcctata aacttctgagagggtaactttatcctgctt ctttcagccaagtatcctcctccagcagct ggtcacaaagctggttaatctcccagagtg ctcagcttaaaacccgtgactcacagcaca gccagtgtgggggagggggtggctgcctcc aatacgtggcgcccagagtcagctgttctg gggccttctctggtttctccaactgagtcc tgaggtttggggccttgtcttccttcctgg agtcatgttcccggcgaagggccagctgtc ccccgccagctagactcagcacttagttta ggaaccagtgagcaagtcagcccttggggc agcccatacaaggccatggggctgggcaag ctgcacgcctgggtccggggtgggcacggt gcccgggcaacgagctgaaagctcatctgc tctcaggggcccctccctggggacagcccc tcctggctagtcacaccctgtaggctcctc tatataacccaggggcacaggggctgccct cattctaccaccacctccacagcacagaca gacactcaggagccagccagcgccacc SP0465 caccgcggtggcggccgtccgccctcggca 772 (SEQ ID ccatcctcacgacacccaaatatggcgacg NO: 501) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctgggccccacag cagctgggggcatttatgggccttcctata aacttctgagagggtaactttatcctgctt ctttcagccaagtatcctcctccagcagct ggtcacaaagctggttaatctcccagagtg ctcagcttaaaacccgtgactcacagcaca gccagtgtgggggagggggtggctgcctcc aatacgtggcgcccagagtcagctgttctg gggccttctctggtttctccaactgagtcc tgaggtttggggccttgtcttccttcctgg agtccactacgggtctaggctgcccatgta aggaggcaaggcctggggacacccgagatg cctggttataattaacccagacatgtggct gcccccccccccccaacacctgctgcctct aaaaataaccctgtccctggtggatcccct gcatgcgaagatcttcgaacaaggctgtgg gggactgagggcaggctgtaacaggcttgg gggccagggcttatacgtgcctgggactcc caaagtattactgttcgccacc SP0466 caccgcggtggcggccgtccgccctcggca 764 (SEQ ID ccatcctcacgacacccaaatatggcgacg NO: 502) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctccacagcagct gggggcatttatgggccttcctataaactt ctgagagggtaactttatcctgcttctttc agccaagtatcctcctccaaaacccgtgac tcacagcacagccagtgtgggggagggggt ggctgcctccaatacgtggcgcccagagtc agctgttctggggccttctctggtttctcc aactgagtcctgaggtttggcatgttcccg gcgaagggccagctgtcccccgccagctag actcagcacttagtttaggaaccagtgagc aagtcagcccttggggcagcccatacaagg ccatggggctgggcaagctgcacgcctggg tccggggtgggcacggtgcccgggcaacga gctgaaagctcatctgctctcaggggcccc tccctggggacagcccctcctggctagtca caccctgtaggctcctctatataacccagg ggcacaggggctgccctcattctaccacca cctccacagcacagacagacactcaggagc cagccagcgccacc SP0467 gccactacgggtctaggctgcccatgtaag 671 (SEQ ID gaggcaaggcctggggacacccgagatgcc NO: 503) tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcc cgggagttatttttagagcggaggaatggt ggacacccaaatatggcgacggttcctcac ccgtcgccatatttgggtgtccgccctata aatacccgctctggtatttggggttctcct ctataaatacccgctctggtatttggggtt ggcagctgttgcgggatcttgcagctgtca ggggaggggaggcgggggctgatgtcagga gggatacaaatagtgccgacggctgggggc cctgtctcccctcgccgcatccactctccg gccggccgcctgcccgccgcctcctccgtg cgcccgccagcctcgcccgcgccgtcaccg ccacc SP0468 caccgcggtggcggccgtccgccctcggca 671 (SEQ ID ccatcctcacgacacccaaatatggcgacg NO: 504) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctgccactacggg tctaggctgcccatgtaaggaggcaaggcc tggggacacccgagatgcctggttataatt aacccagacatgtggctgcccccccccccc aacacctgctgcctgagcctcacccccacc ccggtgcctgggtcttaggctctgtacacc atggaggagaagctcgctctaaaaataacc ctgataaatacccgctctggtatttggggt tctcctctataaatacccgctctggtattt ggggttggcagctgttgcgggatcttgcag ctgtcaggggaggggaggcgggggctgatg tcaggagggatacaaatagtgccgacggct gggggccctgtctcccctcgccgcatccac tctccggccggccgcctgcccgccgcctcc tccgtgcgcccgccagcctcgcccgcgccg tcaccgccacc SP0469 ccacagcagctgggggcatttctgagaggg 506 (SEQ ID taactttatcctgcttctttcagccaagta NO: 505) ctcacagcacagccagtgtgggggaggggg tggctgcctccgtggcgcccagagtcagct gttctggggccttctctggtttctccaact gagtcctgaggtttggcaccgcggtggcgg ccgtccgccctcggcaccatcctcacgaca cccaaatatggcgacgggtgaggaatggtg gggagttatttttagagcggtgaggaaggt gggcaggcagcaggtgttggcgctctaaaa ataactcccgggagttatttttagagcgga ggaatggtggacacccaaatatggcgacgg ttcctcacccgtcgccatatttgggtgtcc gccctcggccggggccgcattcctgggggc cgggcggtgctcccgcccgcctcgataaaa ggctccggggccggcggcggcccacgagct acccggaggagcgggaggcggccacc SP0470 caccgcggtggcggccgtccgccctcggca 365 (SEQ ID ccatcctcacgacacccaaatatggcgacg NO: 506) ggtgaggaatggtggggataaacgagctat gcggtgaggaaggtgggcaggcagcaggtg ttggcgcatagctcgtttatcccgggataa acgagctatgcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctcggccggggcc gcattcctgggggccgggcggtgctcccgc ccgcctcgataaaaggctccggggccggcg gcggcccacgagctacccggaggagcggga ggcgccaagctctagaactagtggatcccg ccacc SP0471 caccgcggtggcggccgtccgccctcggca 624 (SEQ ID ccatcctcacgacacccaaatatggcgacg NO: 507) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctgggccccacag cagctgggggcatttatgggccttcctata aacttctgagagggtaactttatcctgctt ctttcagccaagtatcctcctccagcagct ggtcacaaagctggttaatctcccagagtg ctcagcttaaaacccgtgactcacagcaca gccagtgtgggggagggggtggctgcctcc aatacgtggcgcccagagtcagctgttctg gggccttctctggtttctccaactgagtcc tgaggtttggggccttgtcttccttcctgg agtcggccggggccgcattcctgggggccg ggcggtgctcccgcccgcctcgataaaagg ctccggggccggcggcggcccacgagctac ccggaggagcgggaggcggccacc SP0473 gggccccacagcagctgggggcatttatgg 718 (SEQ ID gccttcctataaacttctgagagggtaact NO: 508) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcgagctctataaatacc cgctctggtatttggggttttgaacccgtc gccatatttgggtgtccgccctttctcctc tataaatacccgctctggtatttggggttg gcagctgttgctgccagggagatggttggg ttgacgggatcttgcagctgtcaggggagg ggaggcgggggctgatgtcaggagggatac aaatagtgccgacggctgggggccctgtct cccctcgccgcatccactctccggccggcc gcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcaccgccacc SP0474 ccacagcagctgggggcatttctgagaggg 465 (SEQ ID taactttatcctgcttctttcagccaagta NO: 509) ctcacagcacagccagtgtgggggaggggg tggctgcctccgtggcgcccagagtcagct gttctggggccttctctggtttctccaact gagtcctgaggtttggacacccaaatatgg cgacgggtgaggaatggtggggagttattt ttagagcggtgaggaaggtgggcaggcagc aggtgttggcgctctaaaaataactcccgg gagttatttttagagcgagctctataaata cccgctctggtatttggggttttgaacccg tcgccatatttgggtgtccgccctcggccg gggccgcattcctgggggccgggcggtgct cccgcccgcctcgataaaaggctccggggc cggcggcggcccacgagctacccggaggag cgggaggcggccacc
TABLE-US-00013 TABLE 2 CRMs from promoters of Table 1 CRM NAME SEQUENCE CRM_ gggccccacagcagctgggggcatttatgg SP0020 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagt (SEQ ID NO: 138) CRM_ Gccactacgggtctaggctgcccatgtaag SP0033 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 139) CRM_ Taagtccgggcagggtcctgtccataaaag SP0038 gcttttcccgggccggctccccgccggcag cgtgccccgccccggcccgctccatctcca aagcatgcagagaatgtctcggcagccccg gtagactgctccaacttggtgtctttcccc aaatatggagcctgtgtggagtcactgggg gagccgggggtggggagcggagccggcttc ctctag (SEQ ID NO: 141) CRM_ Ctgagattttcctagcattttgtgtttcat SP0040 gactaaatatggtttgtgtttcaagaccaa tgagctgggaactgtactgttctttcccct cccatcaactcatttttggcacaagacgca ctctagtcagttggagcaaatcccctgacc cgggtgcagttccaaaagcagacactcgag cgtgttttacctaattaggaaatgctttgc tccaaaccgaactgctcattcaggttagag aggag (SEQ ID NO: 142) CRM_ Ctgagattttcctagcattttgtgtttcat SP0042 gactaaatatggtttgtgtttcaagaccaa tgagctgggaactgtactgttctttcccct cccatcaactcatttttggcacaagacgca ctctagtcagttggagcaaatcccctgacc cgggtgcagttccaaaagcagacactcgag cgtgttttacctaattaggaaatgctttgc tccaaaccgaactgctcattcaggttagag aggag (SEQ ID NO: 143) CRM_ Gggccccacagcagctgggggcatttatgg SP0051 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagt (SEQ ID NO: 144) CRM_ Ctctgtctcctcaggtgcctggctcccagt SP0057 ccccagaacgcctctcctgtaccttgcttc ctagctgggcctttccttctcctctataaa taccagctctggtatttcgccttggcagct gttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtgg tgtgagtgggtgtgggcggtgtgagtaggg ggatgaatcagagagggggccaccgcggtg gcggccgtccgccctcggcaccatcctcac gacacccaaatatggcgacgggtgaggaat ggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctct aaaaataactcccgggagttatttttagag cggaggaatggtggacacccaaatatggcg acggttcctcacccgtcgccatatttgggt gtccgccct (SEQ ID NO: 145) CRM_ Ccttgcctgactattggcaggcggacctgg SP0058 tggtcagacctcagtgatcctcagggacca gtgaatatttcaggctggggctgagcatca cctgctcccttggccccacttatagggcaa aggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgct ctggccccacctcgccctctcccctacttg gaagttcctttcctgaaccactgactgcca aagcttgagggattaaataaatcatctggc ccaa (SEQ ID NO: 146) CRM_ Ccttgcctgactattggcaggcggacctgg SP0061 tggtcagacctcagtgatcctcagggacca gtgaatatttcaggctggggctgagcatca cctgctcccttggccccacttatagggcaa aggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgct ctggccccacctcgccctctcccctacttg gaagttcctttcctgaaccactgactgcca aagcttgagggattaaataaatcatctggc ccaa (SEQ ID NO: 147) CRM_ Ctgtgtgtttctgtggctgagtcagatgga SP0062 ggagtcctcatgtttcactgcttagcagtt tttgtccttcctagtacccgttcccagccc acaagatgcagaaagagctgttgctagcgt gagttatttttgtcagctgagtcaccacgc cagaaagcaagaaatgacccgctttatgtc tgctctgaggagctggaacc (SEQ ID NO: 148) CRM_ Tacatcatttacctagaaaagaggacagct SP0064 gtcctttcccaaagctccggtgaccctgcc ccgcccagtgtgactagcccaggttggtga ttctgatctgttgccaaaccaaactggctc cccggggagccatttggtaatgttccctgg agtcatttccttgcgaagcattccttttcg gtgagaggacatttttttcatccctgataa acaaccacagcctgcgccag (SEQ ID NO: 149) CRM_ Taagtgtgatgcacagtgcttgcattttct SP0065 tgatacgttagtcatatgagagctgacaaa gaaggaaaaagagcagcgatgtggtgcaat attaacaggcagctgtcccctggcttcccg atacgtgggatgactcgcattgctgagcgg tgtggtcactgccaaaggaatgaccctctc acatttcttcctgattcgcatacgccgcgg c (SEQ ID NO: 150) CRM_ Ctctgtctcctcaggtgcctggctcccagt SP0066 ccccagaacgcctctcctgtaccttgcttc ctagctgggcctttccttctcctctataaa taccagctctggtatttcgccttggcagct gttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtgg tgtgagtgggtgtgggcggtgtgagtaggg ggatgaatcagagagggggc (SEQ ID NO: 151) CRM_ Cccttcagattaaaaataactgaggtaagg SP0067 gcctgggtaggggaggtggtgtgagacgct cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctg (SEQ ID NO: 152) CRM_ Gccactacgggtctaggctgcccatgtaag SP0068 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 153) CRM_ Ccttgcctgactattggcaggcggacctgg SP0069 tggtcagacctcagtgatcctcagggacca gtgaatatttcaggctggggctgagcatca cctgctcccttggccccacttatagggcaa aggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgct ctggccccacctcgccctctcccctacttg gaagttcctttcctgaaccactgactgcca aagcttgagggattaaataaatcatctggc ccaa (SEQ ID NO: 154) CRM_ Ctgtgtgtttctgtggctgagtcagatgga SP0070 ggagtcctcatgtttcactgcttagcagtt tttgtccttcctagtacccgttcccagccc acaagatgcagaaagagctgttgctagcgt gagttatttttgtcagctgagtcaccacgc cagaaagcaagaaatgacccgctttatgtc tgctctgaggagctggaacc (SEQ ID NO: 155) CRM_ Gcgccctgatgaatatgcatcgcggcgcgc SP0071 ccgcccccggctcctcctttcggtttcctt cccgccgccaggcggaagcgaagagccgcg cttcccgcgcgcccaggccggccgtggtag ggtggggcggggcgggccgcgagccggaga aagagaaagc (SEQ ID NO: 156) CRM_ Cccttcagattaaaaataactgaggtaagg SP0075 gcctgggtaggggaggtggtgtgagacgct cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctg (SEQ ID NO: 157) CRM_ Gccactacgggtctaggctgcccatgtaag SP0076 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 158) CRM_ Gggccccacagcagctgggggcatttatgg SP0132 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagt (SEQ ID NO: 159) CRM_ Gggccccacagcagctgggggcatttatgg SP0133 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagt (SEQ ID NO: 160) CRM_ Gggccccacagcagctgggggcatttatgg SP0134 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cct (SEQ ID NO: 161) CRM_ Gggccccacagcagctgggggcatttatgg SP0136 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagt (SEQ ID NO: 162) CRM_ Ctagactagcatgctgcccatgtaaggagg SP0146 caaggcctggggacacccgagatgcctggt tataattaacccagacatgtggctgccccc ccccccccaacacctgctgcctctaaaaat aaccctgc (SEQ ID NO: 163) CRM_ Gggccccacagcagctgggggcatttatgg SP0147 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagt (SEQ ID NO: 164) CRM_ Gggccccacagcagctgggggcatttatgg SP0148 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagt (SEQ ID NO: 165) CRM_ Gcgccctgatgaatatgcatcgcggcgcgc SP0150 ccgcccccggctcctcctttcggtttcctt cccgccgccaggcggaagcgaagagccgcg cttcccgcgcgcccaggccggccgtggtag ggtggggcggggcgggccgcgagccggaga aagagaaagc (SEQ ID NO: 166) CRM_ Gccactacgggtctaggctgcccatgtaag SP0153 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 167) CRM_ Gccactacgggtctaggctgcccatgtaag SP0155 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgttctcctctataaata cccgctctggtatttggggttggcagctgt tgttctcctctataaatacccgctctggta tttggggttggcagctgttg (SEQ ID NO: 168) CRM_ Gccactacgggtctaggctgcccatgtaag SP0156 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctggggccccacagcagct gggggcatttatgggccttcctataaactt ctgagagggtaactttatcctgcttctttc agccaagtatcctcctccagcagctggtca caaagctg gttaatctcccagagtgctcagcttaaaac ccgtgactcacagcacagccagtgtggggg agggggtggctgcctccaatacgtggcgcc cagagtcagctgttctggggccttctctgg tttctccaactgagtcctgaggtttggggc cttgtcttccttcctggagt (SEQ ID NO: 169) CRM_ Ctagactagcatgctgcccatgtaaggagg SP0157 caaggcctggggacacccgagatgcctggt tataattaacccagacatgtggctgccccc ccccccccaacacctgctgcctctaaaaat aaccctgc (SEQ ID NO: 170) CRM_ Gggccccacagcagctgggggcatttatgg SP0158 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtctgagattttcctagc attttgtgtttcatgactaaatatggtttg tgtttcaagaccaatgagctgggaactgta ctgttctttcccctcccatcaactcatttt tggcacaagacgcactctagtcagttggag caaatcccctgacccgggtgcagttccaaa agcagacactcgagcgtgttttacctaatt aggaaatgctttgctccaaaccgaactgct