COMPOSITIONS AND METHODS FOR COMBINATORIAL ASSEMBLY AND SCREENING FOR FUNCTIONAL SITE-DIRECTED NUCLEOTIDE MODIFIERS

Abstract

The present invention discloses a method where a site-directed nuclease (e.g. Cas nuclease) as well as a nucleotide modifying enzyme (e.g. deaminase) are provided as modules of a sequence assembly system, such as a golden gate cloning system, comprising cloning sites and/or regulatory sites. The assembly system provides capacities for generating a polypeptide consisting of at least two standardised modules, each which can be composed of multiple peptide motifs, which optionally can be joined along with other standardised modules for extending the polypeptide's functionality further. New assemblies intended for site-directed nucleotide modification are also provided in this invention.

Claims

1. A method for obtaining assemblies of site-directed nucleases and nucleotide-modifying enzymes, the method comprising: a. providing a library of modular nucleic acid sequences comprising i. two or more site-directed nuclease modules each comprising a nucleic acid sequence encoding a different site-directed nuclease, ii. two or more nucleotide-modifying enzyme modules each comprising a nucleic acid sequence encoding a different nucleotide-modifying enzyme, and b. constructing two or more nucleic acid assemblies in vitro, wherein each nucleic acid assembly is constructed by joining a site-directed nuclease module with a nucleotide-modifying enzyme module to generate an nucleic acid assembly that encodes the site-directed nuclease and the nucleotide-modifying enzyme operably linked to express as a single polypeptide; c. expressing the two or more nucleic acid assemblies constructed in step (b) to produce the site-directed nucleases and the nucleotide-modifying enzymes as single polypeptides; and d. detecting a nucleotide-modifying activity for each of the single polypeptides expressed in step (c).

2. The method of claim 1, further comprising: e. analyzing each nucleotide-modifying activity detected to select one or more optimal nucleic acid assemblies.

3. The method of claim 1, wherein: i. the site directed nucleases comprise one or more Cas nucleases, one or more Cas nickases, one or more dead Cas nickases, or any combination thereof; and/or ii. the nucleotide-modifying enzymes comprise one or more deaminases, one or more demethylases, one or more methyltransferases, or any combination thereof.

4. The method of claim 1, wherein: i. the site-directed nucleases are each independently selected from the group consisting of AsCas12a, Cas12a (Cpf1), Cas12b, Cas12e (CasX), Cas12j, Cas12f, Cas13a, Cas13b, Cas13d, Cas14a, Cas9, dCas9, Cas9-NGv1, CasX, CasY, CasΦ, CasΦ-2 (CasPhi2), dCasΦ-2 (dCasPhi2), CjCas9, eCas9, enAsCas12a, enAsCas12a-HF1, enLbCas12a, ErCas12a, eSpCas9, eSpCas9-1.1, FnCas12a, FnCas9, HF-nCAS9, HF2-CAS9, HypaCas9, LbCas12a, d(LbCas12a), MbCas12a, NmCas9, SaCas9, SaurCas9, SauriCas9, ScCas9, SpCas9, SpCas9-HF1, SpCas9-NG, SpG, SpRY, SpyoCas9, St1Cas9, St3Cas9, StCas9, ttLbCas12a, xCas9, xCas9(3.6), and xCas9(3.7); and/or ii. the nucleotide-modifying enzymes are selected from the group consisting of APOBEC, APOBEC-like enzymes, AID, AID-like enzymes, A3A, DNMT3A, MQ3, LSD1, RrA3F, RrA3F-F130L, AmA1, SsA3B, SsA3B-R54Q, PpA1, PpA1-H122A, PpA1-R33A, Anc-rA1, rA1, AID, pmCDA1, A3A, eA3A, rA1-YE1, rA1-EE, rA1-YE2, rA1-YEE, A3A-Y130F, A3A-Y132D, A3B, AIDmono, TadA-7.10, CGBE1, hA3G-CTD, evoAPOBEC1, evoCDA1, evoFERNY, TadA-8e, TadA-9, minStart, and mTadA8e.

5. The method of claim 1, wherein step (b) comprises: (i) constructing a combinatorial library of nucleic acid assemblies in vitro; (ii) constructing a plurality of nucleic acid assemblies in parallel in a single reaction; and/or (iii) constructing two or more destination vectors, each comprising one of the nucleic acid assemblies.

6. The method claim 5, wherein constructing the two or more destination vectors comprises mixing two or more nucleic acid molecules each comprising one of the site-directed nuclease modules, one of the nucleotide-modifying enzyme modules, one of the additional modules, a protein-coding sequence, a regulatory sequence, or any combination thereof to produce the destination vectors.

7. The method of claim 6, wherein the nucleic acid molecules comprise: i. one or more donor vectors each comprising one of the site-directed nuclease modules or one of the nucleotide-modifying enzyme modules; and/or ii. one or more receiver vectors each comprising one of the site-directed nuclease modules or one of the nucleotide-modifying enzyme modules.

8. The method of claim 5, wherein each destination vector further comprises a first promoter, a terminator, or a combination thereof, each operably linked to the nucleic acid assembly for expression of the nucleic acid assembly.

9. The method of claim 5, wherein the destination vector further comprises a gRNA expression cassette comprising a gRNA sequence operably linked to a second promoter, a target-reporter expression cassette, or a combination thereof.

10. The method of claim 9, wherein the target-reporter expression cassette comprises a target sequence and a reporter sequence operably linked to a third promoter, wherein the target sequence and the reporter sequence are operably linked to express as a single reporter polypeptide, wherein the target sequence comprises one or more target nucleotides for editing, wherein editing of the one or more target nucleotides results in the formation of an edited target sequence having one or more stop codons, and wherein editing of the one or more target nucleotides results in the non-expression of the reporter polypeptide.

11. The method of claim 10, wherein step (e) further comprises: i. identifying the modified sites in each of the edited target sequences; ii. determining the sequence context of the modified sites in each of the edited target sequences; and/or iii. identifying the window of modification in each of the target sequences.

12. A method of selecting an optimal nucleic acid assembly for editing a target nucleotide, comprising the steps of claim 2.

13. A library of nucleic acid assemblies of site-directed nucleases and nucleotide-modifying enzymes, comprising i. two or more site-directed nuclease modules each comprising a nucleic acid sequence encoding a different site-directed nuclease, and ii. two or more nucleotide-modifying enzyme modules each comprising a nucleic acid sequence encoding a different nucleotide-modifying enzyme; wherein each nucleic acid assembly comprises a site-directed nuclease module and a nucleotide-modifying enzyme module, wherein each nucleic acid assembly encodes the site-directed nuclease, the nucleotide-modifying enzyme.

14. The library of claim 13, wherein: i. the site directed nucleases comprise one or more Cas nucleases, one or more Cas nickases, one or more dead Cas nickases, or any combination thereof; and/or ii. the nucleotide-modifying enzymes comprise one or more deaminases, one or more demethylases, one or more methyltransferases, or any combination thereof.

15. The library of claim 13, wherein: i. the site-directed nucleases are each independently selected from the group consisting of AsCas12a, Cas12a (Cpf1), Cas12b, Cas12e (CasX), Cas12j, Cas12f, Cas13a, Cas13b, Cas13d, Cas14a, Cas9, dCas9, Cas9-NGv1, CasX, CasY, CasΦ, CasΦ-2 (CasPhi2), dCasΦ-2 (dCasPhi2), CjCas9, eCas9, enAsCas12a, enAsCas12a-HF1, enLbCas12a, ErCas12a, eSpCas9, eSpCas9-1.1, FnCas12a, FnCas9, HF-nCAS9, HF2-CAS9, HypaCas9, LbCas12a, dLbCas12a, MbCas12a, NmCas9, SaCas9, SaurCas9, SauriCas9, ScCas9, SpCas9, SpCas9-HF1, SpCas9-NG, SpG, SpRY, SpyoCas9, St1Cas9, St3Cas9, StCas9, ttLbCas12a, xCas9, xCas9(3.6), and xCas9(3.7); and/or ii. the nucleotide-modifying enzymes are selected from the group consisting of APOBEC, APOBEC-like enzymes, AID, AID-like enzymes, A3A, DNMT3A, MQ3, LSD1, RrA3F, RrA3F-F130L, AmA1, SsA3B, SsA3B-R54Q, PpA1, PpA1-H122A, PpA1-R33A, Anc-rA1, rA1, AID, pmCDA1, A3A, eA3A, rA1-YE1, rA1-EE, rA1-YE2, rA1-YEE, A3A-Y130F, A3A-Y132D, A3B, AIDmono, TadA-7.10, CGBE1, hA3G-CTD, evoAPOBEC1, evoCDA1, evoFERNY, TadA-8e, TadA-9, minStart, and mTadA8e.