cattcaggttagagaggag (SEQ ID NO: 171) CRM_ Gccactacgggtctaggctgcccatgtaag SP0159 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgctgagattttcctagc attttgtgtttcatgactaaatatggtttg tgtttcaagaccaatgagctgggaactgta ctgttctttcccctcccatcaactcatttt tggcacaagacgcactctagtcagttggag caaatcccctgacccgggtgcagttccaaa agcagacactcgagcgtgttttacctaatt aggaaatgctttgctccaaaccgaactgct cattcaggttagagaggag (SEQ ID NO: 172) CRM_ Gccactacgggtctaggctgcccatgtaag SP0160 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgtaagtccgggcagggt cctgtccataaaaggcttttcccgggccgg ctccccgccggcagcgtgccccgccccggc ccgctccatctccaaagcatgcagagaatg tctcggcagccccggtagactgctccaact tggtgtctttccccaaatatggagcctgtg tggagtcactgggggagccgggggtgggga gcggagccggcttcctctag (SEQ ID NO: 173) CRM_ Gggccccacagcagctgggggcatttatgg SP0161 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtctgagattttcctagc attttgtgtttcatgactaaatatggtttg tgtttcaagaccaatgagctgggaactgta ctgttctttcccctcccatcaactcatttt tggcacaagacgcactctagtcagttggag caaatcccctgacccgggtgcagttccaaa agcagacactcgagcgtgttttacctaatt aggaaatgctttgctccaaaccgaactgct cattcaggttagagaggag (SEQ ID NO: 174) CRM_ Gccactacgggtctaggctgcccatgtaag SP0162 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgctgagattttcctagc attttgtgtttcatgactaaatatggtttg tgtttcaagaccaatgagctgggaactgta ctgttctttcccctcccatcaactcatttt tggcacaagacgcactctagtcagttggag caaatcccctgacccgggtgcagttccaaa agcagacactcgagcgtgttttacctaatt aggaaatgctttgctccaaaccgaactgct cattcaggttagagaggag (SEQ ID NO: 175) CRM_ Gccactacgggtctaggctgcccatgtaag SP0163 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgtaagtccgggcagggt cctgtccataaaaggcttttcccgggccgg ctccccgccggcagcgtgccccgccccggc ccgctccatctccaaagcatgcagagaatg tctcggcagccccggtagactgctccaact tggtgtctttccccaaatatggagcctgtg tggagtcactgggggagccgggggtgggga gcggagccggcttcctctag (SEQ ID NO: 176) CRM_ Cccacccatgcctcctcaggtaccccctgc SP0164 cccccacagctcctctcctgtgccttgttt cccagccatgcgttctcctctataaatacc cgctctggtatttggggttggcagctgttg ctgccagggagatggttgggttgacatgcg gctcctgacaaaacacaaacccctggtgtg tgtgggcgtgggtggtgtgagtagggggat gaatcagggagggggcggggggggccccac agcagctgggggcatttatgggccttccta taaacttctgagagggtaactttatcctgc ttctttcagccaagtatcctcctccagcag ctggtcacaaagctggttaatctcccagag tgctcagcttaaaacccgtgactcacagca cagccagtgtgggggagggggtggctgcct ccaatacgtggcgcccagagtcagctgttc tggggccttctctggtttctccaactgagt cctgaggtttggggccttgtcttccttcct ggagt (SEQ ID NO: 177) CRM_ Cccacccatgcctcctcaggtaccccctgc SP0165 cccccacagctcctctcctgtgccttgttt cccagccatgcgttctcctctataaatacc cgctctggtatttggggttggcagctgttg ctgccagggagatggttgggttgacatgcg gctcctgacaaaacacaaacccctggtgtg tgtgggcgtgggtggtgtgagtagggggat gaatcagggagggggcggggg (SEQ ID NO: 178) CRM_ Caccgcggtggcggccgtccgccctcggca SP0166 ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctcggccggggcc (SEQ ID NO: 179) CRM_ Caccgcggtggcggccgtccgccctcggca SP0170 ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctcggccggggcc (SEQ ID NO: 180) CRM_ Gtttcttagcagctgctgctgtgtccaagg SP0171 cttggaattgctgtggtgaatctaaaactg tctcagtagtggtgagctgacctcacccaa gttcaaagccctactctgcctgatcctttt ttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcgg (SEQ ID NO: 181) CRM_ Gtttcttagcagctgctgctgtgtccaagg SP0173 cttggaattgctgtggtgaatctaaaactg tctcagtagtggtgagctgacctcacccaa gttcaaagccctactctgcctgatcctttt ttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaag gcctggggacacccgagatgcctggttata attaacccagacatgtggctgccccccccc cccaacacctgctgcctgagcctcaccccc accccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaata accctg (SEQ ID NO: 182) CRM_ Gggccccacagcagctgggggcatttatgg SP0227 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagt (SEQ ID NO: 183) CRM_ Gggccccacagcagctgggggcatttatgg SP0228 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtctctgtctcctcaggt gcctggctcccagtccccagaacgcctctc ctgtaccttgcttcctagctgggcctttcc ttctcctctataaataccagctctggtatt tcgccttggcagctgttgctgctagggaga cggctggcttgacatgcatctcctgacaaa acacaaacccgtggtgtgagtgggtgtggg cggtgtgagtagggggatgaatcagagagg gggccaccgcggtggcggccgtccgccctc ggcaccatcctcacgacacccaaatatggc gacgggtgaggaatggtggggagttatttt tagagcggtgaggaaggtgggcaggcagca ggtgttggcgctctaaaaataactcccggg agttatttttagagcggaggaatggtggac acccaaatatggcgacggttcctcacccgt cgccatatttgggtgtccgccct (SEQ ID NO: 184) CRM_ Gggccccacagcagctgggggcatttatgg SP0229 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtctctgtctcctcaggt gcctggctcccagtccccagaacgcctctc ctgtaccttgcttcctagctgggcctttcc ttctcctctataaataccagctctggtatt tcgccttggcagctgttgctgctagggaga cggctggcttgacatgcatctcctgacaaa acacaaacccgtggtgtgagtgggtgtggg cggtgtgagtagggggatgaatcagagagg gggccaccgcggtggcggccgtccgccctc ggcaccatcctcacgacacccaaatatggc gacgggtgaggaatggtggggagttatttt tagagcggtgaggaaggtgggcaggcagca ggtgttggcgctctaaaaataactcccggg agttatttttagagcggaggaatggtggac acccaaatatggcgacggttcctcacccgt cgccatatttgggtgtccgccct (SEQ ID NO: 185) CRM_ Gggccccacagcagctgggggcatttatgg SP0230 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtatcaagcttggtacgg gccccacagcagctgggggcatttatgggc cttcctataaacttctgagagggtaacttt atcctgcttctttcagccaagtatcctcct ccagcagctggtcacaaagctggttaatct cccagagtgctcagcttaaaacccgtgact cacagcacagccagtgtgggggagggggtg gctgcctccaatacgtggcgcccagagtca gctgttctggggccttctctggtttctcca actgagtcctgaggtttggggccttgtctt ccttcctggagtcaccgcggtggcggccgt ccgccctcggcaccatcctcacgacaccca aatatggcgacgggtgaggaatggtgggga gttatttttagagcggtgaggaaggtgggc aggcagcaggtgttggcgctctaaaaataa ctcccgggagttatttttagagcggaggaa tggtggacacccaaatatggcgacggttcc tcacccgtcgccatatttgggtgtccgccc t (SEQ ID NO: 186) CRM_ Gggccccacagcagctgggggcatttatgg SP0231 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cct (SEQ ID NO: 187) CRM_ Gccactacgggtctaggctgcccatgtaag SP0232 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gca ggcagcaggtgttggcgctctaaaaataac tcccgggagttatttttagagcggaggaat ggtggacacccaaatatggcgacggttcct cacccgtcgccatatttgggtgtccgccct (SEQ ID NO: 188) CRM_ Gtttcttagcagctgctgctgtgtccaagg SP0257 cttggaattgctgtggtgaatctaaaactg tctcagtagtggtgagctgacctcacccaa gttcaaagccctactctgcctgatcctttt ttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaag gcctggggacacccgagatgcctggttata attaacccagacatgtggctgccccccccc cccaacacctgctgcctgagcctcaccccc accccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaata accctg (SEQ ID NO: 189) CRM_ Gtttcttagcagctgctgctgtgtccaagg SP0262 cttggaattgctgtggtgaatctaaaactg tctcagtagtggtgagctgacctcacccaa gttcaaagccctactctgcctgatcctttt ttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaag gcctggggacacccgagatgcctggttata attaacccagacatgtggctgccccccccc cccaacacctgctgcctgagcctcaccccc accccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaata accctg (SEQ ID NO: 190) CRM_ Gccactacgggtctaggctgcccatgtaag SP0264 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 191) CRM_ Gtttcttagcagctgctgctgtgtccaagg SP0265 cttggaattgctgtggtgaatctaaaactg tctcagtagtggtgagctgacctcacccaa gttcaaagccctactctgcctgatcctttt ttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcgg (SEQ ID NO: 192) CRM_ Gtttcttagcagctgctgctgtgtccaagg SP0266 cttggaattgctgtggtgaatctaaaactg tctcagtagtggtgagctgacctcacccaa gttcaaagccctactctgcctgatcctttt ttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaag gcctggggacacccgagatgcctggttata attaacccagacatgtggctgccccccccc cccaacacctgctgcctgagcctcaccccc accccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaata accctg (SEQ ID NO: 193) CRM_ cccttcagattaaaaataactgaggtaagg SP0267 gcctgggtaggggaggtggtgtgagacgct cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctgcaccgcggtggcggccgtccg ccctcggcaccatcctcacgacacccaaat atggcgacgggtgaggaatggtggggagtt atttttagagcggtgaggaaggtgggcagg cagcaggtgttggcgctctaaaaataactc ccgggagttatttttagagcggaggaatgg tggacacccaaatatggcgacggttcctca cccgtcgccatatttgggtgtccgccct (SEQ ID NO: 194) CRM_ Gccactacgggtctaggctgcccatgtaag SP0268 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctggtttcttagcagctgc tgctgtgtccaaggcttggaattgctgtgg tgaatctaaaactgtctcagtagtggtgag ctgacctcacccaagttcaaagccctactc tgcctgatccttttttcctgagcctcagag ctaaaatgcccccgagctctttcctattgg ctggaaagacgaattgaagttcccttgccc atgttaggaggtgtacgcctcctgaactaa agatagaaacagctggcccttccaggcagc taaaagcctccagactaagaggtgttcccc attcgg (SEQ ID NO: 195) CRM_ Gccactacgggtctaggctgcccatgtaag SP0270 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgtcaaagccctactctg cctgatccttttttcctgagcctcagagct aaaatgcccccgagctctttcctattggct ggaaagacgaattgaagttcccttgcccat gttaggaggtgtacgcctcctgaactaaag atagaaacagctggcccttccaggcagcta aaagcctccagactaagaggtgttccccat tcgg (SEQ ID NO: 196) CRM_ Gccactacgggtctaggctgcccatgtaag SP0271 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 197) CRM_ gggccccacagcagctgggggcatttatgg SP0279 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cct (SEQ ID NO: 198) CRM_ Gtttcttagcagctgctgctgtgtccaagg SP0305 cttggaattgctgtggtgaatctaaaactg tctcagtagtggtgagctgacctcacccaa gttcaaagccctactctgcctgatcctttt ttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaag gcctggggacacccgagatgcctggttata attaacccagacatgtggctgccccccccc cccaacacctgctgcctgagcctcaccccc accccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaata accctg (SEQ ID NO: 199) CRM_ Ctctgtctcctcaggtgcctggctcccagt SP0306 ccccagaacgcctctcctgtaccttgcttc ctagctgggcctttccttctcctctataaa taccagctctggtatttcgccttggcagct gttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtgg tgtgagtgggtgtgggcggtgtgagtaggg ggatgaatcagagagggggcgccactacgg gtctaggctgcccatgtaaggaggcaaggc ctggggacacccgagatgcctggttataat taacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccac cccggtgcctgggtcttaggctctgtacac catggaggagaagctcgctctaaaaataac cctg (SEQ ID NO: 200) CRM_ Gggccccacagcagctgggggcatttatgg SP0307 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtgccactacgggtctag gctgcccatgtaaggaggcaaggcctgggg acacccgagatgcctggttataattaaccc agacatgtggctgccccccccccccaacac ctgctgcctgagcctcacccccaccccggt gcctgggtcttaggctctgtacaccatgga ggagaagctcgctctaaaaataaccctg (SEQ ID NO: 201) CRM_ Gccactacgggtctaggctgcccatgtaag SP0309 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctggccactacgggtctag gctgcccatgtaaggaggcaaggcctgggg acacccgagatgcctggttataattaaccc agacatgtggctgccccccccccccaacac ctgctgcctgagcctcacccccaccccggt gcctgggtcttaggctctgtacaccatgga ggagaagctcgctctaaaaataaccctg (SEQ ID NO: 202) CRM_ Gccactacgggtctaggctgcccatgtaag SP0310 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 203) CRM_ Gccactacgggtctaggctgcccatgtaag SP0311 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgttctcctctataaata cccgctctggtatttggggttggcagctgt tg (SEQ ID NO: 204) CRM_ Cccacccatgcctcctcaggtaccccctgc SP0312 cccccacagctcctctcctgtgccttgttt cccagccatgcgttctcctctataaatacc cgctctggtatttggggttggcagctgttg ctgccagggagatggttgggttgacatgcg gctcctgacaaaacacaaacccctggtgtg tgtgggcgtgggtggtgtgagtagggggat gaatcagggagggggcggggggccactacg ggtctaggctgcccatgtaaggaggcaagg cctggggacacccgagatgcctggttataa ttaacccagacatgtggctgcccccccccc ccaacacctgctgcctgagcctcaccccca ccccggtgcctgggtcttaggctctgtaca ccatggaggagaagctcgctctaaaaataa ccctg (SEQ ID NO: 205) CRM_ Gccactacgggtctaggctgcccatgtaag SP0313 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgcccctgccccccacag ctcctctcctgtgccttgtttcccagccat gcgttctcctctataaatacccgctctggt atttggggttggcagctgttgctgccaggg agatggttgggttgacatg (SEQ ID NO: 206) CRM_ Gccactacgggtctaggctgcccatgtaag SP0314 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgctctataaatacccgc tctggtatttggggttctctataaataccc gctctggtatttggggtt (SEQ ID NO: 207) CRM_ Ctagactagcatgctgcccatgtaaggagg SP0315 caaggcctggggacacccgagatgcctggt tataattaacccagacatgtggctgccccc ccccccccaacacctgctgcctctaaaaat aaccctgc (SEQ ID NO: 208) CRM_ Ctagactagcatgctgcccatgtaaggagg SP0316 caaggcctggggacacccgagatgcctggt tataattaacccagacatgtggctgccccc ccccccccaacacctgctgcctctaaaaat aaccctgc (SEQ ID NO: 209) CRM_ gtttcttagcagctgctgctgtgtccaagg SP0320 cttggaattgctgtggtgaatctaaaactg tctcagtagtggtgagctgacctcacccaa gttcaaagccctactctgcctgatcctttt ttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcgggccactac gggtctaggctgcccatgtaaggaggcaag gcctggggacacccgagatgcctggttata attaacccagacatgtggctgccccccccc cccaacacctgctgcctgagcctcaccccc accccggtgcctgggtcttaggctctgtac accatggaggagaagctcgctctaaaaata accctg (SEQ ID NO: 210) CRM_ Agactggggcaggtgcaggctggattgggt SP0322 ttccagaggctatatatataaaggctgccg ggagccccagggccgctccctgagggcaca acactgtgggggcccagccaggcccacatt cctttccagaggccagctctccatttatag cccctgggcagagcagccaccgcggtggcg gccgtccgccctcggcaccatcctcacgac acccaaatatggcgacgggtgaggaatggt ggggagttatttttagagcggtgaggaagg tgggcaggcagcaggtgttggcgctctaaa aataactcccgggagttatttttagagcgg aggaatggtggacacccaaatatggcgacg gttcctcacccgtcgccatatttgggtgtc cgccctcggccggggcc (SEQ ID NO: 211) CRM_ Agactggggcaggtgcaggctggattgggt SP0323 