16. A base editor for editing a target nucleotide, wherein the base editor comprises: i. a site-directed nuclease module comprising a site-directed nuclease selected from the group consisting of AsCas12a, Cas12a (Cpf1), Cas12b, Cas12e (CasX), Cas12j, Cas12f, Cas13a, Cas13b, Cas13d, Cas14a, Cas9, dCas9, Cas9-NGv1, CasX, CasY, CasΦ, CasΦ-2 (CasPhi2), dCasΦ-2 (dCasPhi2), CjCas9, eCas9, enAsCas12a, enAsCas12a-HF1, enLbCas12a, ErCas12a, eSpCas9, eSpCas9-1.1, FnCas12a, FnCas9, HF-nCAS9, HF2-CAS9, HypaCas9, LbCas12a, dLbCas12a, MbCas12a, NmCas9, SaCas9, SaurCas9, SauriCas9, ScCas9, SpCas9, SpCas9-HF1, SpCas9-NG, SpG, SpRY, SpyoCas9, St1Cas9, St3Cas9, StCas9, ttLbCas12a, xCas9, xCas9(3.6), and xCas9(3.7); and ii. a nucleotide-modifying enzyme module comprising a nucleotide-modifying enzyme selected from the group consisting of APOBEC, APOBEC-like enzymes, AID, AID-like enzymes, A3A, DNMT3A, MQ3, LSD1, RrA3F, RrA3F-F130L, AmA1, SsA3B, SsA3B-R54Q, PpA1, PpA1-H122A, PpA1-R33A, Anc-rA1, rA1, AID, pmCDA1, A3A, eA3A, rA1-YE1, rA1-EE, rA1-YE2, rA1-YEE, A3A-Y130F, A3A-Y132D, A3B, AIDmono, TadA-7.10, CGBE1, hA3G-CTD, evoAPOBEC1, evoCDA1, evoFERNY, TadA-8e, TadA-9, minStart, and mTadA8e; wherein the site-directed nuclease module and the nucleotide-modifying enzyme module are fused as a single polypeptide.

17. The base editor of claim 16, wherein: i. the site-directed nuclease module comprises a site-directed nuclease selected from the group consisting of dCas9, dLbCas12a (dCpf1), and CasΦ-2 (CasPhi2); and/or ii. the nucleotide-modifying enzyme module comprises a nucleotide-modifying enzyme selected from the group consisting of A3A, Anc-rA1, eA3A, evoCDA1, minStart, mTadA8e, rA1, rA1-YE1, A3A-Y130F, A3B, AID, AmA1, evoAPOBEC1, evoFERNY, hA3G-CTD, pmCDA1, PpA1-R33A, rA1-YEE, RrA3F-F130L, and SsA3B-R54Q.

18. The base editor of claim 16, wherein: (1) the site-directed nuclease module comprises dCas9 and the nucleotide-modifying enzyme module comprises A3A; (2) the site-directed nuclease module comprises dCas9 and the nucleotide-modifying enzyme module comprises Anc-rA1; (3) the site-directed nuclease module comprises dCas9 and the nucleotide-modifying enzyme module comprises eA3A; (4) the site-directed nuclease module comprises dCas9 and the nucleotide-modifying enzyme module comprises evoCDA1; (5) the site-directed nuclease module comprises dCas9 and the nucleotide-modifying enzyme module comprises minStart; (6) the site-directed nuclease module comprises dCas9 and the nucleotide-modifying enzyme module comprises mTadA8e; (7) the site-directed nuclease module comprises dCas9 and the nucleotide-modifying enzyme module comprises rA1; (8) the site-directed nuclease module comprises dCas9 and the nucleotide-modifying enzyme module comprises rA1-YE1; (9) the site-directed nuclease module comprises dCasΦ-2 (dCasPhi2) and the nucleotide-modifying enzyme module comprises A3A; (10) the site-directed nuclease module comprises dCasΦ-2 (dCasPhi2) and the nucleotide-modifying enzyme module comprises A3A-Y130F; (11) the site-directed nuclease module comprises dCasΦ-2 (dCasPhi2) and the nucleotide-modifying enzyme module comprises eA3A; (12) the site-directed nuclease module comprises dCasΦ-2 (dCasPhi2) and the nucleotide-modifying enzyme module comprises evoCDA1; (13) the site-directed nuclease module comprises dCasΦ-2 (dCasPhi2) and the nucleotide-modifying enzyme module comprises minStart; (14) the site-directed nuclease module comprises dCasΦ-2 (dCasPhi2) and the nucleotide-modifying enzyme module comprises mTadA8e; (15) the site-directed nuclease module comprises dCasΦ-2 (dCasPhi2) and the nucleotide-modifying enzyme module comprises rA1; (16) the site-directed nuclease module comprises dCasΦ-2 (dCasPhi2) and the nucleotide-modifying enzyme module comprises rA1-YE1; (17) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises A3A; (18) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises A3B; (19) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises AID; (20) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises AmA1; (21) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises evoAPOBEC1; (22) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises evoFERNY; (23) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises hA3G-CTD; (24) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises minStart; (25) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises pmCDA1; (26) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises PpA1-R33A; (27) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises rA1-YEE; (28) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises RrA3F-F130L; or (29) the site-directed nuclease module comprises dLbCas12a and the nucleotide-modifying enzyme module comprises SsA3B-R54Q.

19. The base editor of claim 16, wherein the base editor comprises one or more additional modules comprising one or more additional polypeptides comprising a polypeptide for detecting the presence or the expression of the base editor in a cell or in tissue.

20. The base editor of claim 16, wherein the one or more additional polypeptides comprise a fluorescent protein or a reporter protein.

Description

DESCRIPTION OF THE FIGURES

[0201] The present application can be understood by reference to the following description taken in conjunction with the accompanying figures.

[0202] FIG. 1. General depiction of the system here disclosed. The system comprises a number of steps which separates different subprocesses. These steps can be considered as part of a flowchart which comprises, but is not limited to, one or more of one through six logical steps, namely: selection of nucleases and nucleotide-modifying enzymes, e.g. deaminase (step 1); modular design and combinatorial assembly (step 2), construction of the assemblies (step 3), detection in vivo and isolation in vitro (step 4), characterisation of constructs (step 5); and optimised production of assemblies for use (step 6).

[0203] FIG. 2. Combinatorial assembly process as part of step 2 of the system here disclosed. Modular components representing LO elemental DNA parts including promoters, protein domains of particular function and terminator sequences are flanked by specific nucleotide sequences (herein defined by the symbols A, C, X, D, E, F) used for directional assembly using a Golden Gate-mediated cloning strategy. Specific overhang sequences used for directional assembly of LO parts are also used in order to establish functional designation of modules according to a gene model with determined ontology (promoter and 5′ untranslated region (UTR) with RBS, CDS segment 1, CDS segment 2, CDS segment 3,3′UTR and terminator). A detailed illustration of a nucleic acid-modifying domain (deaminase) and of a site-directed nuclease (Cas module) with constituting elements (6×His, NLS, XTEN, SGGS) is also shown.

[0204] FIG. 3. Main components for pBE vectors comprising: sfGFP editing target (for cytosine or adenine deaminase based BEs), gRNA (for Cas9 or Cas12 based BEs) and BE entry site (Top) or cloned BE (Bottom).

[0205] FIG. 4. Design of pre-sfGFP region in detail. Top: four putative stop codons that can be converted to stop codons by CBEs. Bottom: one stop codon that can be reversed to a nonstop stop codon by ABEs.

[0206] FIG. 5. Efficiency and prevalence of BE (deaminase-nuclease) in a combinatorial assembly experiment.

[0207] FIG. 6. Frequency of editing by CBEs on the cytidine of each four putative stop codons in the pre-sfGFP region.

[0208] FIGS. 7A-7B. Overview of combinatorial experiment. FIG. 7A shows the first half of a combinatorial experiment. FIG. 7B shows the second half of a combinatorial experiment.

[0209] FIGS. 8A-8C. Overall editing efficiency (all nucleotide positions tested on the pre-sfGFP sequence) of exemplary assembled base editors. FIG. 8A shows editing efficiency of base editors assembled in a combinatorial experiment with dCas9 and a list of deaminases. FIG. 8B shows editing efficiency of base editors assembled in a combinatorial experiment with dLbCas12a and a list of deaminases. FIG. 8C shows editing efficiency of base editors assembled in a combinatorial experiment with dCasPhi2 and a list of deaminases.