ttccagaggctatatatataaaggctgccg ggagcccacattcctttccagaggccagct ctccatttatagcccctgggcagagcagcc accgcggtggcggccgtccgccctcggcac catcctcacgacacccaaatatggcgacgg gtgaggaatggtggggagttatttttagag cggtgaggaaggtgggcaggcagcaggtgt tggcgctctaaaaataactcccgggagtta tttttagagcggaggaatggtggacaccca aatatggcgacggttcctcacccgtcgcca tatttgggtgtccgccctcggccggggcc (SEQ ID NO: 212) CRM_ Agactggggcaggtgcaggctggattgggt SP0324 ttccagaggctatatatataaaggctgccg ggagccccagggccgctccctgagggcaca acactgtgggggcccagccaggcccacatt cctttccagaggccagctctccatttatag cccctgggcagagcagc (SEQ ID NO: 213) CRM_ Agactggggcaggtgcaggctggattgggt SP0325 ttccagaggctatatatataaaggctgccg ggagccccagggccgctccctgagggcaca acactgtgggggcccagccaggcccacatt cctttccagaggccagctctccatttatag cccctgggcagagcagc (SEQ ID NO: 214) CRM_ Caccgcggtggcggccgtccgccctcggca SP0326 ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccct (SEQ ID NO: 215) CRM_ Agactggggcaggtgcaggctggattgggt SP0327 ttccagaggctatatatataaaggctgccg ggagccccagggccgctccctgagggcaca acactgtgggggcccagccaggcccacatt cctttccagaggccagctctccatttatag cccctgggcagagcagccaccgcggtggcg gccgtccgccctcggcaccatcctcacgac acccaaatatggcgacgggtgaggaatggt ggggagttatttttagagcggtgaggaagg tgggcaggcagcaggtgttggcgctctaaa aataactcccgggagttatttttagagcgg aggaatggtggacacccaaatatggcgacg gttcctcacccgtcgccatatttgggtgtc cgccct (SEQ ID NO: 216) CRM_ gggccccacagcagctgggggcatttatgg SP0328 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtagactggggcaggtgc aggctggattgggtttccagaggctatata tataaaggctgccgggagccccagggccgc tccctgagggcacaacactgtgggggccca gccaggcccacattcctttccagaggccag ctctccatttatagcccctgggcagagcag ccaccgcggtggcggccgtccgccctcggc accatcctcacgacacccaaatatggcgac gggtgaggaatggtggggagttatttttag agcggtgaggaaggtgggcaggcagcaggt gttggcgctctaaaaataactcccgggagt tatttttagagcggaggaatggtggacacc caaatatggcgacggttcctcacccgtcgc catatttgggtgtccgccct (SEQ ID NO: 217) CRM_ Acacccaaatatggcgacgggtgaggaatg SP0329 gtggggagttatttttagagcggtgaggaa ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc ggaggaatggtggacacccaaatatggcga cggttcctcacccgtcgccatatttgggtg tccgccct (SEQ ID NO: 218) CRM_ Caccgcggtggcggccgtccgccctcggca SP0330 ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagttatttttaga gcgtaaacgagctattagttgcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccct (SEQ ID NO: 219) CRM_ Caccgcggtggcggccgtccgccctcggca SP0331 ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcgaggtaaacgagctattag ttatgaggtccgtagattgaacccgtcgcc atatttgggtgtccgccct (SEQ ID NO: 220) CRM_ gccactacgggtctaggctgcccatgtaag SP0332 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cct (SEQ ID NO: 221) CRM_ Gccactacgggtctaggctgcccatgtaag SP0333 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 222) CRM_ Gccactacgggtctaggctgcccatgtaag SP0334 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 223) CRM_ Gccactacgggtctaggctgcccatgtaag SP0335 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 224) CRM_ Tcaaagccctactctgcctgatcctttttt SP0336 cctgagcctcagagctaaaatgcccccgag ctctttcctattggctggaaagacgaattg aagttcccttgcccatgttaggaggtgtac gcctcctgaactaaagatagaaacagctgg cccttccaggcagctaaaagcctccagact aagaggtgttccccattcgg (SEQ ID NO: 140) CRM_ Gccactacgggtctaggctgcccatgtaag SP0337 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgtcaaagccctactctg cctgatccttttttcctgagcctcagagct aaaatgcccccgagctctttcctattggct ggaaagacgaattgaagttcccttgcccat gttaggaggtgtacgcctcctgaactaaag atagaaacagctggcccttccaggcagcta aaagcctccagactaagaggtgttccccat tcgg (SEQ ID NO: 225) CRM_ Agactggggcaggtgcaggctggattgggt SP0338 ttccagaggctatatatataaaggctgccg ggagccccagggccgctccctgagggcaca acactgtgggggcccagccaggcccacatt cctttccagaggccagctctccatttatag cccctgggcagagcagcgccactacgggtc taggctgcccatgtaaggaggcaaggcctg gggacacccgagatgcctggttataattaa cccagacatgtggctgccccccccccccaa cacctgctgcctgagcctcacccccacccc ggtgcctgggtcttaggctctgtacaccat ggaggagaagctcgctctaaaaataaccct gtcaaagccctactctgcctgatccttttt tcctgagcctcagagctaaaatgcccccga gctctttcctattggctggaaagacgaatt gaagttcccttgcccatgttaggaggtgta cgcctcctgaactaaagatagaaacagctg gcccttccaggcagctaaaagcctccagac taagaggtgttccccattcgg (SEQ ID NO: 226) CRM_ Gccactacgggtctaggctgcccatgtaag SP0339 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgttctcctctataaata cccgctctggtatttggggttggcagctgt tgtcaaagccctactctgcctgatcctttt ttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcgg (SEQ ID NO: 227) CRM_ Gccactacgggtctaggctgcccatgtaag SP0340 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgcccggcagacgctcct tatacggcccggcctcgctcacctgggccg cggccaggagcgccttctttgggcagcgcc gggccggggccgcgccgggcccgacaccca aatatggcgacggccggggccgcattcctg ggggccgggcggcgctcccgcccgcctcga taaaaggctccggggccggcggcggcccac gagctacccggaggagcgggag (SEQ ID NO: 228) CRM_ Gccactacgggtctaggctgcccatgtaag SP0341 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgtcaaagccctactctg cctgatccttttttcctgagcctcagagct aaaatgcccccgagctctttcctattggct ggaaagacgaattgaagttcccttgcccat gttaggaggtgtacgcctcctgaactaaag atagaaacagctggcccttccaggcagcta aaagcctccagactaagaggtgttccccat tcgg (SEQ ID NO: 229) CRM_ Agactggggcaggtgcaggctggattgggt SP0342 ttccagaggctatatatataaaggctgccg ggagccccagggccgctccctgagggcaca acactgtgggggcccagccaggcccacatt cctttccagaggccagctctccatttatag cccctgggcagagcagc (SEQ ID NO: 230) CRM_ Gccactacgggtctaggctgcccatgtaag SP0343 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg (SEQ ID NO: 231) CRM_ Gggccccacagcagctgggggcatttatgg SP0345 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cct (SEQ ID NO: 232) CRM_ Agactggggcaggtgcaggctggattgggt SP0346 ttccagaggctatatatataaaggctgccg ggagccccagggccgctccctgagggcaca acactgtgggggcccagccaggcccacatt cctttccagaggccagctctccatttatag cccctgggcagagcagccaccgcggtggcg gccgtccgccctcggcaccatcctcacgac acccaaatatggcgacgggtgaggaatggt ggggagttatttttagagcggtgaggaagg tgggcaggcagcaggtgttggcgctctaaa aataactcccgggagttatttttagagcgg aggaatggtggacacccaaatatggcgacg gttcctcacccgtcgccatatttgggtgtc cgccct (SEQ ID NO: 233) CRM_ Ctctgtctcctcaggtgcctggctcccagt SP0347 ccccagaacgcctctcctgtaccttgcttc ctagctgggcctttccttctcctctataaa taccagctctggtatttcgccttggcagct gttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtgg tgtgagtgggtgtgggcggtgtgagtaggg ggatgaatcagagagggggcctagact agcatgctgcccatgtaaggaggcaaggcc tggggacacccgagatgcctggttataatt aacccagacatgtggctgcccccccccccc caacacctgctgcctctaaaaataaccctg c (SEQ ID NO: 234) CRM_ Ctctgtctcctcaggtgcctggctgcttcc SP0348 tagctgggcctttccttctcctctataaat accagctctggtatttcgccttggcagctg ttgctgctagggagacggctggcttgacat gcatctcctgacaaaacacaaacccgtggt gtgagtgggtgtgggcggtgtgagtagggg gatgaatcagagagggggcctagactagca tgctgcccatgtaaggaggcaaggcctggg gacacccgagatgcctggttataattaacc cagacatgtggctgcccccccccccccaac acctgctgcctctaaaaataaccctgc (SEQ ID NO: 235) CRM_ Ctctgtctcctcaggtgcctggctcccagt SP0349 ccccagaacgcctctcctgtaccttgcttc ctagctgggcctttccttctcctctataaa taccagctctggtatttcgccttggcagct gttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtgg tgtgagtgggtgtgggcggtgtgagtaggg ggatgaatcagagagggggcgccactacgg gtctaggctgcccatgtaaggaggcaaggc ctggggacacccgagatgcctggttataat taacccagacatgtggctgccccccccccc caacacctgctgcctgagcctcacccccac cccggtgcctgggtcttaggctctgtacac catggaggagaagctcgctctaaaaataac cctgcaccgcggtggcggccgtccgccctc ggcaccatcctcacgacacccaaatatggc gacgggtgaggaatggtggggagttatttt tagagcggtgaggaaggtgggcaggcagca ggtgttggcgctctaaaaataactcccggg agttatttttagagcggaggaatggtggac acccaaatatggcgacggttcctcacccgt cgccatatttgggtgtccgccct (SEQ ID NO: 236) CRM_ Gggccccacagcagctgggggcatttatgg SP0350 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtttctcctctataaata cccgctctggtatttggggttggcagctgt tgctgccagggagatggttgggttgacacc gcggtggcggccgtccgccctcggcaccat cctcacgacacccaaatatggcgacgggtg aggaatggtggggagttatttttagagcgg tgaggaaggtgggcaggcagcaggtgttgg cgctctaaaaataactcccgggagttattt ttagagcggaggaatggtggacacccaaat atggcgacggttcctcacccgtcgccatat ttgggtgtccgccct (SEQ ID NO: 237) CRM_ Caccgcggtggcggccgtccgccctcggca SP0351 ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcgagctctataaatacccgc tctggtatttggggttttgaacccgtcgcc atatttgggtgtccgccct (SEQ ID NO: 238) CRM_ Caccgcggtggcggccgtccgccctcggca SP0352 ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagctatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaatagctcccgggagct atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccct (SEQ ID NO: 239) CRM_ Tccctaacctcctgcttgcgaggcctctct SP0353 ctggcctctgagagggtcagtgtcctgccc caacccatgagatgacagactataatagcc acaggattaacatagcaggcattgtctttc tctgactatagggtgggtattatgtgttca tcaaccatcctaaaaatacccggtaaacag gtgcagcccctgtggctccagtcccctggg atctgttggcttctggctggagatgaagat tagggcagaggagaggtgaattagtctcac tgagttccaggcatgagactcgggtgtcct ttggaacctgggaaatctagattccaggaa acccatctggaggg (SEQ ID NO: 240) CRM_ Ccatcctaaaaatacccggtaaacaggtgc SP0354 agcccctgtggctccagtcccctgggatct gttggcttctggctggagatgaagattagg gcagaggagaggtgaattagtctcactgag ttccaggcatgagactcgggtgtcctttgg aa (SEQ ID NO: 241) CRM_ Agggtcagtgtcctgccccaacccatgaga SP0355 tgacagactataatagccacaggattaaca tagcaggcattg (SEQ ID NO: 242) CRM_ Ctgaggggtgtcagagcacaggctgaggcc SP0356 tcttgcctgacgtgggaccccttggtctgg catttgtcagtgaggcaggctgggggcagg ccccggagcttggcaggaggtgtaaaccgg ccttggaaggtagggccccacaatggggac agttggatctctgagggagacagggaggca tgatcactgccaaatgcccaccaaggacaa ggcacatcccagggagacagacgcagacct ggtgccctctggacactggcattcctggag gctgatgatggacagatgggcctggaggtg gctcttcgccagctggtgtttcctttggac ttcctcagtgtctttggagaagcagagccc taagaataagcagctgcccataaaatctaa taccagccaagcatctcaggaattcatgga ttgtctccat (SEQ ID NO: 243) CRM_ Ttctgagtcctctaaggtccctcactccca SP0358 actcagccccatgtcctgtcaattcccact cagtgtctgatctccttctcctcacctttc ccatctcccgtttgacccaagcttcctgag ctctcctcccattcccctttttggagtcct cctcctctcccagaacccagtaataagtgg gctcctccctggcctggacccccgtggtaa ccctataaggcgaggcagctgctgtctgag gcagggaggggctggtgtgggaggctaagg gcagctgctaagtttagggtggctccttct ctcttcttagagacaacaggtggctggggc ctcagtgcccagaaaagaaaatgtcttaga ggtatcggcatgggcctggaggagggggga cagggcagggggaggcatcttcctcaggac atcgggtcctagagg (SEQ ID NO: 244) CRM_ Cctccctggcctggacccccgtggtaaccc SP0359 tataaggcgaggcagctgctgtctgaggca gggaggggctggtgtgggaggctaagggca gctgctaagtttagggtg (SEQ ID NO: 245) CRM_ Caccgcggtggcggccgtccgccctcggca SP0361 ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcgagctctataaatacccgc tctggtatttggggttttgaacccgtcgcc atatttgggtgtccgccct (SEQ ID NO: 246) CRM_ Agactggggcaggtgcaggctggattgggt SP0362 ttccagaggctatatatataaaggctgccg ggagccccagggccgctccctgagggcaca acactgtgggggcccagccaggcccacatt cctttccagaggccagctctccatttatag cccctgggcagagcagcacacccaaatatg gcgacgggtgaggaatggtggggagttatt tttagagcggtgaggaaggtgggcaggcag caggtgttggcgctctaaaaataactcccg ggagttatttttagagcgagctctataaat acccgctctggtatttggggttttgaaccc gtcgccatatttgggtgtccgccct (SEQ ID NO: 247) CRM_ Ctctgtctcctcaggtgcctggctcccagt SP0363 ccccagaacgcctctcctgtaccttgcttc ctagctgggcctttccttctcctctataaa taccagctctggtatttcgccttggcagct gttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtgg tgtgagtgggtgtgggcggtgtgagtaggg ggatgaatcagagagggggcacacccaaat atggcgacgggtgaggaatggtggggagtt atttttagagcggtgaggaaggtgggcagg cagcaggtgttggcgctctaaaaataactc ccgggagttatttttagagcgagctctata aatacccgctctggtatttggggttttgaa cccgtcgccatatttgggtgtccgccct (SEQ ID NO: 248) CRM_ Ctctgtctcctcaggtgcctggctcccagt SP0364 ccccagaacgcctctcctgtaccttgcttc ctagctgggcctttccttctcctctataaa taccagctctggtatttcgccttggcagct gttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtgg tgtgagtgggtgtgggcggtgtgagtaggg ggatgaatcagagagggggccaccgcggtg gcggccgtccgccctcggcaccatcctcac gacacccaaatatggcgacgggtgaggaat ggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctct aaaaataactcccgggagttatttttagag cggaggaatggtggacacccaaatatggcg acggttcctcacccgtcgccatatttgggt gtccgccct (SEQ ID NO: 249) CRM_ Caccgcggtggcggccgtccgccctcggca SP0365 ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccct (SEQ ID NO: 250) CRM_ Cctccctggcctggacccccgtggtaaccc SP0366 tataaggcgaggcagctgctgtctgaggca gggaggggctggtgtgggaggctaagggca gctgctaagtttagggtgcaccgcggtggc ggccgtccgccctcggcaccatcctcacga cacccaaatatggcgacgggtgaggaatgg tggggagttatttttagagcggtgaggaag gtgggcaggcagcaggtgttggcgctctaa aaataactcccgggagttatttttagagcg gaggaatggtggacacccaaatatggcgac ggttcctcacccgtcgccatatttgggtgt ccgccct (SEQ ID NO: 251) CRM_ Cctccctggcctggacccccgtggtaaccc SP0367 tataaggcgaggcagctgctgtctgaggca gggaggggctggtgtgggaggctaagggca gctgctaagtttagggtg (SEQ ID NO: 252) CRM_ Cctccctggcctggacccccgtggtaaccc SP0368 tataaggcgaggcagctgctgtctgaggca gggaggggctggtgtgggaggctaagggca gctgctaagtttagggtggccactacgggt ctaggctgcccatgtaaggaggcaaggcct ggggacacccgagatgcctggttataatta acccagacatgtggctgcccccccccccca acacctgctgcctgagcctcacccccaccc cggtgcctgggtcttaggctctgtacacca tggaggagaagctcgctctaaaaataaccc tg (SEQ ID NO: 253) CRM_ Cgacacccaaatatggcgacgggtgaggaa SP0369 tggtggggagttatttttagagcggtgagg aaggtgggcaggcagcaggtgttggcgctc taaaaataactcccgggagttatttttaga gcggagcgacacccaaatatggcgacgggt gaggaatggtggggagttatttttagagcg gtgaggaaggtgggcaggcagcaggtgttg gcgctctaaaaataactcccgggagttatt tttagagcggag (SEQ ID NO: 254) CRM_ cgacacccaaatatggcgacgggtgaggaa SP0370 tggtggggagttatttttagagcggtgagg aaggtgggcaggcagcaggtgttggcgctc taaaaataactcccgggagttatttttaga gcggagcgacacccaaatatggcgacgggt gaggaatggtggggagttatttttagagcg gtgaggaaggtgggcaggcagcaggtgttg gcgctctaaaaataactcccgggagttatt tttagagcggagcgacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcggag (SEQ ID NO: 255) CRM_ taaggcgaggcagctgctgtctgaggcagg SP0371 acacccaaatatggcgacgggtgaggaatg gtggggagttatttttagagcggtgaggaa ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc ggaggaatggtggacacccaaatatggcga cggttcctcacccgtcgccatatttgggtg tccgccct (SEQ ID NO: 256) CRM_ Gacacccaaatatggcgacgggtgaggaat SP0372 ggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctct aaaaataactcccgggagttatttttagag cggaggaatggtggacacccaaatatggcg acggttcctcacccgtcgccatatttgggt gtccgccct (SEQ ID NO: 257) CRM_ Taaggcgaggcagctgctgtctgaggcagg SP0373 acacccaaatatggcgacgggtgaggaatg gtggggagttatttttagagcggtgaggaa ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc gctctaaggtccctcactcccaactcagcc ccatgtcctgtcaattcacccgtcgccata tttgggtgtccgccct (SEQ ID NO: 258) CRM_ Ctctaaggtccctcactcccaactcagccc SP0374 catgtcctgtcaattcgacacccaaatatg gcgacgggtgaggaatggtggggagttatt tttagagcggtgaggaaggtgggcaggcag caggtgttggcgctctaaaaataactcccg ggagttatttttagagcgtaaggcgaggca gctgctgtctgaggcagacccgtcgccata tttgggtgtccgccct (SEQ ID NO: 259) CRM_ Taaggcgaggcagctgctgtctgaggcaga SP0375 ggctaagggcagctgctaagtttagggtct ctaaggtccctcactcccaactcagcccca tgtcctgtcaattccgacacccaaatatgg cgacgggtgaggaatggtggggagttattt ttagagcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc gacccgtcgccatatttgggtgtccgccct (SEQ ID NO: 260) CRM_ gccactacgggtctaggctgcccatgtaag SP0376 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgataaatacccgctctg gtatttggggtactaaaaatagaacgacta tttttaggcttttctggcagctggcc (SEQ ID NO: 261) CRM_ gccactacgggtctaggctgcccatgtaag SP0377 gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgataaatacccgctctg gtatttggggcgaggtactataaataccct tagaggtattttatcttggcagctaggt (SEQ ID NO: 262) CRM_ Gggccccacagcagctgggggcatttatgg SP0378 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagttactaaaaatagaacg actatttttaggcttttctggcagctggcc ctgccagacagagttcctcagtaa (SEQ ID NO: 263) CRM_ Gggccccacagcagctgggggcatttatgg SP0379 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcgaggtactataaata cccttagaggtattttatcttggcagctag gtctgccagacagagttcctcagtaa (SEQ ID NO: 264) CRM_ Gggccccacagcagctgggggcatttatgg SP0380 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagttactaaaaatagaacg actatttttaggcttttctggcagctggcc ctgccagacagataaacgagctat (SEQ ID NO: 265) CRM_ Gggccccacagcagctgggggcatttatgg SP0381 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcgaggtactataaata cccttagaggtattttatcttggcagctag gtctgccagacagataaacgagctat (SEQ ID NO: 266) CRM_ Gggccccacagcagctgggggcatttatgg SP0382 gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagttaaacgagctattagt tatgaggtccgtagattgaataaacgagct attagttatgaggtccgtagattgaa (SEQ ID NO: 267) CRM_ Atttttaaagactgaggaattaggcacctg SKM_ tcatttttgccagctggtgtagatgttaaa 20 aattactgtcactcttccgcctgctacttt attttgcacctgctgttacttgagttacag gcatttcacacatggtaatttaataaggtt agttcccatgaca (SEQ ID NO: 268) CRM_ tctgagggagacagggaggcatgatcactg SP0357 ccaaatgcccaccaaggacaaggcacatcc cagggagacagacgcagacctggtgccctc tggacactggcattcctggag (SEQ ID NO: 269) CRM_ gggccccacagcagctgggggcatttatgg SP0229A gccttcctataaacttctgagagggtaact (SEQ ID ttatcctgcttctttcagccaagtatcctc NO: 549) ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtctctgtctcctcaggt gcctggctcccagtccccagaacgcctctc ctgtaccttgcttcctagctgggcctttcc ttctcctctataaataccagctctggtatt tcgccttggcagctgttgctgctagggaga cggctggcttgacatgcatctcctgacaaa acacaaacccgtggtgtgagtgggtgtggg cggtgtgagtagggggatgaatcagagagg gggccaccgcggtggcggccgtccgccctc ggcaccatcctcacgacacccaaatatggc gacgggtgaggaatggtggggagttatttt tagagcggtgaggaaggtgggcaggcagca ggtgttggcgctctaaaaataactcccggg agttatttttagagcggaggaatggtggac acccaaatatggcgacggttcctcacccgt cgccatatttgggtgtccgccct
TABLE-US-00014 TABLE 2A CRMs from promoters of Table 1A CRM NAME SEQUENCE CRM_SP0407 Agctttgaggctgtgggcagctcagctgtc atgcgggcacacaggtgatgtaagacaata gctgtggagtcagctggcttccaaggtgcc tgggatcttttcgttctgcccttggctcct gccctaactggcaaacccca (SEQ ID NO: 369) CRM_SP0408 Agctttgaggctgtgggcagctcagctgtc atgcgggcacacaggtgatgtaagacaata gctgtggagtcagctggcttccaagg (SEQ ID NO: 370) CRM_SP0409 Ccagcccacctgtcccaatgctgacttagt gcaaggcgagccagcaaggagggaggacag gtggcagtggggggtgaggagcatctaaaa atagcc (SEQ ID NO: 371) CRM_SP0410 Agtgattctccctcaagaccttataaaacc actttaaccctcaatgggataatatctagt acattgtcatgggaactaaccttattaaat taccatgtgtgaaatgcctgtaactcaagt aacagcaggtgcaaaataaagtagcaggcg gaagagtgacagtaatttttaacatctaca ccagctggcaaaaatgacaggtgcctaatt cctcagtctttaaaaataacttttgagaag cctacacagcataagcaaatattttcaagt ttattttttagctatcttcgagttaccttc ctgacaaaatgtaataatatacactgattt ttgcagaaaa (SEQ ID NO: 372) CRM_SP0411 Ataacttcagcacactgtcatgggacctaa ccttattaaattaccatgtgtgaagcgtcc ataactcaagtaacagcaggtgcaaaaatg gagctgcaggcagaagagtggtagtcattt ttacaaatccccaccagctggcgaaacaac aggtgcctaattcctcagcttttaaaaata acttttaaaaagcctgtgctgcataagcaa atattttcaagtttgtttttaaaccatctt caagttaccttggtcac (SEQ ID NO: 373) CRM_SP0412 Agggcaccatccggatgcctgcctagttcc cttccggccctgatggaggcatgagcctcc cccaccgcctgctcactgctcactcctcgg ccgccagcccagcagctgttgcctcagatc agtgtggaccatctaatcccctctccagag ccctggccccctcctcaggcagtaaattaa ggaggatgtaagaacagagggcaccagcgt cagcagagcggcatccaaaacatcctcccc aacccgcgcctgagtcacagggccctgaat tggcccctct (SEQ ID NO: 374) CRM_SP0413 Agggcaccatccggatgcctgcctagttcc cttccggccctgatggaggcatgagcctcc cccaccgcctgctcactgctcactcctcgg ccgccagcccagcagctgttgcctcagatc agtgtggaccatctaatcccctctccagag ccctggccccctcctcaggcagtaaattaa ggaggatgtaagaacagagggcaccagcgt cagcagagcggcatccaaaacatcctcccc aacccgcgcctgagtcacagggccctgaat tggcccctct (SEQ ID NO: 375) CRM_SP0414 Agggcaccatccggatgcctgcctagttcc cttccggccctgatggaggcatgagcctcc cccaccgcctgctcactgctcactcctcgg ccgccagcccagcagctgttgcctcagatc agtgtggaccatctaatcccctctccagag ccctggccccctcctcaggcagtaaattaa ggaggatgtaagaacagagggcaccagcgt cagcagagcggcatccaaaacatcctcccc aacccgcgcctgagtcacagggccctgaat tggcccctctagactggggcaggtgcaggc tggattgggtttccagaggctatatatata aaggctgccgggagccccagggccgctccc tgagggcacaacactgtgggggcccagcca ggcccacattcctttccagaggccagctct ccatttatagcccctgggcagagcagc (SEQ ID NO: 376) CRM_SP0415 Atggtgcttccaagtctgctcccgggacgt ttcctgttcttggaacagctgcaccagcct ggggtaccctcctgctacttgatcctatag ggaggtgtccagtggctgtgggcaattttc agatgaccttgttcgtctgacgtcattaga tcgctatttttggctttgctgtttatgctg cagaagttgggctggaatgggagaggagga atgaaggaggggctgctcttggtttcccat tgttccaggg (SEQ ID NO: 377) CRM_SP0416 Actgatgtggaaggggttatatataggaag atgtgtaggaagaaaaaggtagagagctct cctcagagggtgggggattatgggtagcca gagggagcctgggttagtggagttgaagcc ctagtcttgggtgctttgtagcatcagaag cctctggagcctttgctgacacctgcctga tgtacggagccatctgtgggtgtctgtgtg ctggaggattgcccacagctatgattcaga gatgctcatgttgttgcccaagcaattgac agatgatgtttcaggcttggagatggcagg atgggagcaaagagaagccaggtcaggaaa gaacgtgccgttctggccctagtggggaat tctgggcctt (SEQ ID NO: 378) CRM_SP0417 Gggagagccaggacattggctgcctgtggt cttggtggtcgtggtcagttccctctcctg ccagctgtggaatgtgaggcctggcctggg agatatttttgctgcactttgagccacccc gccccctggaactcagaccctgcacagtcc atgccataacaatgacgaccacttccaatt gtttcctagctggagaggcggggaggggag cactgtttgggaagggggggagcctggggg aaatgcttct (SEQ ID NO: 379) CRM_SP0418 Ccagcccacctgtcccaatgctgacttagt gcaaggcgagccagcaaggagggaggacag gtggcagtggggggtgaggagcatctaaaa atagccgggagagccaggacattggctgcc tgtggtcttggtggtcgtggtcagttccct ctcctgccagctgtggaatgtgaggcctgg cctgggagatatttttgctgcactttgagc caccccgccccctggaactcagaccctgca cagtccatgccataacaatgacgaccactt ccaattgtttcctagctggagaggcgggga ggggagcactgtttgggaagggggggagcc tgggggaaatgcttct (SEQ ID NO: 380) CRM_SP0419 Gggccccacagcagctgggggcatttatgg gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagttccatgccataacaat gacgaccacttccaattgtttcctagctgg (SEQ ID NO: 381) CRM_SP0420 Ccttgcctgactattggcaggcggacctgg tggtcagacctcagtgatcctcagggacca gtgaatatttcaggctggggctgagcatca cctgctcccttggccccacttatagggcaa aggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgct ctggccccacctcgccctctcccctacttg gaagttcctttcctgaaccactgactgcca aagcttgagggattaaataaatcatctggc ccaatccatgccataacaatgacgaccact tccaattgtttcctagctgg (SEQ ID NO: 382) CRM_SP0421 Ccacagcagctgggggcatttatgggcctt cctataaacttctgagagggtaactttatc ctgcttctttcagccaagtatcctcctcca gcagctggtcacaaagctggttaatctccc agagtgctcagcttaaaacccgtgactcac agcacagc cagtgtgggggagggggtggctgcctccaa tacgtggcgcccagagtcagctgttctggg gccttctctggtttctccaactgagtcctg aggtttgg (SEQ ID NO: 383) CRM_SP0422 Ccacagcagctgggggcatttatgggcctt cctataaacttctgagagggtaactttatc ctgcttctttcagccaagtatcctcctcca aaacccgtgactcacagcacagccagtgtg ggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttct ctggtttctccaactgagtcctgaggtttg g (SEQ ID NO: 384) CRM_SP0423 Ggcaggcggacctggtggtcagacctcagt gatcctcagggaccagtgaatatttcaggc tggggctgagcatcacctgctcccttggcc ccacttatagggcaaaggggagtctaccag cctactcactgatgacaaactggaaaagtt tgtcctgtctctgctctggccccacctcgc cctctcccctacttggaagttcctttcctg aaccactgactgc (SEQ ID NO: 385) CRM_SP0424 Ttctgactgggtcccttaccactgtctttg caaatggcatttccattaacatttctattt ctggccattaggggcacctaaagatttccc accaagattgacagccactattttaagaaa gtgcttttaaaaagccagtgcttttgctaa gtttaaatctgactttctcaggggatgctt aaaagaaatacacagtttgtttgttttttt tttaagaacctttgcaagttcaaaataaca ttccagaaggagtcactagaaaaacattca agggaagagaaaaaaattgttttcgtttgt agcagacctggcttcatccaaatgttctat ttgttttttactgca (SEQ ID NO: 386) CRM_SP0425 Taagtgtgatgcacagtgcttgcattttct tgatacgttagtcatatgagagctgacaaa gaaggaaaaagagcagcgatgtggtgcaat attaacaggcagctgtcccctggcttcccg atacgtgggatgactcgcattgctgagcgg tgtggtcactgccaaaggaatgaccctctc acatttcttcctgattcgcatacgccgcgg c (SEQ ID NO: 387) CRM_SP0426 Ccttgcctgactattggcaggcggacctgg tggtcagacctcagtgatcctcagggacca gtgaatatttcaggctggggctgagcatca cctgctcccttggccccacttatagggcaa aggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgct ctggccccacctcgccctctcccctacttg gaagttcctttcctgaaccactgactgcca aagcttgagggattaaataaatcatctggc ccaa (SEQ ID NO: 388) CRM_SP0427 Ttctcctctataaatacccgctctggtatt tggggttggcagctgttgcccctgcccccc acagctcctctcctgtgccttgtttcccag ccatgcgttctcctctataaatacccgctc tggtatttggggttggcagctgttgctgcc agggagatggttgggttgacatg (SEQ ID NO: 389) CRM_SP0428 Gccactacgggtctaggctgcccatgtaag gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgttctcctctataaata cccgctctggtatttggggttggcagctgt tgcccctgccccccacagctcctctcctgt gccttgtttcccagccatgcgttctcctct ataaatacccgetctggtatttggggttgg cagctgttgctgccagggagatggttgggt tgacatg (SEQ ID NO: 390) CRM_SP0429 Aaactttaaagattagctattaaaaatgcc attttacataaattaattggtttttatcag agtagtataatagtaaactactttttgtct aatgacttctgttcacaggtgaagtggtat aatctgcccttgtttatatttttggttgtc tgaataagatgggaaatatttttaatatgc aggggcagtagtgaggcaccaagattccat gcacttcctgtcagcaaaggtatcaactgc caggaacccctgataagtcctattttgagc aagcagtgtcaggataacagaagacagaca cagtttactgctgtgaggctggcagcagag ccaactgcactaccatcctaatcacaacag acactctggagttagacaaagccaag (SEQ ID NO: 391) CRM_SP0430 Gaagcaacacatgccccttcccaaaaatat ctagccagtgcctaatgccagattgtcaag tagaaagtctgtccagcagtgagacggagg tcgttctcctaatctgtcctgcattcccct gcactctaaaaggagatccaccaggccagg acaggcaagttggctctacacgtagctgca aatagaagcagggctcaagccatccatagc tcgactcacttactaaataaggatgaaaca ataccgggttcacttctctgacacattccc ctgtctacgacgagggctgggtggagagag cagggaagtccacagtgcactattgttagc ctttatcaagaaacatgacaaatgaccctg aaatggagcctcttatcacccaaacctctc cacagcctgcacaaggagcagctgcagtcc at (SEQ ID NO: 392) CRM_SP0431 Gatcctctgcctggcaggggggtggcctta tttagcctggcctggctcctctgagctttc ttgggaatgtctatatataggggaagagcg cagcccagttgccactgtccatctgccttc cttggactctggtccacccctccctgaccc tgggctccattttctttctgtgccactttc ttctgcgtacccctcctacttgacttgaag aagtaattggactccagagaccagctgcca ttgcccatgcccaactaaaaatagcctatc ctcctggatcaggccaagggccggaggagg gaaggaggaactgggccagctggctgaagg atgtcttgggactcgtcaccccttcttcac catcccgagtccaaagccctgacccagatg gcctggcttg (SEQ ID NO: 393) CRM_SP0432 Tgccactttcttctgcgtacccctcctact tgacttgaagaagtaattggactccagaga ccagctgccattgcccatgcccaactaaaa atagcctatcctcctggatcaggccaaggg ccggaggagggaaggaggaactgggccagc tggctgaaggatgtcttgggactcgtcacc ccttcttcaccatcccgagtccaaagccct gacccagatggcctggcttg (SEQ ID NO: 394)