[0210] FIG. 9A-9C. Example of base editing windows where assembled base editors are tested. Efficiency is indicated as a percentage of single nucleotide editing at known positions on the pre-sfGFP sequence. Positions 1-4 represent the four putative stop codons within the pre-sfGFP sequence of the pBE9 and pBE12 plasmids that can be converted to stop codons when edited by a CBE. FIG. 9A shows editing windows of base editors assembled in a combinatorial experiment with dCas9 and a list of deaminases. FIG. 9B shows editing windows of base editors assembled in a combinatorial experiment with dLbCas12a and a list of deaminases. FIG. 9C shows editing windows of base editors assembled in a combinatorial experiment with dCasPhi2 and a list of deaminases.

[0211] FIGS. 10A-10B. Example of functionalization of base editors. In this case the base editor (A3A-dCas9) was assembled together with a fluorescent protein (NG) as a C-terminal part, and under the regulation of promoters p35S or pCmYLCV. In order to verify the expression as well as the localization of the base editor in a cell/tissue context, the corresponding vector containing the assembly was introduced into Nicotiana benthamiana tissue using Agrobacterium tumefaciens transformation. FIG. 10A shows expression of the NG-labeled A3A-dCas9 base editor under the control of the p35S promoter. FIG. 10B shows expression of the NG-labeled A3A-dCas9 base editor under the control of the pCmYLCV promoter.

DETAILED DESCRIPTION

[0212] The following description of the embodiments is not intended to limit the invention to these embodiments, but rather to enable any person skilled in the art to make and use.

Overview

[0213] This invention provides methods and systems to assemble site-directed nucleases and nucleotide-modifying enzymes to obtain nucleic acid modifiers in a multiple and combinatorial fashion. Furthermore, the invention provides new nucleic acid-modifiers obtained with such methodologies.

[0214] The system provided in this invention (FIG. 1) comprises a component selection step 1, which in turn comprises an in silico selected list of site-directed nucleases and a selected list of nucleotide-modifying enzymes. According to this invention the list of site-directed nucleases comprises, but is not limited to, Cas nucleases, as nickases or dead nickases. In the same way, amongst the nucleotide-modifying enzymes, the disclosed system can comprise any kind of deaminases, demethylases, methyltransferases, or any kind of enzyme able to modify nucleotides.

[0215] As part of the disclosed invention, the system comprises a combinatorial assembly step (step 2, in FIG. 1), which is designed in silico. This step comprises the modularisation of the different components found in a site-directed nuclease nucleotide-modifying enzyme assembly. The different components of such an assembly comprise, but are not limited to, a site-directed nuclease (selected from step 1 of the system), a nucleotide-modifying enzyme (selected also from step 1 of the system), and a linker (which links the nuclease and the nucleotide modifying enzyme). Other components can be present or not in the assemblies. These components comprise other accessory or modifying enzymes and/or event-triggering enzymes, as well as additional linkers and/or useful sequence motifs for post-processing events.

[0216] The step 3 of the system (FIG. 1) comprises the implementation of the steps described above experimentally, namely the construction of the assemblies in vitro. This step involves the combination of components bearers (e.g plasmids) in an in vitro reaction together with all other components allowing this reaction to occur, which comprise a proper medium and restriction endonucleases.

[0217] The step 4 (FIG. 1) involves the detection of the assemblies previously constructed. This process comprises the construction of libraries by cloning the assemblies as vectors into microorganisms able to keep such vectors and reproduce themself (e.g. bacterial cells). The detection can be achieved by incorporating a target sequence to be modified by the expressed assembly encoded in the vector. The modification of the target sequence accounts for a response which is measured or read by a detector or any device able to do so. This target sequence can be encoded in the same vector of the assembly or encoded in a different vector. The target sequence can be modified by guiding the assembly to a specific site inside the sequence. The final part of this step comprises the unveiling of the modified sequence by identifying the encoded nucleotide sequence and comparing it with the original target sequence.

[0218] A characterisation step (step 5, FIG. 1) can be also part of this disclosure, and comprises the determination of key features of the assemblies, according to the different parts composing them. This characterisation process involves the determination of an optimal modifying window that is the range at the target sequence which the assembly acts on, and the sequence context around which the modification can be accomplished e.g. seed/proximal or distal motifs. The step 5 of the disclosed system is optional since the characterisation process is not a mandatory step to provide new functional nuclease-modifying nucleotide enzyme assemblies, but it may be useful to provide information on specificity.

[0219] The final step (step 6, FIG. 1) comprises the expression, production and isolation in vitro of the assemblies previously constructed (and/or characterised). This step involves the combination of the required components and necessary media to accomplish such a production, and comprises the provision of necessary enzymes as well as one or more vectors encoding the assembly and/or the guide-sequence (e.g. guide-RNA) to direct the assembly to specific sequences to be modified. The assembly encoded in a vector certainly comprises at least an encoded nuclease and an encoded nucleotide-modifying enzyme, and may also comprise one or more encoded linkers and/or encoded accessory enzymes responsible for triggering other events associated with the nucleotide modification.

Definitions

[0220] For the purposes and clarity of this disclosure some of the terms used in this invention must be defined.

[0221] The term nuclease is intended to define an enzyme of natural or artificial origin which binds one or more nucleotide sequences (e.g. DNA or RNA) and exerts (or not) one or multiple modifications on them. This nuclease can bind a nucleotide sequence through the recognition of a motif in the sequence (e.g an enzyme containing zinc-fingers which binds DNA at specific sites) or by assistance of another (specific) nucleotide sequence (e.g. Cas systems and related enzymes, which use RNA sequences as a guide to be directed to a specific site in the DNA).

[0222] A nucleotide-modifying enzyme typically defines an enzyme of natural or artificial origin that is able to modify the identity of nucleotides (ribonucleotides and/or deoxyribonucleotides) and/or attach or link other chemical moieties to them. The modification of nucleotides can be accomplished on a single or more free nucleotides, and in a sequence context as well.

[0223] The term linker typically refers to a chemical moiety that is attached (e.g. through covalent bonds) to two or more chemical parts originally isolated. A linker can be a polymer where each of its extremes bind covalently to major molecular complexes (e.g. a polypeptide which links two major proteins). The requirement of a chemical moiety for being a linker is to have a minimal or no effect on the properties and/or function of the parts it binds. Nonetheless, these chemical moieties can have a crucial role on the function of one of the major complexes, e.g. a nucleotide-modifying enzyme when linked to a nuclease may not be able to reach its target if the linker is not long enough.

[0224] In this invention, an accessory enzyme typically refers to an enzyme that can help or assist the process of nucleotide modification by interfering with the molecular events that promote such a modification or the events that prevent it. For example, if the modification of a nucleotide occurs in an in vivo context and there is a molecular machinery that can revert the modification, then it is desirable to have an accessory enzyme that impedes such a molecular machinery to act in order for the modification to linger.

[0225] A target sequence is typically a sequence of natural or artificial origin that contains the nucleotide(s) to be modified. This sequence must fulfill the requirements that allow a nuclease and a nucleotide-modifying enzyme to exert their function (e.g. binding and recognition requirements). This sequence can code a protein, can have a regulatory element, and/or any site of interest to be modified.

[0226] A guide nucleotide sequence is typically a sequence (e.g. RNA or DNA) that helps or assists a nuclease to recognise or to be directed to a specific site inside a target sequence. The guide nucleotide can be of natural or artificial origin and can be attached to the nuclease itself.

[0227] The term assembly is typically defined as a combination of elements that form a composite that has one or multiple properties and/or functions. In the context of this invention, an assembly refers to the combination of components encoded in a nucleotide sequence (e.g proteins, promoters, and/or regulatory sites encoded in a vector), and/or to the product encoded in such a nucleotide sequence (e.g. a number of linked proteins).

[0228] The term combinatorial assembly typically refers to the combination of elements in all possible configurations yielding, in turn, all possible composites or assemblies, taking into account the term assembly defined above.

[0229] The term reporter protein typically refers to a protein or enzyme that encompasses an observable or measurable characteristic in a cell or tissue context. Examples of reporter proteins include, e.g. a fluorescent protein, a luciferase enzyme, a beta-galactosidase enzyme, a (3-glucuronidase enzyme (e.g., encoded by a GUS reporter gene) and the like.