TABLE-US-00015 TABLE 2B CRMs from promoters of Table 1B CRM NAME SEQUENCE CRM_SP0433 Cccttcagattaaaaataactgaggtaagg (SEQ ID NO: gcctgggtaggggaggtggtgtgagacgct 454) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctgcaccgcggtggcggccgtccg ccctcggcaccatcctcacgacacccaaat atggcgacgggtgaggaatggtggggagtt atttttagagcgtaaacgagctattagttg cagcaggtgttggcgctctaaaaataactc ccgggagttatttttagagcggaggaatgg tggacacccaaatatggcgacggttcctca cccgtcgccatatttgggtgtccgccct CRM_SP0436 cccttcagattaaaaataactgaggtaagg (SEQ ID NO: gcctgggtaggggaggtggtgtgagacgct 455) cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctgcccttcagattaaaaataact gaggtaagggcctgggtaggggaggtggtg tgagacgctcctgtctctcctctatctgcc catcggccctttggggaggaggaatgtgcc caaggactaaaaaaaggccatggagccaga ggggcgagggcaacagacctttcatgggca aaccttggggccctgctg CRM_SP0449 tctgactgggtcccttaccactgtctttgc (SEQ ID NO: aaatggcatttccattaacatttctatttc 456) tggccattaggggcacctaaagatttccca ccaagattgacagccactattttaagaaag tgcttttaaaaagccagtgcttttgctaag tttaaatctgactttctcaggggatgctta aaagaaatacacagtttgtttgtttttttt ttaagaacctttgcaagttcaaaataacat tccagaaggagtcactagaaaaacattcaa gggaagagaaaaaaattgttttcgtttgta gcagacctggcttcatccaaatgttctatt tgttttttactgcacccttcagattaaaaa taactgaggtaagggcctgggtaggggagg tggtgtgagacgctcctgtctctcctctat ctgcccatcggccctttggggaggaggaat gtgcccaaggactaaaaaaaggccatggag ccagaggggcgagggcaacagacctttcat gggcaaaccttggggccctgctg CRM_SP0450 aaactttaaagattagctattaaaaatgcc (SEQ ID NO: attttacataaattaattggtttttatcag 457) agtagtataatagtaaactactttttgtct aatgacttctgttcacaggtgaagtggtat aatctgcccttgtttatatttttggttgtc tgaataagatgggaaatatttttaatatgc aggggcagtagtgaggcaccaagattccat gcacttcctgtcagcaaaggtatcaactgc caggaacccctgataagtcctattttgagc aagcagtgtcaggataacagaagacagaca cagtttactgctgtgaggctggcagcagag ccaactgcactaccatcctaatcacaacag acactctggagttagacaaagccaagccct tcagattaaaaataactgaggtaagggcct gggtaggggaggtggtgtgagacgctcctg tctctcctctatctgcccatcggccctttg gggaggaggaatgtgcccaaggactaaaaa aaggccatggagccagaggggcgagggcaa cagacctttcatgggcaaaccttggggccc tgctg CRM_SP0451 gaagcaacacatgccccttcccaaaaatat (SEQ ID NO: ctagccagtgcctaatgccagattgtcaag 458) tagaaagtctgtccagcagtgagacggagg tcgttctcctaatctgtcctgcattcccct gcactctaaaaggagatccaccaggccagg acaggcaagttggctctacacgtagctgca aatagaagcagggctcaagccatccatagc tcgactcacttactaaataaggatgaaaca ataccgggttcacttctctgacacattccc ctgtctacgacgagggctgggtggagagag cagggaagtccacagtgcactattgttagc ctttatcaagaaacatgacaaatgaccctg aaatggagcctcttatcacccaaacctctc cacagcctgcacaaggagcagctgcagtcc atcccttcagattaaaaataactgaggtaa gggcctgggtaggggaggtggtgtgagacg ctcctgtctctcctctatctgcccatcggc cctttggggaggaggaatgtgcccaaggac taaaaaaaggccatggagccagaggggcga gggcaacagacctttcatgggcaaaccttg gggccctgctg CRM_SP0452 gggataaaagcagtctgggctttcacatga (SEQ ID NO: cagcatctggggctgcggcagagggtcggg 459) tccgaagcgctgccttatcagcgtccccag ccctgggaggtgacagctggctggcttgtg tcagcccctcgggcactcacgtatctccgt ccgacgggtttaaaatagcaaaactctgag gccacacaatagcttgggcttatatgggct cctgtgggggaagggggagcacggaggggg ccggggccgctgctgccaaaatagcagctc acaagtgttgcattcctctctgggcgccgg gcacattcctgctggctctgcccgccccgg ggtgggcgccggggggaccttaaagcctct gccccccaaggagcccttcccagacagccg ccggcacccaccgctccgtgggaccccttc agattaaaaataactgaggtaagggcctgg gtaggggaggtggtgtgagacgctcctgtc tctcctctatctgcccatcggccctttggg gaggaggaatgtgcccaaggactaaaaaaa ggccatggagccagaggggcgagggcaaca gacctttcatgggcaaaccttggggccctg ctg CRM_SP0495 gtcaccctctgcttccctgcatgggtcctg (SEQ ID NO: ttgccagggagaaagaatcctgaggcgagc 460) gcccaggaagataaccaaggactcttttct gctcctctcacacctttgaagtgggggcct cttgaggcaaatcagcaagaatgtgactct tgcagctgagggtctgggggaggggggtga gtggagctgctcaaggcaaaggggccgtga caagctttgccgaactgatacccttcagat taaaaataactgaggtaagggcctgggtag gggaggtggtgtgagacgctcctgtctctc ctctatctgcccatcggccctttggggagg aggaatgtgcccaaggactaaaaaaaggcc atggagccagaggggcgagggcaacagacc tttcatgggcaaaccttggggccctgctg CRM_SP0496 cctgggctcctggcatctgctttatcggga (SEQ ID NO: ttctcaagagggacagctggtttatgttac 461) aagcctgttccctgcatatctgctctggtt ttaaatagctttatctgagcagctggagga ccacatgagcttatatggcgtggggtactt gttcttttagccctgtgccgggcacctgcc aaaatagcagccaacaccccccattgtgtt gcccttcagattaaaaataactgaggtaag ggcctgggtaggggaggtggtgtgagacgc tcctgtctctcctctatctgcccatcggcc ctttggggaggaggaatgtgcccaaggact aaaaaaaggccatggagccagaggggcgag ggcaacagacctttcatgggcaaaccttgg ggccctgctg
TABLE-US-00016 TABLE 2C CRMs from promoters of Table 1C CRM NAME SEQUENCE CRM_ SP0440 gggccccacagcagctgggggcatttatgg (SEQ ID NO: gccttcctataaacttctgagagggtaact 510) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcggaggaatggtggaca cccaaatatggcgacggttcctcacccgtc gccatatttgggtgtccgccct CRM_SP0441 gggccccacagcagctgggggcatttatgg (SEQ ID NO: gccttcctataaacttctgagagggtaact 511) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcgcccgtcgccatattt gggtgtccgccct CRM_SP0442 gggccccacagcagctgggggcatttatgg (SEQ ID NO: gccttcctataaacttctgagagggtaact 512) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcgagctctataaatacc cgctctggtatttggggttttgaacccgtc gccatatttgggtgtccgccct CRM_SP0446 agctttgaggctgtgggcagctcagctgtc (SEQ ID NO: atgcgggcacacaggtgatgtaagacaata 513) gctgtggagtcagctggcttccaaggtgcc tgggatcttttcgttctgcccttggctcct gccctaactggcaaacccca CRM_SP0453 gggccccacagcagctgggggcatttatgg (SEQ ID NO: gccttcctataaacttctgagagggtaact 514) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cct CRM_SP0454 gggccccacagcagctgggggcatttatgg (SEQ ID NO: gccttcctataaacttctgagagggtaact 515) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcgagctctataaatacc cgctctggtatttggggttttgaacccgtc gccatatttgggtgtccgccct CRM_SP0455 ccacagcagctgggggcatttatgggcctt (SEQ ID NO: cctataaacttctgagagggtaactttatc 516) ctgcttctttcagccaagtatcctcctcca aaacccgtgactcacagcacagccagtgtg ggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttct ctggtttctccaactgagtcctgaggtttg gcaccgcggtggcggccgtccgccctcggc accatcctcacgacacccaaatatggcgac gggtgaggaatggtggggagttatttttag agcggtgaggaaggtgggcaggcagcaggt gttggcgctctaaaaataactcccgggagt tatttttagagcggaggaatggtggacacc caaatatggcgacggttcctcacccgtcgc catatttgggtgtccgccct CRM_SP0456 ccacagcagctgggggcatttatgggcctt (SEQ ID NO: cctataaacttctgagagggtaactttatc 517) ctgcttctttcagccaagtatcctcctcca aaacccgtgactcacagcacagccagtgtg ggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttct ctggtttctccaactgagtcctgaggtttg gcaccgcggtggcggccgtccgccctcggc accatcctcacgacacccaaatatggcgac gggtgaggaatggtggggagttatttttag agcggtgaggaaggtgggcaggcagcaggt gttggcgctctaaaaataactcccgggagt tatttttagagcggaggaatggtggacacc caaatatggcgacggttcctcacccgtcgc catatttgggtgtccgccct CRM_SP0457 ccccacagcagctgggggcatttatgggcc (SEQ ID NO: ttcctataaacttctgagagggtaacttta 518) tcctgcttctttcagccaagtatcctcctc caaggcagtgtatactcttccataaacgag ctattagttatgaggtcaaacccgtgactc acagcacagccagtgtgggggagggggtgg ctgcctccaatacgtggcgcccagagtcag ctgttctggggccttctctggtttctccaa ctgagtcctgaggtttggtgacggaattcg gccgaacgggacaccgcggtggcggccgtc cgccctcggcaccatcctcacgacacccaa atatggcgacgggtgaggaatggtggggag ttatttttagagcggtgaggaaggtgggca ggcagcaggtgttggcgctctaaaaataac tcccgggagttatttttagagcggaggaat ggtggacacccaaatatggcgacggttcct cacccgtcgccatatttgggtgtccgccct CRM_SP0458 gggccccacagcagctgggggcatttatgg (SEQ ID NO: gccttcctataaacttctgagagggtaact 519) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cct CRM_SP0459 gggccccacagcagctgggggcatttatgg (SEQ ID NO: gccttcctataaacttctgagagggtaact 520) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cct CRM_SP0461 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 521) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcgaggcagtgtatactcttc cataaacgagctattagttatgaggtccgt agattgaaaagggtgacgg CRM_SP0462 ctctataaatacccgctctggtatttgggg (SEQ ID NO: ttacacccaaatatggcgacgggtgaggaa 522) tggtggggagttatttttagagcggtgagg aaggtgggcaggcagcaggtgttggcgctc taaaaataactcccgggagttatttttaga gcggaggaatggtggacacccaaatatggc gacggttcctcacccgtcgccatatttggg tgtccgccct CRM_SP0463 gggccccacagcagctgggggcatttatgg (SEQ ID NO: gccttcctataaacttctgagagggtaact 523) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cct CRM_SP0464 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 524) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctgggccccacag cagctgggggcatttatgggccttcctata aacttctgagagggtaactttatcctgctt ctttcagccaagtatcctcctccagcagct ggtcacaaagctggttaatctcccagagtg ctcagcttaaaacccgtgactcacagcaca gccagtgtgggggagggggtggctgcctcc aatacgtggcgcccagagtcagctgttctg gggccttctctggtttctccaactgagtcc tgaggtttggggccttgtcttccttcctgg agt CRM_SP0465 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 525) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctgggccccacag cagctgggggcatttatgggccttcctata aacttctgagagggtaactttatcctgctt ctttcagccaagtatcctcctccagcagct ggtcacaaagctggttaatctcccagagtg ctcagcttaaaacccgtgactcacagcaca gccagtgtgggggagggggtggctgcctcc aatacgtggcgcccagagtcagctgttctg gggccttctctggtttctccaactgagtcc tgaggtttggggccttgtcttccttcctgg agt CRM_SP0466 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 526) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctccacagcagct gggggcatttatgggccttcctataaactt ctgagagggtaactttatcctgcttctttc agccaagtatcctcctccaaaacccgtgac tcacagcacagccagtgtgggggagggggt ggctgcctccaatacgtggcgcccagagtc agctgttctggggccttctctggtttctcc aactgagtcctgaggtttgg CRM_SP0467 gccactacgggtctaggctgcccatgtaag (SEQ ID NO: gaggcaaggcctggggacacccgagatgcc 527) tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctgcaccgcggtggcggcc gtccgccctcggcaccatcctcacgacacc caaatatggcgacgggtgaggaatggtggg gagttatttttagagcggtgaggaaggtgg gcaggcagcaggtgttggcgctctaaaaat aactcccgggagttatttttagagcggagg aatggtggacacccaaatatggcgacggtt cctcacccgtcgccatatttgggtgtccgc cct CRM_SP0468 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 528) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctgccactacggg tctaggctgcccatgtaaggaggcaaggcc tggggacacccgagatgcctggttataatt aacccagacatgtggctgcccccccccccc aacacctgctgcctgagcctcacccccacc ccggtgcctgggtcttaggctctgtacacc atggaggagaagctcgctctaaaaataacc ctg CRM_SP0469 ccacagcagctgggggcatttctgagaggg (SEQ ID NO: taactttatcctgcttctttcagccaagta 529) ctcacagcacagccagtgtgggggaggggg tggctgcctccgtggcgcccagagtcagct gttctggggccttctctggtttctccaact gagtcctgaggtttggcaccgcggtggcgg ccgtccgccctcggcaccatcctcacgaca cccaaatatggcgacgggtgaggaatggtg gggagttatttttagagcggtgaggaaggt gggcaggcagcaggtgttggcgctctaaaa ataactcccgggagttatttttagagcgga ggaatggtggacacccaaatatggcgacgg ttcctcacccgtcgccatatttgggtgtcc gccct CRM_SP0471 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 530) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctgggccccacag cagctgggggcatttatgggccttcctata aacttctgagagggtaactttatcctgctt ctttcagccaagtatcctcctccagcagct ggtcacaaagctggttaatctcccagagtg ctcagcttaaaacccgtgactcacagcaca gccagtgtgggggagggggtggctgcctcc aatacgtggcgcccagagtcagctgttctg gggccttctctggtttctccaactgagtcc tgaggtttggggccttgtcttccttcctgg agt CRM_SP0473 gggccccacagcagctgggggcatttatgg (SEQ ID NO: gccttcctataaacttctgagagggtaact 531) ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagtacacccaaatatggcg acgggtgaggaat ggtggggagttatttttagagcggtgagga aggtgggcaggcagcaggtgttggcgctct aaaaataactcccgggagttatttttagag cgagctctataaatacccgctctggtattt ggggttttgaacccgtcgccatatttgggt gtccgccct CRM_SP0474 ccacagcagctgggggcatttctgagaggg (SEQ ID NO: taactttatcctgcttctttcagccaagta 532) ctcacagcacagccagtgtgggggaggggg tggctgcctccgtggcgcccagagtcagct gttctggggccttctctggtttctccaact gagtcctgaggtttggacacccaaatatgg cgacgggtgaggaatggtggggagttattt ttagagcggtgaggaaggtgggcaggcagc aggtgttggcgctctaaaaataactcccgg gagttatttttagagcgagctctataaata cccgctctggtatttggggttttgaacccg tcgccatatttgggtgtccgccct
TABLE-US-00017 TABLE 3 Cis-regulatory elements comprised in the promoters of Table 1 Name Sequence CRE0016 (SEQ ccttgcctgactattggcaggcggacctgg ID NO: 301) tggtcagacctcagtgatcctcagggacca gtgaatatttcaggctggggctgagcatca cctgctcccttggccccacttatagggcaa aggggagtctaccagcctactcactgatga caaactggaaaagtttgtcctgtctctgct ctggccccacctcgccctctcccctacttg gaagttcctttcctgaaccactgactgcca aagcttgagggattaaataaatcatctggc ccaa CRE0018 (SEQ ctgtgtgtttctgtggctgagtcagatgga ID NO: 302) ggagtcctcatgtttcactgcttagcagtt tttgtccttcctagtacccgttcccagccc acaagatgcagaaagagctgttgctagcgt gagttatttttgtcagctgagtcaccacgc cagaaagcaagaaatgacccgctttatgtc tgctctgaggagctggaacc CRE0020 (SEQ gggccccacagcagctgggggcatttatgg ID NO: 303) gccttcctataaacttctgagagggtaact ttatcctgcttctttcagccaagtatcctc ctccagcagctggtcacaaagctggttaat ctcccagagtgctcagcttaaaacccgtga ctcacagcacagccagtgtgggggaggggg tggctgcctccaatacgtggcgcccagagt cagctgttctggggccttctctggtttctc caactgagtcctgaggtttggggccttgtc ttccttcctggagt CRE0025 (SEQ gcgccctgatgaatatgcatcgcggcgcgc ID NO: 304) ccgcccccggctcctcctttcggtttcctt cccgccgccaggcggaagcgaagagccgcg cttcccgcgcgcccaggccggccgtggtag ggtggggcggggcgggccgcgagccggaga aagagaaagc CRE0027 (SEQ tacatcatttacctagaaaagaggacagct ID NO: 305) gtcctttcccaaagctccggtgaccctgcc ccgcccagtgtgactagcccaggttggtga ttctgatctgttgccaaaccaaactggctc cccggggagccatttggtaatgttccctgg agtcatttccttgcgaagcattccttttcg gtgagaggacatttttttcatccctgataa acaaccacagcctgcgccag CRE0028 (SEQ taagtgtgatgcacagtgcttgcattttct ID NO: 306) tgatacgttagtcatatgagagctgacaaa gaaggaaaaagagcagcgatgtggtgcaat attaacaggcagctgtcccctggcttcccg atacgtgggatgactcgcattgctgagcgg tgtggtcactgccaaaggaatgaccctctc acatttcttcctgattcgcatacgccgcgg c CRE0029 (SEQ ctctgtctcctcaggtgcctggctcccagt ID NO: 307) ccccagaacgcctctcctgtaccttgcttc ctagctgggcctttccttctcctctataaa taccagctctggtatttcgccttggcagct gttgctgctagggagacggctggcttgaca tgcatctcctgacaaaacacaaacccgtgg tgtgagtgggtgtgggcggtgtgagtaggg ggatgaatcagagagggggc CRE0031 (SEQ taagtccgggcagggtcctgtccataaaag ID NO: 308) gcttttcccgggccggctccccgccggcag cgtgccccgccccggcccgctccatctcca aagcatgcagagaatgtctcggcagccccg gtagactgctccaacttggtgtctttcccc aaatatggagcctgtgtggagtcactgggg gagccgggggtggggagcggagccggcttc ctctag CRE0033 (SEQ cccttcagattaaaaataactgaggtaagg ID NO: 309) gcctgggtaggggaggtggtgtgagacgct cctgtctctcctctatctgcccatcggccc tttggggaggaggaatgtgcccaaggacta aaaaaaggccatggagccagaggggcgagg gcaacagacctttcatgggcaaaccttggg gccctgctg CRE0035 (SEQ gccactacgggtctaggctgcccatgtaag ID NO: 310) gaggcaaggcctggggacacccgagatgcc tggttataattaacccagacatgtggctgc cccccccccccaacacctgctgcctgagcc tcacccccaccccggtgcctgggtcttagg ctctgtacaccatggaggagaagctcgctc taaaaataaccctg CRE0036 (SEQ ctgagattttcctagcattttgtgtttcat ID NO: 311) gactaaatatggtttgtgtttcaagaccaa tgagctgggaactgtactgttctttcccct cccatcaactcatttttggcacaagacgca ctctagtcagttggagcaaatcccctgacc cgggtgcagttccaaaagcagacactcgag cgtgttttacctaattaggaaatgctttgc tccaaaccgaactgctcattcaggttagag aggag CRE0047 (SEQ cccacccatgcctcctcaggtaccccctgc ID NO: 312) cccccacagctcctctcctgtgccttgttt cccagccatgcgttctcctctataaatacc cgctctggtatttggggttggcagctgttg ctgccagggagatggttgggttgacatgcg gctcctgacaaaacacaaacccctggtgtg tgtgggcgtgggtggtgtgagtagggggat gaatcagggagggggcggggg CRE0050 (SEQ ctagactagcatgctgcccatgtaaggagg ID NO: 313) caaggcctggggacacccgagatgcctggt tataattaacccagacatgtggctgccccc ccccccccaacacctgctgcctctaaaaat aaccctgc CRE0051 (SEQ caccgcggtggcggccgtccgccctcggca ID NO: 314) ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccctcggccggggcc CRE0052 (SEQ atttttaaagactgaggaattaggcacctg ID NO: 315) tcatttttgccagctggtgtagatgttaaa aattactgtcactcttccgcctgctacttt attttgcacctgctgttacttgagttacag gcatttcacacatggtaatttaataaggtt agttcccatgaca HTMB ev_4 ataaatacccgctctggtatttgggg (SEQ ID NO: 316) CRE0059 (SEQ cccctgccccccacagctcctctcctgtgc ID NO: 317) cttgtttcccagccatgcgttctcctctat aaatacccgctctggtatttggggttggca gctgttgctgccagggagatggttgggttg acatg CRE0060 (SEQ ctctataaatacccgctctggtatttgggg ID NO: 318) tt CRE0065_short gtgtgtgtgtgtgcgcccgcgtgtgcgtgt (SEQ ID NO: gtgcatgtatgtgtgtgtgtggtgggtttt 319) attgttgttttagcggggctgctccaggag tggggctgcgccggtcagatgcagccggca cggccccggggtcgcgcgatcgccccttcc ccgccctcggattggcctggcccgcggcgg ggctgccccggaaccgccacccagcagcgc acccttccgcgcccggcccgcgctcctcct gcagtcgcctccctggctttctctttctcc ggctcgcggcccgccccgccccaccctacc acggccggcctgggcgcgcgggaagcgcgg ctcttcgcttccgcctggcggcgggaagga aaccgaaaggaggagccgggggcgggcgcg ccgcgatgcatattcatca CRE0069 (SEQ agactggggcaggtgcaggctggattgggt ID NO: 320) ttccagaggctatatatataaaggctgccg ggagccccagggccgctccctgagggcaca acactgtgggggcccagccaggcccacatt cctttccagaggccagctctccatttatag cccctgggcagagcagc CRE0071 (SEQ caccgcggtggcggccgtccgccctcggca ID NO: 321) ccatcctcacgacacccaaatatggcgacg ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccct CRE0071.5 acacccaaatatggcgacgggtgaggaatg (SEQ ID NO: gtggggagttatttttagagcggtgaggaa 322) ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc gagctctataaatacccgctctggtatttg gggttttgaacccgtcgccatatttgggtg tccgccct CRE0071.2 gacacccaaatatggcgacgggtgaggaat (SEQ ID NO: ggtggggagttatttttagagcggtgagga 323) aggtgggcaggcagcaggtgttggcgctct aaaaataactcccgggagttatttttagag cggaggaatggtggacacccaaatatggcg acggttcctcacccgtcgccatatttgggt gtccgccct CRE0073 (SEQ tccctaacctcctgcttgcgaggcctctct ID NO: 324) ctggcctctgagagggtcagtgtcctgccc caacccatgagatgacagactataatagcc acaggattaacatagcaggcattgtctttc tctgactatagggtgggtattatgtgttca tcaaccatcctaaaaatacccggtaaacag gtgcagcccctgtggctccagtcccctggg atctgttggcttctggctggagatgaagat tagggcagaggagaggtgaattagtctcac tgagttccaggcatgagactcgggtgtcct ttggaacctgggaaatctagattccaggaa acccatctggaggg CRE0074 (SEQ ccatcctaaaaatacccggtaaacaggtgc ID NO: 325) agcccctgtggctccagtcccctgggatct gttggcttctggctggagatgaagattagg gcagaggagaggtgaattagtctcactgag ttccaggcatgagactcgggtgtcctttgg aa CRE0075 (SEQ agggtcagtgtcctgccccaacccatgaga ID NO: 326) tgacagactataatagccacaggattaaca tagcaggcattg CRE0076 (SEQ ctgaggggtgtcagagcacaggctgaggcc ID NO: 327) tcttgcctgacgtgggaccccttggtctgg catttgtcagtgaggcaggctgggggcagg ccccggagcttggcaggaggtgtaaaccgg ccttggaaggtagggccccacaatggggac agttggatctctgagggagacagggaggca tgatcactgccaaatgcccaccaaggacaa ggcacatcccagggagacagacgcagacct ggtgccctctggacactggcattcctggag gctgatgatggacagatgggcctggaggtg gctcttcgccagctggtgtttcctttggac ttcctcagtgtctttggagaagcagagccc taagaataagcagctgcccataaaatctaa taccagccaagcatctcaggaattcatgga ttgtctccat CRE0078 (SEQ ttctgagtcctctaaggtccctcactccca ID NO: 328) actcagccccatgtcctgtcaattcccact cagtgtctgatctccttctcctcacctttc ccatctcccgtttgacccaagcttcctgag ctctcctcccattcccctttttggagtcct cctcctctcccagaacccagtaataagtgg gctcctccctggcctggacccccgtggtaa ccctataaggcgaggcagctgctgtctgag gcagggaggggctggtgtgggaggctaagg gcagctgctaagtttagggtggctccttct ctcttcttagagacaacaggtggctggggc ctcagtgcccagaaaagaaaatgtcttaga ggtatcggcatgggcctggaggagggggga cagggcagggggaggcatcttcctcaggac atcgggtcctagagg CRE0079 (SEQ cctccctggcctggacccccgtggtaaccc ID NO: 329) tataaggcgaggcagctgctgtctgaggca gggaggggctggtgtgggaggctaagggca gctgctaagtttagggtg 48 bp (SEQ ID ttctcctctataaatacccgctctggtatt NO: 330) tggggttggcagctgttg CRE0071.7 cgacacccaaatatggcgacgggtgaggaa (SEQ ID NO: tggtggggagttatttttagagcggtgagg 331) aaggtgggcaggcagcaggtgttggcgctc taaaaataactcccgggagttatttttaga gcggagcgacacccaaatatggcgacgggt gaggaatggtggggagttatttttagagcg gtgaggaaggtgggcaggcagcaggtgttg gcgctctaaaaataactcccgggagttatt tttagagcggagcgacacccaaatatggcg acgggtgaggaatggtggggagttattttt agagcggtgaggaaggtgggcaggcagcag gtgttggcgctctaaaaataactcccggga gttatttttagagcggag CRE0071.10 taaggcgaggcagctgctgtctgaggcagg (SEQ ID NO: acacccaaatatggcgacgggtgaggaatg 332) gtggggagttatttttagagcggtgaggaa ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc gctctaaggtccctcactcccaactcagcc ccatgtcctgtcaattcacccgtcgccata tttgggtgtccgccct CRE0071.11 ctctaaggtccctcactcccaactcagccc (SEQ ID NO: catgtcctgtcaattcgacacccaaatatg 333) gcgacgggtgaggaatggtggggagttatt tttagagcggtgaggaaggtgggcaggcag caggtgttggcgctctaaaaataactcccg ggagttatttttagagcgtaaggcgaggca gctgctgtctgaggcagacccgtcgccata tttgggtgtccgccct CRE0071.12 taaggcgaggcagctgctgtctgaggcaga (SEQ ID NO: ggctaagggcagctgctaagtttagggtct 334) ctaaggtccctcactcccaactcagcccca tgtcctgtcaattccgacacccaaatatgg cgacgggtgaggaatggtggggagttattt ttagagcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc gacccgtcgccatatttgggtgtccgccct DES_MT_ tactaaaaatagaacgactatttttaggct Enhancer_ tttctggcagctggcc 48bp_v2 (SEQ ID NO: 335) DES_MT_ cgaggtactataaatacccttagaggtatt Enhancer_ ttatcttggcagctaggt 48bp_v3 (SEQ ID NO: 336) DES_MT_ tactaaaaatagaacgactatttttaggct Enhancer_ tttctggcagctggccctgccagacagagt 72 bp_v2 (SEQ ID NO: tcctcagtaa 337) DES_MT_Enha cgaggtactataaatacccttagaggtatt ncer_72 bp_v3 ttatcttggcagctaggtctgccagacaga (SEQ ID NO: gttcctcagtaa 338) DES_MT_Enha tactaaaaatagaacgactatttttaggct ncer_72 bp_v4 tttctggcagctggccctgccagacagata (SEQ ID NO: aacgagctat 339) DES_MT_Enha cgaggtactataaatacccttagaggtatt ncer_72 bp_v5 ttatcttggcagctaggtctgccagacaga (SEQ ID NO: taaacgagctat 340) DES_MT_Enha ttaaacgagctattagttatgaggtccgta ncer_72 gattgaataaacgagctattagttatgagg bp_v6 tccgtagattgaa (SEQ ID NO: 341) CRE0071.3 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 293) ggtgaggaatggtggggagttatttttaga gcgtaaacgagctattagttgcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccct CRE0071.4 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 294) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcgaggtaaacgagctattag ttatgaggtccgtagattgaacccgtcgcc atatttgggtgtccgccct CRE0071.6 cgacacccaaatatggcgacgggtgaggaa (SEQ ID NO: tggtggggagttatttttagagcggtgagg 295) aaggtgggcaggcagcaggtgttggcgctc taaaaataactcccgggagttatttttaga gcggagcgacacccaaatatggcgacgggt gaggaatggtggggagttatttttagagcg gtgaggaaggtgggcaggcagcaggtgttg gcgctctaaaaataactcccgggagttatt tttagagcggag CRE0071.8 taaggcgaggcagctgctgtctgaggcagg (SEQ ID NO: acacccaaatatggcgacgggtgaggaatg 296) gtggggagttatttttagagcggtgaggaa ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc ggaggaatggtggacacccaaatatggcga cggttcctcacccgtcgccatatttgggtg tccgccct CRE0071.9 aggctaagggcagctgctaagtttagggtg (SEQ ID NO: acacccaaatatggcgacgggtgaggaatg 297) gtggggagttatttttagagcggtgaggaa ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc ggaggaatggtggacacccaaatatggcga cggttcctcacccgtcgccatatttgggtg tccgccct CRE0077 tctgagggagacagggaggcatgatcactg (SEQ ID NO: ccaaatgcccaccaaggacaaggcacatcc 298) cagggagacagacgcagacctggtgccctc tggacactggcattcctggag CRE0029.2 ctctgtctcctcaggtgcctggctgcttcc (SEQ ID NO: tagctgggcctttccttctcctctataaat 395) accagctctggtatttcgccttggcagctg ttgctgctagggagacggctggcttgacat gcatctcctgacaaaacacaaacccgtggt gtgagtgggtgtgggcggtgtgagtagggg gatgaatcagagagggggc CRE0069.2 agactggggcaggtgcaggctggattgggt (SEQ ID NO: ttccagaggctatatatataaaggctgccg 396) ggagcccacattcctttccagaggccagct ctccatttatagcccctgggcagagcagc CRE0071.13 acacccaaatatggcgacgggtgaggaatg (SEQ ID NO: gtggggagttatttttagagcggtgaggaa 397) ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc ggaggaatggtggacacccaaatatggcga cggttcctcacccgtcgccatatttgggtg tccgccct CRE0071.14 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 398) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcgagctctataaatacccgc tctggtatttggggttttgaacccgtcgcc atatttgggtgtccgccct CRE0071.15 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 399) ggtgaggaatggtggggagctatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaatagctcccgggagct atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccct DES_MT_ ttctcctctataaatacccgctctggtatt enhancer_ tggggttggcagctgttgctgccagggaga 72 bp tggttgggttga (SEQ ID NO: 400) DES_MT_ ttctcctctataaatacccgctctggtatt enhancer_ tggggttggcagctgttg 48bp (SEQ ID NO: 547)
TABLE-US-00018 TABLE 4 Minimal/Proximal Promoters comprised in the promoters of Table 1 Name Sequence CRE0005 (SEQ actcgggggccaggcactggcgctgacgca ID NO: 270) ggctagcagggcgccactggctggtcccca cccacctcggtgggttgggggatgggcgca ccagcccctcctgggtgagccctagcctgg ggcttcctatttcgggagccgggggcgtgg gccacgtctcctcatgtgatgcgagggcta tttaaagcggcagcccgggcagggagccgc cgtcggagcccttgcacgcctgctctcttg tagct CRE0009 (SEQ ctgagtccttttgcatacatttttcaaatg ID NO: 271) ataactcactctacccaccccccttcccta cccccaaggcgatttattgaaaaaaccacc ttatatggtaatattgctaacacaccgtca gctggcctttttagggactttgtttaaaga agatccgcctctggggttttatattgctct ggtattcatgccaaagacacaccag CRE0010 gtttcttagcagctgctgctgtgtccaagg otherwise cttggaattgctgtggtgaatctaaaactg known as: tctcagtagtggtgagctgacctcacccaa CRE0010_ITGB gttcaaagccctactctgcctgatcctttt 1BP2 (SEQ ID ttcctgagcctcagagctaaaatgcccccg NO: 272) agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcgg CRE0010_ALD gccgcgaagaccggaagctggggcggcccc OA (SEQ ID gggccgcgcgcgctgggcctgggaggcgaa NO: 273) actcagcttccttcgtttccgacttttcca tccgcgtcctccacttccccgttccgccct cccccattgccaacattctggctgagtcac ggcgccccagagcgcgccaggctgggggaa aggagcagaagggagggccctagcgacccg cgggatgtggtccgagtcacgtccgagggg ggtggggagggatcgtgttctcggcgcccg ccccttcctagcgcggcctctgggctgcgc ctctcgggggcggcccgtagcccagtccgt cgcctgccattggacgccgcccgctcctcg taaaggaaaaagctcggcggagggcggagt ggtgcctttaaaaggccgggcgccgccttc cgcctgcccgcctcctgcgccgccccttcc gaggctaaatcggctgcgttcctctcggaa cgcgccgcagaaggggtcctggtgacgagt cccgcgttctctcc CRE0034 (SEQ ccatgttcccggcgaagggccagctgtccc ID NO: 274) ccgccagctagactcagcacttagtttagg aaccagtgagcaagtcagcccttggggcag cccatacaaggccatggggctgggcaagct gcacgcctgggtccggggtgggcacggtgc ccgggcaacgagctgaaagctcatctactc tcaggggcccctccctggggacagcccctc ctggctagtcacaccctgtaggctcctcta tataacccaggggcacaggggctgcccccg ggtcaccaccacctccacagcacagacaga cactcaggagccagc CRE0037 (SEQ aggtccctatatggttgtgttagagtgaac ID NO: 275) ggccagcttcagcccgtctttgctccttgt ttgggaagcgagtgggaggggatcagagca aggggctatataacccttcagcgttcagcc tcccgggacaccacccacccagagtggaga agcccagccagtcgctgtca CRE0046 (SEQ cccggcagacgctccttatacggcccggcc ID NO: 276) tcgctcacctgggccgcggccaggagcgcc ttctttgggcagcgccgggccggggccgcg ccgggcccgacacccaaatatggcgacggc cggggccgcattcctgggggccgggcggcg ctcccgcccgcctcgataaaaggctccggg gccggcggcggcccacgagctacccggagg agcgggag CRE0048 (SEQ gactcaggggcgcaggcctcttgcggggga ID NO: 277) gctggcctccccgcccccacggccacgggc cgccctttcctggcaggacagcgggatctt gcagctgtcaggggaggggaggcgggggct gatgtcaggagggatacaaatagtgccgac ggctgggggccctgtctcccctcgccgcat ccactctccggccggccgcctgcccgccgc ctcctccgtgcgcccgccagcctcgcccgc gccgtcacc CRE0049 (SEQ catgttcccggcgaagggccagctgtcccc ID NO: 278) cgccagctagactcagcacttagtttagga accagtgagcaagtcagcccttggggcagc ccatacaaggccatggggctgggcaagctg cacgcctgggtccggggtgggcacggtgcc cgggcaacgagctgaaagctcatctgctct caggggcccctccctggggacagcccctcc tggctagtcacaccctgtaggctcctctat ataacccaggggcacaggggctgccctcat tctaccaccacctccacagcacagacagac actcaggagccagccagc CRE0053 caccgcctgctgccacggccggccgtataa (SRL_mp) atagaggcgaggagcagctgggctctcttg (SEQ ID NO: gcagtcacc 279) CRE0053. 