DETAILED DESCRIPTION OF THE EMBODIMENTS

[0230] In a preferred embodiment, the system or method for obtaining assemblies of site-directed nucleases and nucleotide-modifying enzymes, comprises providing, in first step, a library of modular nucleic acid sequences composed of two or more site-directed nuclease modules each comprising a nucleic acid sequence encoding a different site-directed nuclease, two or more nucleotide-modifying enzyme modules each comprising a nucleic acid sequence encoding a different nucleotide-modifying enzyme, and optionally, one or more additional modules each comprising one or more nucleic acid sequences encoding other components. In a next step, the method comprises constructing two or more nucleic acid assemblies in vitro, wherein each nucleic acid assembly is constructed by joining a site-directed nuclease module with a nucleotide-modifying enzyme module to generate a nucleic acid assembly that encodes the site-directed nuclease and the nucleotide-modifying enzyme operably linked to express as a single polypeptide, and optionally, further joining one or more additional modules to the assembly nucleic acid sequence. In a further step, the method comprises expressing the two or more nucleic acid assemblies constructed in step in the previous step to produce the site-directed nucleases and the nucleotide-modifying enzymes as single polypeptides. In a final stage, the method comprises a step for detecting the nucleotide-modifying activity for each of the single polypeptides expressed in the previous step. Optionally, the method can comprise analyzing each nucleotide-modifying activity detected to select one or more optimal nucleic acid assemblies and/or expressing the one or more optimal nucleic acid assemblies and purifying one or more polypeptides expressed from the optimal nucleic acid assemblies. Additionally, the library aforementioned, is provided by selecting two or more nucleic acid sequences each encoding a site-directed nuclease and two or more nucleic acid sequences each encoding a nucleotide-modifying enzyme; by generating the two or more site-directed nuclease modules each comprising one of the two or more nucleic acid sequences encoding a site-directed nuclease selected previously; and by generating the two or more nucleotide-modifying enzyme modules each comprising one of the two or more nucleic acid sequences encoding a nucleotide-modifying enzyme selected previously. Optionally, the library can be provided by generating one or more additional modules each comprising one or more nucleic acid sequences encoding other components; and by codon optimizing one or more of the site-directed nuclease modules, the nucleotide modifying modules, the additional modules, or any combination thereof.

[0231] In a preferred embodiment, step 1 of the system here disclosed, comprises the selection of nucleases of the Cas type, which include, but are not limited to, AsCas12a, Cas12a (Cpf1), Cas12b, Cas12e (CasX), Cas12j, Cas12f, Cas13a, Cas13b, Cas13d, Cas14a, Cas9, dCas9, Cas9-NGv1, CasX, CasY, CasΦ, CasΦ-2 (CasPhi2), dCasΦ-2 (dCasPhi2), CjCas9, eCas9, enAsCas12a, enAsCas12a-HF1, enLbCas12a, ErCas12a, eSpCas9, eSpCas9-1.1, FnCas12a, FnCas9, HF-nCAS9, HF2-CAS9, HypaCas9, LbCas12a, dLbCas12a, MbCas12a, NmCas9, SaCas9, SaurCas9, SauriCas9, ScCas9, SpCas9, SpCas9-HF1, SpCas9-NG, SpG, SpRY, SpyoCas9, St1Cas9, St3Cas9, StCas9, ttLbCas12a, xCas9, xCas9(3.6), xCas9(3.7), and their corresponding nickase and dead versions. In the same way, amongst the nucleotide modifying enzymes, the disclosed system can comprise: APOBEC, APOBEC-like enzymes, AID, AID-like enzymes, A3A, DNMT3A, MQ3, LSD1, RrA3F, RrA3F-F130L, AmA1, SsA3B, SsA3B-R54Q, PpA1, PpA1-H122A, PpA1-R33A, Anc-rA1, rA1, AID, pmCDA1, A3A, eA3A, rA1-YE1, rA1-EE, rA1-YE2, rA1-YEE, A3A-Y130F, A3A-Y132D, A3B, AIDmono, TadA-7.10, CGBE1, hA3G-CTD, evoAPOBEC1, evoCDA1, evoFERNY, TadA-8e, TadA-9, minStart, and mTadA8e.

[0232] Embodiments of the invention disclosed herein, comprises the modularisation of the different components found in a nuclease-nucleotide modifying enzyme assembly through a combinatorial assembly step (step 2, FIG. 2). The different components of such an assembly may comprise, but are not limited to, a site-directed nuclease, a nucleotide-modifying enzyme (both described above), and a linker (which links the site-directed nuclease and the nucleotide-modifying enzyme). Thus, one or more of the site-directed nuclease modules may further comprise one or more linker sequences, each encoding a peptide linker and each operably linked to the nucleic acid sequence encoding a site-directed nuclease to express as a single polypeptide. The assembly can comprise further accessory or modifying enzymes and/or event-triggering enzymes, as well as additional linkers and/or useful sequence motifs for post-processing events. Amongst the other modifying enzymes and/or event-triggering enzymes, this invention comprises: uracil-DNA glycosylase inhibitors (UGI), fluorescent proteins, FokI, methyltransferases (e.g. m5U (like TrmA), 2′-O (like SpoU), DNMT3A or MQ3), Ψ synthases (like TruA), demethylases (e.g. LSD1), proteins of the plant abscisic acid (ABA) stress response pathway (e.g. PYL1 or ABI1), heterodimerising leucine zippers, Kruppel-associated Box (KRAB), transcriptional activators (e.g. VP64, P65, Rta, P65-HSF1 transactivation complex or MCP-fused VP64), repressive domains (e.g. SRDX), additional APOBEC or APOBEC-like enzymes, additional AID or AID-like enzymes. Additional modules may further comprise one or more sequence motifs, each encoding a polypeptide motif and each operably linked to one or more of the accessory component sequences encoding one or more accessory component polypeptides to express as a single polypeptide, wherein the sequence motifs comprise a purification tag, a nuclear localization sequence, or a combination thereof. The additional linkers and/or sequence motifs can be selected from: 6×His purification tag with TEV protease cleavage site, a SV40 nuclear localisation sequence, a XTEN peptide linker (US2011312881A1), a flexible linker such as a GGS(xN) repetition, more rigid linkers including polyproline motifs and an all α-helical linker A(EAAAK)nA; a nucleoplasmin nuclear localisation sequence; or any combination thereof.

[0233] In another embodiment of the invention, the method in the second step comprises constructing a combinatorial library of nucleic acid assemblies in vitro; constructing a plurality of nucleic acid assemblies in parallel; constructing a plurality of nucleic acid assemblies in parallel in a single reaction; and/or constructing two or more destination vectors, each comprising one of the nucleic acid assemblies. Regarding the latter, constructing the two or more destination vectors comprises, in turn, mixing two or more nucleic acid molecules each comprising one of the site-directed nuclease modules, one of the nucleotide-modifying enzyme modules, one of the additional modules, a protein-coding sequence, a regulatory sequence, or any combination thereof to produce the destination vectors. In this case, the nucleic acid molecules comprise one or more vectors, one or more linear polynucleotides, or a combination thereof, wherein the vectors may comprise one or more donor vectors each comprising one of the site-directed nuclease modules or one of the nucleotide-modifying enzyme modules, and wherein the vectors may comprise one or more receiver vectors each comprising one of the site-directed nuclease modules or one of the nucleotide-modifying enzyme modules. For its part, the protein-coding sequences may comprise sequences encoding nucleotide-modifying enzymes, sequences encoding site-directed nucleases, sequences encoding linker peptides, sequences encoding polypeptide motifs, sequences encoding accessory component polypeptides, or any combination thereof; and the regulatory sequences comprise promoters, ribosome binding sites (RBSs), terminators, or any combination thereof.

[0234] In addition, constructing the two or more destination vectors involves mixing the two or more nucleic acid molecules in a single reaction to produce the destination vectors, wherein the nucleic acid molecules comprise nucleic acid molecules that were synthesized in vitro. In some embodiments, each destination vector further comprises a first promoter, a terminator, or a combination thereof, each operably linked to the nucleic acid assembly for expression of the nucleic acid assembly. In this case, the first promoter can be a constitutive promoter.