2 ccaccgcctgctgccacggccggccgtata SRL_mp (SEQ aatagaggcgaggagcagctgggctctctt ID NO: 280) ggcagtcacc CRE0054 (SEQ ccagctgcctgccccctgcctggcacagcc ID NO: 281) cgtacctggccgcacgctccctcacaggtg aagctcgaaaactccgtccccgtaaggagc cccgctgccccccgaggcctcctccctcac gcctcgctgcgctcccggctcccgcacggc cctgggagaggcccccaccgcttcgtcctt aacgggcccggcggtgccgggggattattt cggccccggccccgggggggcccggcagac gctccttatacggcccggcctcgctcacct gggccgcggccaggagcgccttctttgggc agcgccgggccggggccgcgccgggcccga cacccaaatatggcgacggccggggccgca ttcctgggggccgggcggcgctcccgcccg cctcgataaaaggctccggggccggcggcg gcccacgagctacccggaggagcgggaggc g CRE0055 (SEQ tcaaagccctactctgcctgatcctttttt ID NO: 282) cctgagcctcagagctaaaatgcccccgag ctctttcctattggctggaaagacgaattg aagttcccttgcccatgttaggaggtgtac gcctcctgaactaaagatagaaacagctgg cccttccaggcagctaaaagcctccagact aagaggtgttccccattcgg CRE0056 (SEQ tcaaagccctactctgcctgatcctttttt ID NO: 283) cctgagcctcagagctaaaatgcccccgag ctctttcctattggctggaaagacgaattg aagttcccttgcccatgttaggaggtgtac gcctcctgaactaaagatagaaacagctgg cccttccaggcagctaaaagcctccagact aagaggtgttccccattcggcagccagact ccttgaaataccctttcagtaatcattcaa ccaacgcttcc CRE0070 (SEQ cggccggggccgcattcctgggggccgggc ID NO: 284) ggtgctcccgcccgcctcgataaaaggctc cggggccggcggcggcccacgagctacccg gaggagcgggaggcg CRE0070.2 cggccggggccgcattcctgggggccgggc (SEQ ID NO: ggtgctcccgcccgcctcgataaaaggctc 285) cggggccggcggcggcccac CRE0072 (SEQ gtttcttagcagctgctgctgtgtccaagg ID NO: 286) cttggaattgctgtggtgaatctaaaactg tctcagtagtggtgagctgacctcacccaa gttcaaagccctactctgcctgatcctttt ttcctgagcctcagagctaaaatgcccccg agctctttcctattggctggaaagacgaat tgaagttcccttgcccatgttaggaggtgt acgcctcctgaactaaagatagaaacagct ggcccttccaggcagctaaaagcctccaga ctaagaggtgttccccattcggcagccaga ctccttgaaataccctttcagtaatcattc aaccaacgcttcc SKM_14 (SEQ ttctcctctataaatacccgctctggtatt ID NO: 287) tggggttggcagctgttgctgccagggaga tggttgggttgacgggatcttgcagctgtc aggggaggggaggcgggggctgatgtcagg agggatacaaatagtgccgacggctggggg ccctgtctcccctcgccgcatccactctcc ggccggccgcctgcccgccgcctcctccgt gcgcccgccagcctcgcccgcgccgtcacc SKM_18.2 ataaatacccgctctggtatttggggttct (SEQ ID NO: cctctataaatacccgctctggtatttggg 288) gttggcagctgttgcgggatcttgcagctg tcaggggaggggaggcgggggctgatgtca ggagggatacaaatagtgccgacggctggg ggccctgtctcccctcgc SKM_18 (SEQ ataaatacccgctctggtatttggggttct ID NO: 289) cctctataaatacccgctctggtatttggg gttggcagctgttgcgggatcttgcagctg tcaggggaggggaggcgggggctgatgtca ggagggatacaaatagtgccgacggctggg ggccctgtctcccctcgccgcatccactct ccggccggccgcctgcccgccgcctcctcc gtgcgcccgccagcctcgcccgcgccgtca cc SKM_20 (SEQ atttttaaagactgaggaattaggcacctg ID NO: 290) tcatttttgccagctggtgtagatgttaaa aattactgtcactcttccgcctgctacttt attttgcacctgctgttacttgagttacag gcatttcacacatggtaatttaataaggtt agttcccatgacacaccgcctgctgccacg gccggccgtataaatagaggcgaggagcag ctgggctctcttggcagtcacc CRE0011_RSV caattctcatgtttgacagcttatcatcgc promoter agatccgtatggtgcactctcagtacaatc (SEQ tgctctgatgccgcatagttaagccagtat ID NO: 291) ctgctccctgcttgtgtgttggaggtcgct gagtagtgcgcgagcaaaatttaagctaca acaaggcaaggcttgaccgacaattgcatg aagaatctgcttagggttaggcgttttgcg ctgcttcgcgatgtacgggccagatatacg cgtatctgaggggactagggtgtgtttagg cgaaaagcggggcttcggttgtacgcggtt aggagtcccctcaggatatagtagtttcgc ttttgcatagggagggggaaatgtagtctt atgcaatactcttgtagtcttgcaacatgg taa cgatgagttagcaacatgccttacaaggag agaaaaagcaccgtgcatgccgattggtgg aagtaaggtggtacgatcgtgccttattag gaaggcaacagacgggtctgacatggattg gacgaaccactgaattccgcattgcagaga tattgtatttaagtgcctagctcgatacaa taaacgccatttgaccattcaccacattgg tgtgcacctccaagctg DES_mp_v1 cgggatcttgcagctgtcaggggaggggag (SEQ ID NO: gcgggggctgatgtcaggagggatacaaat 292) agtgccgacggctgggggccctgtctcccc tcgccgcatccactctccggccggccgcct gcccgccgcctcctccgtgcgcccgccagc ctcgcccgcgccgtcacc
TABLE-US-00019 TABLE 5 Other elements (e.g. introns/UTR) Name Sequence HBB caggtagggactgtactagcagctacaatc (SEQ ID cagctaccattctgcttttattttatggtt NO: 299) gggataaggctggattattctgagtccaag ctaggcccttttgctaatcatgttcatacc tcttatcttcctcccacagctcctgggcaa cgtgctggtctgtgtgctggcccatcactt tggcaaagaatt CMV-IE 5′UTR tcagatcgcctggagacgccatccacgctg and intron ttttgacctccatagaagacaccgggaccg (SEQ atccagcctccgcggccgggaacggtgcat ID NO: 368) tggaacgcggattccccgtgccaagagtga cgtaagtaccgcctatagactctataggca cacccctttggctcttatgcatgaacggtg gagggcagtgtagtctgagcagtactcgtt gctgccgcgcgcgccaccagacataatagc tgacagactaacagactgttcctttccatg ggtcttttctgcag CMV-IE 5′UTR tcagatcgcctggagacgccatccacgctg and intron_v2 ttttgacctccatagaagacaccgggaccg (SEQ ID NO: atccagcctccgcggccgggaacggtgcat 550) tggaacgcggattccccgtgccaagagtga cgtaagtaccgcctatagactctataggca cacccctttggctcttatgcatgaacggtg gagggcagtgtagtctgagcagtactcgtt gctgccgcgcgcgccaccagacataatagc tgacagactaacagactgttcctttccatg ggtcttttctgcagtcaccgtccttgacac g
TABLE-US-00020 TABLE 6 Cis-regulatory elements comprised in the promoters of Table 1A in addition to the CREs presented in Table 3. Name Sequence CRE0080 (SEQ agctttgaggctgtgggcagctcagctgtc ID NO: 401) atgcgggcacacaggtgatgtaagacaata gctgtggagtcagctggcttccaagg CRE0081 (SEQ tgcctgggatcttttcgttctgcccttggc ID NO: 402) tcctgccctaactggcaaacccca CRE0083 (SEQ ccagcccacctgtcccaatgctgacttagt ID NO: 403) gcaaggcgagccagcaaggagggaggacag gtggcagtggggggtgaggagcatctaaaa atagcc CRE0084 (SEQ agtgattctccctcaagaccttataaaacc ID NO: 404) actttaaccctcaatgggataatatctagt acattgtcatgggaactaaccttattaaat taccatgtgtgaaatgcctgtaactcaagt aacagcaggtgcaaaataaagtagcaggcg gaagagtgacagtaatttttaacatctaca ccagctggcaaaaatgacaggtgcctaatt cctcagtctttaaaaataacttttgagaag cctacacagcataagcaaatattttcaagt ttattttttagctatcttcgagttaccttc ctgacaaaatgtaataatatacactgattt ttgcagaaaa CRE0085 (SEQ ataacttcagcacactgtcatgggacctaa ID NO: 405) ccttattaaattaccatgtgtgaagcgtcc ataactcaagtaacagcaggtgcaaaaatg gagctgcaggcagaagagtggtagtcattt ttacaaatccccaccagctggcgaaacaac aggtgcctaattcctcagcttttaaaaata acttttaaaaagcctgtgctgcataagcaa atattttcaagtttgtttttaaaccatctt caagttaccttggtcac CRE0086 (SEQ agggcaccatccggatgcctgcctagttcc ID NO: 406) cttccggccctgatggaggcatgagcctcc cccaccgcctgctcactgctcactcctcgg ccgccagcccagcagctgttgcctcagatc agtgtggaccatctaatcccctctccagag ccctggccccctcctcaggcagtaaattaa ggaggatgtaagaacagagggcaccagcgt cagcagagcggcatccaaaacatcctcccc aacccgcgcctgagtcacagggccctgaat tggcccctct CRE0088 (SEQ atggtgcttccaagtctgctcccgggacgt ID NO: 407) ttcctgttcttggaacagctgcaccagcct ggggtaccctcctgctacttgatcctatag ggaggtgtccagtggctgtgggcaattttc agatgaccttgttcgtctgacgtcattaga tcgctatttttggctttgctgtttatgctg cagaagttgggctggaatgggagaggagga atgaaggaggggctgctcttggtttcccat tgttccaggg CRE0089 (SEQ actgatgtggaaggggttatatataggaag ID NO: 408) atgtgtaggaagaaaaaggtagagagctct cctcagagggtgggggattatgggtagcca gagggagcctgggttagtggagttgaagcc ctagtcttgggtgctttgtagcatcagaag cctctggagcctttgctgacacctgcctga tgtacggagccatctgtgggtgtctgtgtg ctggaggattgcccacagctatgattcaga gatgctcatgttgttgcccaagcaattgac agatgatgtttcaggcttggagatggcagg atgggagcaaagagaagccaggtcaggaaa gaacgtgccgttctggccctagtggggaat tctgggcctt CRE0090 (SEQ gggagagccaggacattggctgcctgtggt ID NO: 409) cttggtggtcgtggtcagttccctctcctg ccagctgtggaatgtgaggcctggcctggg agatatttttgctgcactttgagccacccc gccccctggaactcagaccctgcacagtcc atgccataacaatgacgaccacttccaatt gtttcctagctggagaggcggggaggggag cactgtttgggaagggggggagcctggggg aaatgcttct CRE0091 (SEQ tccatgccataacaatgacgaccacttcca ID NO: 410) attgtttcctagctgg CRE0020.2 ccacagcagctgggggcatttatgggcctt (SEQ ID NO: cctataaacttctgagagggtaactttatc 411) ctgcttctttcagccaagtatcctcctcca gcagctggtcacaaagctggttaatctccc agagtgctcagcttaaaacccgtgactcac agcacagccagtgtgggggagggggtggct gcctccaatacgtggcgcccagagtcagct gttctggggccttctctggtttctccaact gagtcctgaggtttgg CRE0093 (SEQ ccacagcagctgggggcatttatgggcctt ID NO: 412) cctataaacttctgagagggtaactttatc ctgcttctttcagccaagtatcctcctcca CRE0094 (SEQ aaacccgtgactcacagcacagccagtgtg ID NO: 413) ggggagggggtggctgcctccaatacgtgg cgcccagagtcagctgttctggggccttct ctggtttctccaactgagtcctgaggtttg g CRE0016.1 ggcaggcggacctggtggtcagacctcagt (SEQ ID NO: gatcctcagggaccagtgaatatttcaggc 414) tggggctgagcatcacctgctcccttggcc ccacttatagggcaaaggggagtctaccag cctactcactgatgacaaactggaaaagtt tgtcctgtctctgctctggccccacctcgc cctctcccctacttggaagttcctttcctg aaccactgactgc CRE0004 (SEQ ttctgactgggtcccttaccactgtctttg ID NO: 415) caaatggcatttccattaacatttctattt ctggccattaggggcacctaaagatttccc accaagattgacagccactattttaagaaa gtgcttttaaaaagccagtgcttttgctaa gtttaaatctgactttctcaggggatgctt aaaagaaatacacagtttgtttgttttttt tttaagaacctttgcaagttcaaaataaca ttccagaaggagtcactagaaaaacattca agggaagagaaaaaaattgttttcgtttgt agcagacctggcttcatccaaatgttctat ttgttttttactgca CRE0095 (SEQ aaactttaaagattagctattaaaaatgcc ID NO: 416) attttacataaattaattggtttttatcag agtagtataatagtaaactactttttgtct aatgacttctgttcacaggtgaagtggtat aatctgcccttgtttatatttttggttgtc tgaataagatgggaaatatttttaatatgc aggggcagtagtgaggcaccaagattccat gcacttcctgtcagcaaaggtatcaactgc caggaacccctgataagtcctattttgagc aagcagtgtcaggataacagaagacagaca cagtttactgctgtgaggctggcagcagag ccaactgcactaccatcctaatcacaacag acactctggagttagacaaagccaag CRE0096 (SEQ gaagcaacacatgccccttcccaaaaatat ID NO: 417) ctagccagtgcctaatgccagattgtcaag tagaaagtctgtccagcagtgagacggagg tcgttctcctaatctgtcctgcattcccct gcactctaaaaggagatccaccaggccagg acaggcaagttggctctacacgtagctgca aatagaagcagggctcaagccatccatagc tcgactcacttactaaataaggatgaaaca ataccgggttcacttctctgacacattccc ctgtctacgacgagggctgggtggagagag cagggaagtccacagtgcactattgttagc ctttatcaagaaacatgacaaatgaccctg aaatggagcctcttatcacccaaacctctc cacagcctgcacaaggagcagctgcagtcc at CRE0097 (SEQ gatcctctgcctggcaggggggtggcctta ID NO: 418) tttagcctggcctggctcctctgagctttc ttgggaatgtctatatataggggaagagcg cagcccagttgccactgtccatctgccttc cttggactctggtccacccctccctgaccc tgggctccattttctttctg CRE0098 (SEQ tgccactttcttctgcgtacccctcctact ID NO: 419) tgacttgaagaagtaattggactccagaga ccagctgccattgcccatgcccaactaaaa atagcctatcctcctggatcaggccaaggg ccggaggagggaaggaggaactgggccagc tggctgaaggatgtcttgggactcgtcacc ccttcttcaccatcccgagtccaaagccct gacccagatggcctggcttg
TABLE-US-00021 TABLE 7 Minimal/Proximal Promoters comprised in the promoters of Table 1A in addition to the minimal or proximal promoters in Table 4. Name Sequence CRE0092 (SEQ tgacaatccctgcctgggatcttttcgttc ID NO: 420) tgcccttggctcctgccctaactggcaaac cccaccccctcatcaccagctttcaagtat cagattgcgtttccggcctcttctttccaa acccctaaaccaccagcacctgtccccttg cttgcctcattccacagccaacaggctgaa gggaagacaaaccctagtcagtcagaggtg gggg CRE0087 (SEQ attattcacctgttcgccttagatgaagaa ID NO: 421) tcaaggaacagcagctctagggggttggga ggagttagggtccggccctgccccagacct ctcagtgtccaatttctctgtgtcagctgt gtttctcagctgtccactttcctccagccc tgtcatttcagccctgacaccaaggcagga ggctaggaggtctacaaatagcgactgggt agctggtgtgaacacagggggtactggggg ggcttagcccccaaggaagaggaccagt CRE0082 (SEQ gggataaaagcagtctgggctttcacatga ID NO: 422) cagcatctggggctgcggcagagggtcggg tccgaagcgctgccttatcagcgtccccag ccctgggaggtgacagctggctggcttgtg tcagcccctcgggcactcacgtatctccgt ccgacgggtttaaaatagcaaaactctgag gccacacaatagcttgggcttatatgggct cctgtgggggaagggggagcacggaggggg ccggggccgctgctgccaaaatagcagctc acaagtgttgcattcctctctgggcgccgg gcacattcctgctggctctgcccgccccgg ggtgggcgccggggggaccttaaagcctct gccccccaaggagcccttcccagacagccg ccggcacccaccgctccgtgggac CRE0048.1 gactcaggggcgcaggcctcttgcggggga (SEQ ID NO: gctggcctccccgcccccacggccacgggc 423) cgccctttcctggcaggacagcgggatctt gcagctgtcaggggaggggaggcgggggct gatgtcaggagggatacaaatagtgccgac ggctgggggccctgtctcccctcgccgcat ccactctccggccggccgcctgcccgccgc ctcctccgtgcgcccgccagcctcgcccgc gcc