[0235] Additionally or alternatively, the nucleic acid molecules each can comprise one or more Type IIS restriction sites such that digestion of the nucleic acid molecules with one or more corresponding Type IIS restriction enzymes produces linear polynucleotides with cohesive overhangs, which makes possible a combinatorial assembly step involving the digestion by a Type IIS restriction enzyme and consequent molecular ligation between compatible cohesive overhangs through the action of a DNA ligase. Multiple modules harbouring compatible overhangs can participate in the one-pot reaction to generate all possible combinations with cognate partners specified through the overhangs. Therefore, if added in equimolar concentrations, all possible combinations will be produced according to a probabilistic distribution. This method does not rely on sequence homology, but only on the compatibility of specified overhangs and enables defining the precise boundaries of the combinatorial assembly, as in the Golden Gate Shuffling method (Engler, C. et al., 2009, Golden Gate Shuffling: A One-Pot DNA Shuffling Method Based on Type IIs Restriction Enzymes. PLoS ONE 4(5), e5553). Thus the nucleic acid molecules can comprise a promoter flanked by Type IIS restriction sites, wherein digestion of the nucleic acid molecule with one or more corresponding Type IIS restriction enzymes produces a linear polynucleotide comprising 5′ overhang A, the promoter, and 3′ overhang B; a 5′ untranslated region (UTR) and a ribosome binding site (RBS) flanked by Type IIS restriction sites, wherein digestion of the nucleic acid molecule with one or more corresponding Type IIS restriction enzymes produces a linear polynucleotide comprising 5′ overhang B, the 5′ UTR, the RBS, and 3′ overhang C; a nucleotide-modifying enzyme module flanked by Type IIS restriction sites, wherein digestion of the nucleic acid molecule with one or more corresponding Type IIS restriction enzymes produces a linear polynucleotide comprising 5′ overhang C, the nucleotide-modifying enzyme module, and 3′ overhang X; a site-directed nuclease module flanked by Type IIS restriction sites, wherein digestion of the nucleic acid molecule with one or more corresponding Type IIS restriction enzymes produces a linear polynucleotide comprising 5′ overhang X, the site-directed nuclease module, and 3′ overhang D; one or more additional modules flanked by Type IIS restriction sites, wherein digestion of the nucleic acid molecule with one or more corresponding Type IIS restriction enzymes produces a linear polynucleotide comprising 5′ overhang D, the one or more additional modules, and 3′ overhang E; and/or a 3′ UTR and a terminator sequence flanked by Type IIS restriction sites, wherein digestion of the nucleic acid molecule with one or more corresponding Type IIS restriction enzymes produces a linear polynucleotide comprising 5′ overhang E, the site-directed nuclease module, and 3′ overhang F. Namely, in some embodiments, the overhang A is GGAG, overhang B is TACT, overhang C is AATG, overhang X is TGGA, overhang D is AGGT, overhang E is GCTT, and/or overhang F is CGCT. Additionally, these overhangs can be the results of the action of one or more Type IIS restriction enzymes, which comprise BsaI, SapI, or a combination thereof.

[0236] In the preferred embodiment, the step 3 of the system comprises the implementation of the steps described above experimentally, namely the synthesis of the different parts in order to construct the assemblies in vitro. This step involves the combination of synthesised vectors containing suitable restriction flanking sites for a proper cloning of nucleases and nucleotide-modifying enzymes. An in vitro reaction together with all other components (Type IIS restriction enzymes, a ligase enzyme, or a combination thereof) and a proper medium, allows the ligation to occur.

[0237] Additionally or alternatively, the step 4 of the method disclosed herein, comprises the construction of libraries by cloning the assemblies as vectors into microorganisms able to keep such vectors and reproduce themself (e.g. bacterial cells). The detection is achieved by means of a strategy which incorporates a target sequence to be modified by the expressed assembly encoded in the vector. This target sequence comprises, but is not limited to, a fluorescent protein or a reporter enzyme, which can be encoded in the same vector of the assembly or encoded in a different vector. The target sequence is modified by guiding the assembly to a specific site inside the sequence. To do so, the assembly comprises specific nucleotide sequences attached so as to be directed to the target to be modified (e.g. guide-sequence, guide-RNA). The final part of this step comprises the sequencing of the modified sequence by any means or technology available to do so, comprising Sanger sequencing, capillary electrophoresis, next-generation sequencing (NGS) such as Illumina or third-generation sequencing (TGS), including technologies such as Oxford Nanopore Technology (ONT), Pacific Biosciences (PB) or DNBSeq Technology (BGI).

[0238] In a variant of the embodiment, a characterisation step 5 can be performed. This step involves the determination of on-targets, off-targets, optimal editing window (position and scope), seed/proximal or distal motifs (e.g. sequence next to or distant from protospacer adjacent motifs in cases where nucleases require them), substrate preference and processivity, which are main parameters that define the performance of a nuclease-nucleotide modifying enzyme assembly.

[0239] In the preferred embodiment, the final step comprises the expression, production and isolation in vitro of the assemblies previously constructed (and/or characterised). This is performed by provisioning necessary enzymes as well as one or more vectors encoding the assembly and/or the guide-sequence (e.g. gRNA) to direct the assembly to specific sequences to be modified. The assembly encoded in a vector certainly comprises at least an encoded nuclease and an encoded nucleotide-modifying enzyme, and may also comprise one or more encoded linkers and/or encoded accessory enzymes responsible for triggering other events associated with the nucleotide modification. In this case, protein expression can be induced in a medium, and then total protein can be extracted, purified, concentrated and stored for later use.

[0240] In another embodiment of the invention, step 4 comprises transforming two or more host cells with two or more destination vectors, and optionally with one or more additional vectors; and culturing the host cells and allowing expression of the nucleotide assembly to produce the site-directed nucleases and the nucleotide-modifying enzymes as single polypeptides. In this case, the host cells can be yeast cells or bacterial cells. In turn, in some embodiments, the destination vector further comprises a gRNA expression cassette comprising a gRNA sequence operably linked to a second promoter, a target-reporter expression cassette, or a combination thereof. Such a target-reporter expression cassette can comprise a target sequence and a reporter sequence operably linked to a third promoter, or a combination thereof, and the target sequence and the reporter sequence can be operably linked to express as a single reporter polypeptide. The reporter sequence can encode a reporter molecule, which can be a fluorescent protein, or more specifically GFP, sfGFP, or mNeonGreen (NG). In turn, the third promoter can be a constitutive promoter, and the target sequence can comprise one or more target nucleotides for editing, wherein editing of the one or more target nucleotides results in the formation of an edited target sequence having one or more stop codons. Thus, editing of the one or more target nucleotides can result in the expression of the reporter polypeptide or in the non-expression of the reporter polypeptide.

[0241] Additionally or alternatively, step 4 of the methodology disclosed herein can comprise spreading the transformed host cells on a solid medium; allowing colonies to form on the solid medium; and allowing expression of the nucleotide assembly in the colonies to produce the site-directed nucleases and the nucleotide-modifying enzymes as single polypeptides.

[0242] In another embodiment of this disclosure, the final step can comprise DNA sequencing, PCR, colony screening, detecting fluorescence, or any combination thereof, as well as detecting expression or non-expression of the reporter polypeptide in the host cells, which can be detected in liquid cultures, or in colonies on solid medium. The step can also involve the identification of cells with non-expression of the reporter polypeptide as edited cells, wherein each colony of edited cells is isolated and grown in a pure culture. Furthermore, the step can comprise sequencing the destination vectors, nucleic acid assemblies, edited target sequences, or any combination thereof of the edited cells; identifying the modified sites in each of the edited target sequences; determining the sequence context of the modified sites in each of the edited target sequences; identifying the window of modification in each of the target sequences; detecting off-target nucleotide edits in the edited cells by isolating and sequencing the DNA of the edited cells, wherein the DNA comprises destination vectors, genomic DNA, or a combination thereof; cloning the one or more optimal nucleic acid assemblies into an expression vector comprising the optimal nucleic acid assembly operably linked to a fourth promoter, wherein the fourth promoter can be a constitutive promoter or an inducible promoter; transforming cells with the expression vector, culturing the transformed cells, and allowing expression of one or more polypeptides encoded by the optimal nucleic acid assembly; transforming cells with the expression vector, culturing the transformed cells, and inducing expression of one or more polypeptides encoded by the optimal nucleic acid assembly; purifying the one or more polypeptides encoded by the optimal nucleic acid assembly; and/or finally concentrating the one or more polypeptides encoded by the optimal nucleic acid assembly.

[0243] As part of this invention, the methodology and components described above are further useful for selecting an optimal nucleic acid assembly for editing a target nucleotide.

[0244] Also, as part of this invention, a library of nucleic acid assemblies of site-directed nucleases and nucleotide-modifying enzymes is provided. This library comprises two or more site-directed nuclease modules each comprising a nucleic acid sequence encoding a different site-directed nuclease; two or more nucleotide-modifying enzyme modules each comprising a nucleic acid sequence encoding a different nucleotide-modifying enzyme; and optionally, one or more additional modules each comprising one or more nucleic acid sequences encoding other components. In this case, each nucleic acid assembly comprises a site-directed nuclease module and a nucleotide-modifying enzyme module, wherein each nucleic acid assembly encodes the site-directed nuclease, the nucleotide-modifying enzyme, and, optionally, one or more additional modules, operably linked to express as a single polypeptide. In this library, the site directed nucleases may comprise one or more Cas nucleases, one or more Cas nickases, one or more dead Cas nickases, or any combination thereof, which can be each independently selected from the group consisting of AsCas12a, Cas12a (Cpf1), Cas12b, Cas12e (CasX), Cas12j, Cas12f, Cas13a, Cas13b, Cas13d, Cas14a, Cas9, dCas9, Cas9-NGv1, CasX, CasY, CasΦ, CasΦ-2 (CasPhi2), dCasΦ-2 (dCasPhi2), CjCas9, eCas9, enAsCas12a, enAsCas12a-HF1, enLbCas12a, ErCas12a, eSpCas9, eSpCas9-1.1, FnCas12a, FnCas9, HF-nCAS9, HF2-CAS9, HypaCas9, LbCas12a, dLbCas12a, MbCas12a, NmCas9, SaCas9, SaurCas9, SauriCas9, ScCas9, SpCas9, SpCas9-HF1, SpCas9-NG, SpG, SpRY, SpyoCas9, St1Cas9, St3Cas9, StCas9, ttLbCas12a, xCas9, xCas9(3.6), and xCas9(3.7). For its part, the nucleotide-modifying enzymes may comprise one or more deaminases, one or more demethylases, one or more methyltransferases, or any combination thereof, which can be selected from the group consisting of APOBEC, APOBEC-like enzymes, AID, AID-like enzymes, A3A, DNMT3A, MQ3, LSD1, RrA3F, RrA3F-F130L, AmA1, SsA3B, SsA3B-R54Q, PpA1, PpA1-H122A, PpA1-R33A, Anc-rA1, rA1, AID, pmCDA1, A3A, eA3A, rA1-YE1, rA1-EE, rA1-YE2, rA1-YEE, A3A-Y130F, A3A-Y132D, A3B, AIDmono, TadA-7.10, CGBE1, hA3G-CTD, evoAPOBEC1, evoCDA1, evoFERNY, TadA-8e, TadA-9, minStart, and mTadA8e.

[0245] The library so disclosed, can be composed of modular nucleic acid sequences which comprise one or more additional modules each comprising, in turn, one or more nucleic acid sequences encoding other components. The additional modules may comprise accessory component sequences encoding one or more accessory component polypeptides comprising a uracil-DNA glycosylase inhibitor (UGI), a fluorescent protein, a FokI protein, a methyltransferase, a Ψ synthase, a demethylase, one or more proteins of the plant abscisic acid (ABA) stress response pathway, a heterodimerizing leucine zipper, a Kruppel-associated Box (KRAB), a transcriptional activator, a repressive protein domain, an APOBEC enzyme, an APOBEC-like enzyme, an AID enzyme, an AID-like enzyme, or any combination thereof. In addition, the one or more of the site-directed nuclease modules may further comprise one or more linker sequences, each encoding a peptide linker and each operably linked to the nucleic acid sequence encoding a site-directed nuclease to express as a single polypeptide. The linker sequences can encode peptide linkers comprising an XTEN peptide linker, a flexible linker GGS(xN), a polyproline motif, an all α-helical linker A(EAAAK)nA, or any combination thereof. The site-directed nuclease modules can further comprise one or more sequence motifs, each encoding a polypeptide motif and each operably linked to the nucleic acid sequence encoding a site-directed nuclease to express as a single polypeptide. The sequence motifs can comprise a purification tag, a nuclear localization sequence, or a combination thereof, wherein the purification tag can be a 6×His peptide, optionally with a TEV protease cleavage site, and the nuclear localization sequence can be a SV40 nuclear localization sequence.

[0246] The nucleic acid assemblies of the library disclosed herein, can also comprise a promoter flanked by 5′ overhang A and 3′ overhang B; a 5′ untranslated region (UTR) and a ribosome binding site (RBS) flanked by 5′ overhang B and 3′ overhang C; a nucleotide-modifying enzyme module flanked by 5′ overhang C and 3′ overhang X; a site-directed nuclease module flanked by 5′ overhang X and 3′ overhang D; one or more additional modules flanked by 5′ overhang D and 3′ overhang E; and/or a 3′ UTR and a terminator sequence flanked by 5′ overhang E and 3′ overhang F. The overhangs can be the sites left by one or more Type IIS restriction enzymes. In this case, overhang A can be GGAG, overhang B can be TACT, overhang C can be AATG, overhang X can be TGGA, overhang D can be AGGT, overhang E can be GCTT, and/or overhang F can be CGCT.

[0247] As part of this invention, the methodology and components described above are further useful for selecting an optimal base editor for editing a target nucleotide.

[0248] As part of this invention, a base editor for editing a target nucleotide is provided. In some embodiments, the base editor comprises a site-directed nuclease module comprising a site-directed nuclease, a nucleotide-modifying enzyme module comprising a nucleotide-modifying enzyme, and, optionally, one or more additional modules comprising one or more additional polypeptides, wherein the site-directed nuclease module, the nucleotide-modifying enzyme module, and, optionally, one or more additional modules, are fused as a single polypeptide. In some embodiments, the a site-directed nuclease is selected from the group consisting of AsCas12a, Cas12a (Cpf1), Cas12b, Cas12e (CasX), Cas12j, Cas12f, Cas13a, Cas13b, Cas13d, Cas14a, Cas9, dCas9, Cas9-NGv1, CasX, CasY, CasΦ, CasΦ-2 (CasPhi2), dCasΦ-2 (dCasPhi2), CjCas9, eCas9, enAsCas12a, enAsCas12a-HF1, enLbCas12a, ErCas12a, eSpCas9, eSpCas9-1.1, FnCas12a, FnCas9, HF-nCAS9, HF2-CAS9, HypaCas9, LbCas12a, dLbCas12a, MbCas12a, NmCas9, SaCas9, SaurCas9, SauriCas9, ScCas9, SpCas9, SpCas9-HF1, SpCas9-NG, SpG, SpRY, SpyoCas9, St1Cas9, St3Cas9, StCas9, ttLbCas12a, xCas9, xCas9(3.6), and xCas9(3.7). In some embodiments, the nucleotide-modifying enzyme is selected from the group consisting of APOBEC, APOBEC-like enzymes, AID, AID-like enzymes, A3A, DNMT3A, MQ3, LSD1, RrA3F, RrA3F-F130L, AmA1, SsA3B, SsA3B-R54Q, PpA1, PpA1-H122A, PpA1-R33A, Anc-rA1, rA1, AID, pmCDA1, A3A, eA3A, rA1-YE1, rA1-EE, rA1-YE2, rA1-YEE, A3A-Y130F, A3A-Y132D, A3B, AIDmono, TadA-7.10, CGBE1, hA3G-CTD, evoAPOBEC1, evoCDA1, evoFERNY, TadA-8e, TadA-9, minStart, and mTadA8e.

[0249] The base editor so disclosed may comprise one or more additional modules comprising one or more additional polypeptides. The additional modules may comprise a polypeptide for detecting the presence or the expression of the base editor in a cell or in tissue. In some embodiments, the one or more additional polypeptides comprise a fluorescent protein (e.g., mNeonGreen (NG)) or a reporter protein (e.g., a reporter enzyme such as a luciferase enzyme, a beta-galactosidase enzyme, a β-glucuronidase enzyme (e.g., encoded by a GUS reporter gene)). The additional modules may comprise accessory component sequences encoding one or more accessory component polypeptides comprising a uracil-DNA glycosylase inhibitor (UGI), a fluorescent protein, a FokI protein, a methyltransferase, a Ψ synthase, a demethylase, one or more proteins of the plant abscisic acid (ABA) stress response pathway, a heterodimerizing leucine zipper, a Kruppel-associated Box (KRAB), a transcriptional activator, a repressive protein domain, an APOBEC enzyme, an APOBEC-like enzyme, an AID enzyme, an AID-like enzyme, or any combination thereof. In addition, the site-directed nuclease modules, nucleotide-modifying enzyme modules, and/or additional modules may further comprise one or more peptide linkers fused to the site-directed nuclease, the nucleotide-modifying enzyme, and/or the additional polypeptide. The peptide linkers may comprise an XTEN peptide linker, a flexible linker GGS(xN), a polyproline motif, an all α-helical linker A(EAAAK)nA, or any combination thereof. The site-directed nuclease modules, nucleotide-modifying enzyme modules, and/or additional modules can further comprise one or more sequence motifs, each encoding a polypeptide motif fused to the site-directed nuclease, the nucleotide-modifying enzyme, and/or the additional polypeptide. The sequence motifs can comprise a purification tag, a nuclear localization sequence, or a combination thereof, wherein the purification tag can be a 6×His peptide, optionally with a TEV protease cleavage site, and the nuclear localization sequence can be a SV40 nuclear localization sequence.