TABLE-US-00022 TABLE 8 Cis-regulatory elements comprised in the promoters of Table 1B and 1C in addition to the CREs presented in Table 3 and/or Table 6. Name Sequence CRE0105 (SEQ Ccagcagtttcatccctagaccatcccaaa ID NO: 462) catggttgagaagctctgaggggaggaccc agcactgcccggcccctgaagtatctaatc agcagtcctgctcagcatatcaatccaagc ccactctagacagagatgccggtgcccagt tttctatttttaactggtgtgaactgaagg aaaagcacagcattagaagtccaagcacta gtcaagaaccaagaatacagggcaccccag ggcaagc CRE0106 (SEQ Gtcaccctctgcttccctgcatgggtcctg ID NO: 463) ttgccagggagaaagaatcctgaggcgagc gcccaggaagataaccaaggactcttttct gctcctctcacacctttgaagtgggggcct cttgaggcaaatcagcaagaatgtgactct tgcagctgagggtctgggggaggggggtga gtggagctgctcaaggcaaaggggccgtga caagctttgccgaactgata CRE0107 (SEQ Cctgggctcctggcatctgctttatcggga ID NO: 464) ttctcaagagggacagctggtttatgttac aagcctgttccctgcatatctgctctggtt ttaaatagctttatctgagcagctggagga ccacatgagcttatatggcgtggggtactt gttcttttagccctgtgccgggcacctgcc aaaatagcagccaacaccccccattgtgtt g CRE0108 (SEQ Ccagttgttcaactcacccttcagattaaa ID NO: 465) aataactgaggtaagggcctgggtagggga ggtggtgtgagacgctcctgtctctcctct atctgcccatcggccctttggggaggagga atgtgcccaaggactaaaaaaaggccatgg agccagaggggcgagggcaacagacctttc atgggcaaaccttggggccctg CRE0109 (SEQ Tgctgagcccagaaaaactgaccgccctgt ID NO: 466) gtcctgcccacctccacactctagagctat attgagaggtgacagtagatagggtgggag ctggtagcagggagagtgttcctgggtgtg agggtgtaggggaaagccagagcaggggag tctggctttgcctcctgaacacaatgtcta cttagttataacaggcatgacctgctaaag acccaacatctacgacctctgaaaagacag ca CRE0111 (SEQ Agcggagccgagggggcagcgcgtgacccc ID NO: 467) gagcggaagggccccagtctgggtcctaat gcgggtggcgtctctcttgacaggcagcgt ttggggacaacagcggggaagggagataag atgacataccagagcagatttggtgtgcgc gctgatactcctggcccgacaggaaactcg gagctatttaaaaaggccctatcgattact ttatcttccccggaggaaaacttcttgccg agagacaaaagatgtccccctac CRE0114 (SEQ Cctctagaggcaggtgaccttgatgaaagg ID NO: 468) ccttcagtgtgacacaggtgtaaaaatagc ctctgtgctgacttaactccctggcttgag caaacggcccctcacacctgtatattgttt gcttggcatagacacactgctacctgtttg caggtgtaaatgactgtttatgtacccaga gttatgag CRE0117 (SEQ Taagtgtgatgcacagtgcttgcattttct ID NO: 469) tgatacgttagtcatatgagagctgacaaa gaaggaaaaagagcagcgatgtggtgcaat attaacaggcagctgtcccctggcttcccg atacgtgggatgactcgcattgctgagcgg tgtggtcactgccaaaggaatgaccctctc acatttcttcctgattcgcatacgccgcgg ccagcttgtcatctccctcttgggcttccc agacactaagtctggaatgaaaattcacct gcctctgaattggccactgg CRE0118 (SEQ aaacttaagtgctgaagatagcacttgcct ID NO: 470) ggttctattttagtaggtccctggcagcca gtcagcaagtgcagttgctcaagtgtgctt ttggatcattgagtttcgtgtactggccat atcaggacaaggagaggccatgggaaaaaa tagtccagcatctgatagtgtcaggtagtg ttatccctgtcagggtgacagttgaagtgt ttgagtaatagcagtgtcagcagatgccca gagtttaacatgtactcacttcaaaaggga cagctgatctaagtgctggat CRE0071.16 caccgcggtggcggccgtccgccctcggat (SEQ ID NO: agctcgtttagacacccaaatatggcgacg 533) gtaaacgagctattgggagttatttttaga gcgtaaacgagctattagttgcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccct CRE0071.17 caccgcggtggcggccgtccgccctcggat (SEQ ID NO: agctcgtttagacacccaaatatggcgacg 534) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccct CRE0071.18 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 535) gtaaacgagctattgggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtccgccct CRE0071.19 acacccaaatatggcgacgggtgaggaatg (SEQ ID NO: gtggggagttatttttagagcggtgaggaa 536) ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc gcccgtcgccatatttgggtgtccgccct CRE0071.5 acacccaaatatggcgacgggtgaggaatg (SEQ ID NO: gtggggagttatttttagagcggtgaggaa 537) ggtgggcaggcagcaggtgttggcgctcta aaaataactcccgggagttatttttagagc gagctctataaatacccgctctggtatttg gggttttgaacccgtcgccatatttgggtg tccgccct CRE0071.20 ggccgtccgccctcggcaccatcctcacga (SEQ ID NO: cacccaaatatggcgacgggtgaggaatgg 538) tggggagctatttttagagcgtaaacgagc tattagttgcagcaggtgttggcgctctaa aaatagctcccgggagctatttttagagcg gaggaatggtggacacccaaatatggcgac ggttcctcacccgtcgccatatttgggtgt ccgccct CRE0071.21 ggccgtccgccctcggcaccatcctcacga (SEQ ID NO: cacccaaatatggcgacgggtgaggaatgg 539) tggggagctatttttagagcgtaaacgagc tattagttgcagcaggtgttggcgctctaa aaatagctcccgggagctatttttagagcg agctctataaatacccgctctggtatttgg ggttttgaacccgtcgccatatttgggtgt ccgccct CRE0071.22 ggccgtccgccctcgggacacccaaatatg (SEQ ID NO: gcgacgggggagttatttttagagcgggca 540) ggcagcaggtgttggcgctctaaaaataac tcccgggagttatttttagagcggaggaat ggtggacacccaaatatggcgacggttcct cacccgtcgccatatttgggtgtccgccct CRE0071.23 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 541) ggtgaggaatggtggggagttatttttaga gcggtgaggaaggtgggcaggcagcaggtg ttggcgctctaaaaataactcccgggagtt atttttagagcg CNTRL_001 aggcagtgtatactcttccataaacgagct (67 bp) attagttatgaggtccgtagattgaaaagg (SEQ ID NO: gtgacgg 542) CRE0071.24 caccgcggtggcggccgtccgccctcggca (SEQ ID NO: ccatcctcacgacacccaaatatggcgacg 543) ggtgaggaatggtggggataaacgagctat gcggtgaggaaggtgggcaggcagcaggtg ttggcgcatagctcgtttatcccgggataa acgagctatgcggaggaatggtggacaccc aaatatggcgacggttcctcacccgtcgcc atatttgggtgtcegccct CNTRL_001 aggcagtgtatactcttccataaacgagct (SEQ ID NO: attagttatgaggtc 544) CRE0093.2 ccacagcagctgggggcatttctgagaggg (SEQ ID NO: taactttatcctgcttctttcagccaagta 545) CRE0094.2 ctcacagcacagccagtgtgggggaggggg (SEQ ID NO: tggctgcctccgtggcgcccagagtcagct 546) gttctggggccttctctggtttctccaact gagtcctgaggtttgg
TABLE-US-00023 TABLE 9 Minimal/Proximal Promoters comprised in the promoters of Table 1B and 1C in addition to the minimal or proximal promoters in Table 4 and/or Table 7. Name Sequence CRE0038 ggccccagccactgtctctttaaccttgaa (SEQ ggcatttttgggtctcacgtgtccacccag ID NO: 471) gcgggtgtcggactttgaacggctcttact tcagaagaacggcatggggtgggggggctt aggtggcctctgcctcacctacaactgcca aaagtggtcatggggttatttttaacccca gggaagaggtatttattgttccacagcagg ggccggccagcaggctccttgaattcttca gaggcagcagccagcctcagacacc CRE0104 gtctagactcttggatttgagagaagaggg (SEQ accttgctccgggttttcctaagtttgagg ID NO: 472) gaggagggagctggggcgctagagtcaaag gaggaggggtgtagatcctgggcaccttgg ttgacccaactggagctttgcacacggctc ccctcacaccctgttatcgcttatcctggg caggggaggagacagcagtatatttagtct ttgtcctcgccccttatctcagtgtcctca gtgaggcttgagcagcccagaggaaaccca acctctagagacctccaaggtcaccaggga cacccttccaggaccctccaggaatctccg atcctgttctctgcctctggagatcatc CRE0110 Tatgtctatattaggtgacgcagaactgcc (SEQ cgtcgctcctgtcatccaggcccctggccc ID NO: 473) aatggcaggctgaatcccccctactccagc ctgctcccgcctcttctgcccctggtgctc cgcgctacctgctgccgcgcgccacatcca gggcagagaggcgggtgcgcgggcgggcgg cgggcaccatgcggggaggctgtccccagg ggtgggcagcaccactctctgctacccacc tggcgctgtgaaacctgcgtcgccacc CRE0112 ggccccagccactgactctttaaccttgaa (SEQ ggcatttttgggtctcacgtgtccacccag ID NO: 474) gcgggtggccgcctttgagcagctcttact tcagaagaacggcatggagtggggggtggg gggcttaggtggcctccgcctcacctacaa ctgccaaaagtggtcatggggttattttta accccaggggagaggtatttattgttccac agcaggggcagaggccagcaggctcctcga actctccagaggtggcaa CRE0113 gactcgctgaattaatgaatcacttttctt (SEQ atctattttttgctgttatctaattctgag ID NO: 475) agggaagccgggagcagagggagttgggag acgtagctcacaacgtctccctcccacccg gctcaaacaggctggaatctctgggcctag agg CRE0115 Gggctggctgaaaggatgtctatatgtgta (SEQ tttttatcacccatgtgtcggatgagcctg ID NO: 476) agagctgccagatagctttctcgacagctt ggcgttagtgttgggaacaggtccatgtat ggaagcgaaagccgaaaggcacagataagc taagagccagctatgcagccatgcttagag acactaaggacaggctccccgggtcctttc tttctggtctatctggagcagccttcagag ctggtcggtttctcatccagcccatgca CRE0116 Aagatacctcagctggatggaatttgtcta (SEQ tatttagcaggtggctagcaggaggctgat ID NO: 477) aagcagggctggggagggggcagtcctcat aaatagtgagaacacaggacactgttcagt ccctccttgggtggcctgcttg CRE0099 ccactacgggtctaggctgcccatgtaagg (SEQ aggcaaggcctggggacacccgagatgcct ID NO: 300) ggttataattaacccagacatgtggctgcc cccccccccccaacacctgctgcctctaaa aataaccctgtccctggtggatcccctgca tgcgaagatcttcgaacaaggctgtggggg actgagggcaggctgtaacaggcttggggg ccagggcttatacgtgcctgggactcccaa agtattactgttc
TABLE-US-00024 TABLE 10 Schematic representation of the cardiac-specific promoters according to embodiments of this invention with the cis-regulatory elements and minimal or proximal promoters indicated Minimal or proximal 5′Intron/ CRE CRE promoter 5′UTR SP0344 CRE0033 CRE0038 SP0433 CRE0033 CRE0071.3 CRE0070 SP0435 CRE0033 CRE0082 SP0436 CRE0033 CRE0033 SKM_18 SP0449 CRE0004 CRE0033 SKM_18 SP0450 CRE0095 CRE0033 SKM_18 SP0451 CRE0096 CRE0033 SKM_18 SP0452 CRE0082 CRE0033 SKM_18 SP0475 CRE0033 SKM_18 CMV-IE 5′UTR and intron SP0476 CRE0105 SKM_18 SP0477 CRE0106 SKM_18 SP0478 CRE0107 SKM_18 SP0479 CRE0108 SKM_18 SP0480 CRE0109 SKM_18 SP0481 CRE0033 CRE0110 SP0482 CRE0111 SKM_18 SP0483 CRE0033 CRE0112 SP0484 CRE0033 CRE0113 SP0485 CRE0114 SKM_18 SP0486 CRE0033 CRE0115 SP0487 CRE0033 CRE0116 SP0488 CRE0117 SKM_18 SP0489 CRE0033 CRE0104 SP0490 CRE0106 CRE0110 SP0491 CRE0107 CRE0110 SP0492 CRE0106 CRE0116 SP0493 CRE0107 CRE0116 SP0494 CRE0118 SKM_18 SP0495 CRE0106 CRE0033 CRE0116 SP0496 CRE0107 CRE033 CRE0116
TABLE-US-00025 TABLE 11 CRE ID Notes CRE0010_ITGB1BP2 (SEQ ID NO: 272) CRE0055 (SEQ ID NO: 282) Shorter version of CRE0010 (SEQ ID NO: 272) CRE0056 (SEQ ID NO: 283) CRE0055 (SEQ ID NO: 282) + 5′ UTR CRE0072 (SEQ ID NO: 286) CRE0010 (SEQ ID NO: 272) + 5′ UTR CRE0020 (SEQ ID NO: 303) CRE0020.2 (SEQ ID NO: 411) Shorter version of CRE0020 (SEQ ID NO: 303) CRE0093 (SEQ ID NO: 412) Portion of MUS_CRE0020 (SEQ ID NO: 303) CRE0094 (SEQ ID NO: 413) Portion of MUS_CRE0020 (SEQ ID NO: 303) CRE0093.2 (SEQ ID NO: 545) Shorter version of CRE0093 (SEQ ID NO: 412) CRE0094.2 (SEQ ID NO: 546) Shorter version of CRE0094 (SEQ ID NO: 413) CRE0028 (SEQ ID NO: 306) CRE0117 (SEQ ID NO: 469) Bigger version of CRE0028 (SEQ ID NO: 306) CRE0029 (SEQ ID NO: 307) CRE0029.2 (SEQ ID NO: 395) Shorter fragment of CRE0029 (SEQ ID NO: 307) CRE0033 (SEQ ID NO: 309) CRE0108 (SEQ ID NO: 465) Variation of CRE0033 (SEQ ID NO: 309) CRE0035 (SEQ ID NO: 310) CRE0050 (SEQ ID NO: 313) Variation of CRE0035 (SEQ ID NO: 310) CRE0099 (SEQ ID NO: 300) Variation of CRE0035 (SEQ ID NO: 310) CRE0047 (SEQ ID NO: 312) DES_MT_enhancer_48bp (SEQ ID NO: 547) Short version of CRE0047 (SEQ ID NO: 312) DES_MT_enhancer_48bp_v2 (SEQ ID NO: 335) Variation of CRE0047 (SEQ ID NO: 312) DES_MT_enhancer_48bp_v3 (SEQ ID NO: 336) Variation of CRE0047 (SEQ ID NO: 312) DES_MT_enhancer_72bp (SEQ ID NO: 400) Short version of CRE0047 (SEQ ID NO: 312) DES_MT_enhancer_72bp_v2 (SEQ ID NO: 337) Variation of CRE0047 (SEQ ID NO: 312) DES_MT_enhancer_72bp_v3 (SEQ ID NO: 338) Variation of CRE0047 (SEQ ID NO: 312) DES_MT_enhancer_72bp_v4 (SEQ ID NO: 339) Variation of CRE0047 (SEQ ID NO: 312) DES_MT_enhancer_72bp_v5 (SEQ ID NO: 340) Variation of CRE0047 (SEQ ID NO: 312) DES_MT_enhancer_72bp_v6 (SEQ ID NO: 341) Variation of CRE0047 (SEQ ID NO: 312) CRE0059 (SEQ ID NO: 317) Shorter version of CRE0047 (SEQ ID NO: 312) CRE0060 (SEQ ID NO: 318) Shorter version of CRE0047 (SEQ ID NO: 312) CRE0049 (SEQ ID NO: 278) CRE0034 (SEQ ID NO: 274) Variant of CRE0049 (SEQ ID NO: 278) CRE0052 (SEQ ID NO: 315) CRE0084 (SEQ ID NO: 404) Longer version of CRE0052 (SEQ ID NO: 315) CRE0053 (SEQ ID NO: 279) CRE0053. 2 (SEQ ID NO: 280) One bp extension of CRE0053 (SEQ ID NO: 279) CRE0069 (SEQ ID NO: 320) CRE0069.2 (SEQ ID NO: 396) Shorter version of CRE0069 (SEQ ID NO: 320) CRE0070 (SEQ ID NO: 284) CRE0054 (SEQ ID NO: 281) Longer version of CRE0070 (SEQ ID NO: 284) CRE0046 (SEQ ID NO: 276) Longer version of CRE0070 (SEQ ID NO: 284) CRE0071 (SEQ ID NO: 321) CRE0051 (SEQ ID NO: 314) Longer version of CRE0071 (SEQ ID NO: 321) CRE0071.2 (SEQ ID NO: 323) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.3 (SEQ ID NO: 293) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.4 (SEQ ID NO: 294) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.5 (SEQ ID NO: 537) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.6 (SEQ ID NO: 295) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.7 (SEQ ID NO: 331) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.8 (SEQ ID NO: 296) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.9 (SEQ ID NO: 297) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.10 (SEQ ID NO: 332) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.11 (SEQ ID NO: 333) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.12 (SEQ ID NO: 334) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.13 (SEQ ID NO: 397) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.14 (SEQ ID NO: 398) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.15 (SEQ ID NO: 399) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.16 (SEQ ID NO: 533) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.17 (SEQ ID NO: 534) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.18 (SEQ ID NO: 535) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.19 (SEQ ID NO: 536) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.20 (SEQ ID NO: 538) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.21 (SEQ ID NO: 539) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.22 (SEQ ID NO: 540) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.23 (SEQ ID NO: 541) Variant of CRE0071 (SEQ ID NO: 321) CRE0071.24 (SEQ ID NO: 543) Variant of CRE0071 (SEQ ID NO: 321) CRE0073 (SEQ ID NO: 324) CRE0074 (SEQ ID NO: 325) Shorter version of CRE0073 (SEQ ID NO: 324) CRE0075 (SEQ ID NO: 326) Shorter version of CRE0073 (SEQ ID NO: 324) CRE0076 (SEQ ID NO: 327) CRE0077 (SEQ ID NO: 298) Shorter version of CRE0076 (SEQ ID NO: 327) CRE0081 (SEQ ID NO: 402) CRE0092 (SEQ ID NO: 420) Longer version of CRE0081 (SEQ ID NO: 402) CRE0090 (SEQ ID NO: 409) CRE0091 (SEQ ID NO: 410) Shorter version of CRE0090 (SEQ ID NO: 409)