[0250] Sequences Encoding Site-Directed Nucleases, Nucleotide-Modifying Enzymes, and Accessory Components

TABLE-US-00001 TABLE 1 Nucleic acid sequences encoding site-directed nucleases, nucleotide-modifying enzymes, and accessory components. SEQ Category Name Nucleotide sequence 1 Base editor A3A-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaagcaagtccagcttcaggacccaggcacctgatggacccgcat attttcacctctaattttaacaacggtattggccgtcacaagacgtacct gtgttatgaagtggaacgtcttgacaacggcacctccgtgaaaatggacc agcatcgtggtttcttgcataatcaagctaaaaacctgctgtgcggtttc tacggccgtcacgcggaactgcgttttttggacctggttccgagcctgca actggacccggcacagatttatcgtgttacttggttcatcagctggtcgc cgtgttttagctggggttgcgccggcgaggtacgcgcgtttttgcaagag aacacccacgtgcgtttgcgcatcttcgccgctcgtatctacgattatga cccactgtataaagaagcgctccagatgctgcgcgatgcaggcgcgcagg tttccatcatgacctacgacgagttcaagcactgctgggatacctttgtc gatcatcagggctgcccgttccagccgtgggatggtctggatgagcacag ccaggcgttaagcggtcgcctcagagcgattctgcaaaaccaaggtaatt ctggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga atggataaaaagtattcaataggactagctattggcaccaacagcgttgg ttgggcagttatcaccgatgaatataaggtcccgagcaagaagtttaagg tcctgggcaacaccgatcgccacagcataaaaaagaaccttattggtgcg ctgctgttcgattctggtgagactgccgaagcgacccgtctgaagagaac cgcgcgtcgtagatacacccggcgcaagaaccgtatctgctatctgcaag aaattttcagcaacgagatggctaaggtcgacgactccttctttcatcgc ctggaggaaagctttctggttgaggaagacaaaaagcacgagcgtcatcc gattttcggtaacattgttgatgaagttgcctaccacgaaaaatacccca caatttatcatctgcgtaaaaaactggtagactccaccgataaggcggat ttacgccttatctatttggcgctggcgcatatgattaagttccgcggtca ttttttgatcgagggcgacctgaatccggataacagcgacgttgacaaac tgtttatccagctggtgcagacctataaccagttgttcgaagagaacccg attaatgcgtctggcgtggacgcgaaggcgatcctgagcgctcgtctgtc caagtcacgccgcctggagaacttgatcgcgcaactgccgggtgagaaga aaaacggcttgttcggcaatctgattgctctgtccctaggtttgaccccg aatttcaaatctaattttgatctggcggaagatgcgaaattacagttgag caaggacacttacgatgacgatctggacaacctgctcgctcagatcggcg atcagtatgccgatcttttcctggccgcgaagaacctgagcgatgccatc ttgctatcggacatcttacgtgttaacaccgaaatcaccaaagctccgct aagcgcgtccatgattaaacgttacgatgaacaccaccaggatctgacgc tgctgaaagcgttggtgcgccagcaactgccggaaaaatacaaggaaatt ttcttcgaccaaagcaagaacggttatgcaggctatatcgacggtggtgc gtcgcaagaagaattttataaattcatcaaaccgattttggagaagatgg atggtaccgaggagctgctggtaaaattgaatcgggaagacctcttgcga aagcagcgtactttcgataatggtagcatcccgcaccagattcatctggg cgaacttcacgcaatcctacgtcgtcaagaggatttctacccgtttctga aggataaccgtgaaaagatcgagaagattctgacctttcgtattccgtat tatgtgggtccgctggcgagaggcaacagccgttttgcgtggatgacccg caagtcggaagagactatcacgccgtggaatttcgaggaggtcgtggaca agggtgcatcagcgcaatcttttattgaacgtatgaccaattttgataaa aaccttccaaatgaaaaagtgttgccgaagcacagcttgctgtacgagta tttcaccgtttacaatgaactgacgaaagtcaagtacgttaccgaaggta tgcgtaagccagcctttctgtctggggagcaaaaaaaagccattgtggat ctgctgttcaagaccaatcgcaaggttaccgtcaagcaactgaaagagga ttacttcaaaaaaatcgaatgttttgactccgtggaaatcagcggcgttg aagaccgctttaatgcatctctgggcacctaccacgatctactcaagatc atcaaggataaggacttcctggacaacgaagaaaatgaggatatcttgga agatattgtgctgactttaacgttgttcgaggatcgtgagatgattgaag aacgcctcaaaacgtacgcacatctgtttgacgataaggtgatgaaacag ctaaagcgccgtcgttacaccggttggggtcgtctgtctagaaagctgat taacggcattcgtgacaaacaatctggcaagaccatcctggacttcctca aatccgacggcttcgcaaatcgtaatttcatgcaactgatccatgatgat agcctgacctttaaagaagatattcagaaggctcaagtgtccggccaggg tgactcgctgcatgagcatatcgcgaatctggctggctcccctgcgataa aaaaaggtattctccaaacggtgaaagttgtggatgaactggttaaagtc atgggtcgtcataaaccggaaaacatcgtgattgagatggcacgtgagaa ccagaccacccagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgta tcgaagaggggattaaggagttaggcagccagattctgaaggagcacccg gttgagaacacccagctgcaaaacgagaagctctacctgtattacctgca aaacggccgtgacatgtatgttgaccaggagctggacatcaatcgtctca gcgactacgacgtggatgctatcgtgccgcagagctttctaaaagatgat tccatcgacaataaagtgctcacccgtagcgacaagaaccgtggtaaaag cgacaacgtgccgagcgaggaagtagttaagaaaatgaaaaactactggc gtcagctattgaacgccaagcttatcacccagcgtaagtttgacaacttg acgaaggcagagcgtggcggcctgagcgagctagacaaggcgggttttat taaacgccagctggtggaaactcgccagattaccaaacacgttgcgcaaa tcttggactcacgcatgaatacgaagtacgacgaaaacgataaattgatc cgcgaggtgaaggtcataaccctgaaatctaaactggttagcgatttccg gaaggactttcaattttataaagtccgggagattaacaactatcaccatg cacacgacgcttacttaaatgcggttgttggcacggccctgatcaagaag tacccgaaactggaaagcgagtttgtttatggtgactacaaggtgtatga cgttcgcaagatgattgcaaaatccgaacaagagattggtaaggcgacgg ctaagtattttttctacagcaatatcatgaacttcttcaagactgaaatc accctggcgaacggtgaaattcgtaaacgtccgttgatcgaaaccaacgg tgaaaccggtgaaatcgtttgggataaaggtagggattttgcgaccgttc gtaaggtcctgagcatgccgcaggttaacatcgtgaaaaagaccgaagtg cagaccggcggtttctccaaggagagtatcttaccgaagcgcaacagtga caagctgatcgcgcgtaaaaaagactgggatccgaaaaaatacggcggct ttgactccccgaccgtcgcgtacagcgtactggtcgtggctaaagtggag aaaggcaaatcgaaaaagctgaaatccgttaaagagttgctgggtattac gattatggaacgttcgagcttcgagaaaaatccgatcgacttcctggagg ccaaaggctacaaggaagttaaaaaagacctgatcattaaactgccgaag tacagcctgttcgagctcgagaacggtcgcaaacgcatgctggcgagcgc gggtgagctccaaaaaggcaacgaattggctctgccgagcaagtacgtga acttcctgtatctggcctcccattatgaaaaactgaagggtagcccggaa gataacgaacaaaagcagctgttcgtggaacaacataaacactatctgga cgagattattgagcaaatcagcgagttcagcaaacgcgtgattctggcgg atgctaatctggacaaggttctttcagcctataataaacaccgtgataag ccgatccgtgaacaggcagaaaatattattcacctgttcaccctgacgaa cctgggtgcgccagcagcgtttaaatacttcgacacaacgatcgaccgga agcgttataccagcaccaaagaggttcttgacgccaccttgattcaccaa agcatcacgggtctgtatgaaacccgtattgacttgagccagttgggcgg agattcagggggaagtggcggaagcggtgggtctacgaacctgagcgaca ttattgaaaaagaaactggtaaacagttggtgatccaagaatccattctg atgttaccggaggaagtggaagaggtgatcggcaacaagccggagtccga catcctggttcacaccgcgtatgatgagtcgaccgatgagaatgttatgc tgctgaccagcgacgccccagagtacaaaccgtgggcgctcgtcatccag gatagcaatggcgaaaacaagatcaagatgttgtctggcggtagcatggc tccgaaaaagaagcgtaaagtaggtattcatggtgttccggcatcaggtt aa 2 Base editor A3A-dCasPhi-2 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaagcaagtccagcttcaggacccaggcacctgatggacccgcat attttcacctctaattttaacaacggtattggccgtcacaagacgtacct gtgttatgaagtggaacgtcttgacaacggcacctccgtgaaaatggacc agcatcgtggtttcttgcataatcaagctaaaaacctgctgtgcggtttc tacggccgtcacgcggaactgcgttttttggacctggttccgagcctgca actggacccggcacagatttatcgtgttacttggttcatcagctggtcgc cgtgttttagctggggttgcgccggcgaggtacgcgcgtttttgcaagag aacacccacgtgcgtttgcgcatcttcgccgctcgtatctacgattatga cccactgtataaagaagcgctccagatgctgcgcgatgcaggcgcgcagg tttccatcatgacctacgacgagttcaagcactgctgggatacctttgtc gatcatcagggctgcccgttccagccgtgggatggtctggatgagcacag ccaggcgttaagcggtcgcctcagagcgattctgcaaaaccaaggtaatt ctggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga atgccaaaacccgctgtagagtcagaattttcaaaagttttgaaaaagca ctttccgggagaacgtttccgctcgagctatatgaaaagaggcggtaaga tcctggctgcccaaggcgaagaggcagttgttgcgtatctacagggcaag tccgaggaggagcctccgaacttccagccaccggcgaagtgccacgtggt gaccaaatcccgtgacttcgcggaatggccgatcatgaaggcgtcggaag cgattcaacgttatatctatgcactgtcgaccaccgaacgcgcggcctgt aaaccgggcaaaagtagtgagagccatgcagcgtggttcgccgctaccgg tgtcagcaaccacggctacagccacgttcagggtctgaacctgatttttg atcataccttgggccgttacgatggtgttctgaaaaaggtccaactgcgc aacgaaaaggcgagagcgcgtttagagagcattaacgcgtctagagcaga tgaaggtttaccggagattaaagccgaggaggaagaagtggctacgaacg aaaccggccacctgttgcaaccgccgggtatcaatccgagcttttacgtg tatcagaccattagcccgcaggcataccgtccgcgtgacgagatcgtgct gccgccggagtacgcaggttacgtacgtgacccgaatgctccgattccgc tgggtgtggtgcgtaaccgttgcgatatccaaaaagggtgcccgggctac atcccggaatggcagcgtgaagcaggtaccgcgatcagcccgaaaacagg caaggccgtaactgtgccgggcctgtctccgaagaaaaacaaacgtatgc gtaggtactggcgctctgagaaggagaaagctcaagatgcgctgttggtt accgtacgcattggtaccgattgggttgtcatcgacgtgcgcggtctgtt gcgcaacgcccgttggcgcaccatcgctcccaaggacatcagcctgaatg cgctcctcgatttgtttaccggtgatccggtgatcgatgtgcgtcgcaat attgttacctttacgtacaccctcgacgcctgtggtacctacgcccgtaa atggaccttgaaaggcaaacagacgaaagcgaccctggacaaactgacgg ccactcagacggttgcgttggttgcgattgcgcttggtcagaccaacccg atttccgctggcattagccgtgttacacaagaaaatggtgcactgcaatg cgaaccgctggaccggttcaccctgccggatgacctgttgaaggacatca gcgcatatcgcattgcttgggacagaaacgaagaggaactacgcgctcgc agcgtcgaggccctgccggaggcgcaacaagcggaggtccgtgcgctgga cggggtgtccaaagaaaccgcgcgtacccaactgtgcgcagatttcggcc tggacccgaaacgtctgccgtgggataaaatgagctccaatactaccttt atcagcgaagccttgctgtctaacagcgtgagccgtgatcaggttttttt cactccggctccgaagaagggtgctaagaaaaaagcgcctgttgaagtta tgcgtaaagaccgcacttgggcacgtgcgtacaagccgcgtctgagcgtc gaagctcagaaactgaagaacgaagccctgtgggcacttaagcgcacctc cccggagtatttgaagctgagccgtcgcaaagaggagctgtgtcgtcgta gcatcaactatgttatcgaaaagacccgtcgccgtacgcaatgtcagatt gtgatcccggtgatcgaggatctgaatgttcgcttctttcatggttctgg taagagactgcccggttgggataatttcttcaccgctaaaaaagagaacc gttggttcatccagggcctgcacaaagcgtttagcgatctgcgtacgcac cgttccttctatgtttttgaagttcgtccggagcgcacctctattacctg tccaaagtgcggtcattgcgaggtgggtaatcgtgacggtgaggcgtttc agtgcctgagctgcggcaagacgtgcaacgcagatcttgacgtcgcgacc cataatctgacccaagtggcgttgaccggtaagaccatgccgaagcgcga ggagccgcgtgacgctcagggtacagcgccagcgcgcaagactaagaagg cgagcaaatcaaaggcgccaccggcggagcgcgaagaccagaccccggcg caagagccaagccagaccagttctggaggtagcgggggtagcggtggtag cactaacttaagtgatattatcgagaaagaaaccgggaaacagctggtga tccaagaaagcattctgatgctgcccgaagaagttgaagaagtgattggt aacaagcctgagtcggacatcttagtgcacaccgcgtacgatgaaagcac ggatgagaatgtgatgctgctcacctctgatgcccccgaatacaagccgt gggctctggtgatccaggactctaacggagaaaacaaaattaagatgctc tctggcggctccatggcgcctaaaaaaaaacgcaaagtggggattcacgg ggttccggcgtaa 3 Base editor A3A- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12 gagcatggctccgaaaaaagaaacgtaaggtgggtatccacggcgttccg gcgatggaagcaagtcca gcttcaggacccaggcacctgatggacccgcatattttcacctctaattt taacaacggtattggccgtcacaagacgtacctgtgttatgaagtggaac gtcttgacaacggcacctccgtgaaaatggaccagcatcgtggtttcttg cataatcaagctaaaaacctgctgtgcggtttctacggccgtcacgcgga actgcgttttttggacctggttccgagcctgcaactggacccggcacaga tttatcgtgttacttggttcatcagctggtcgccgtgttttagctggggt tgcgccggcgaggtacgcgcgtttttgcaagagaacacccacgtgcgttt gcgcatcttcgccgctcgtatctacgattatgacccactgtataaagaag cgctccagatgctgcgcgatgcaggcgcgcaggtttccatcatgacctac gacgagttcaagcactgctgggatacctttgtcgatcatcagggctgccc gttccagccgtgggatggtctggatgagcacagccaggcgttaagcggtc gcctcagagcgattctgcaaaaccaaggtaattctggaagtgagacaccc gggacttcagaatccgcgaccccggagtctggaatgtcaaaactagaaaa gtttacaaattgttactccctgtcgaaaaccctgagattcaaagcgatcc cggtgggtaaaactcaagagaacattgataacaaacgtctgctggttgag gacgaaaagcgcgcggaggattacaaaggcgttaaaaagctgttggaccg ttattacctgtcctttattaatgatgttctgcacagcattaaattaaaga acctaaacaattacatctccctcttccgtaaaaagacccgcaccgaaaag gaaaataaagaactggagaaccttgagattaatctgcgtaaagaaatcgc taaagcgtttaaaggcaacgagggttataaatccttatttaaaaaagaca tcatcgaaacgattctcccagaattcctggacgacaaagacgagatcgcg ctggttaattccttcaacggctttaccaccgcattcaccggcttttttga taaccgcgaaaacatgttctctgaagaggccaaaagcacctcaattgcgt ttcgctgcattaacgaaaatctgacgcgttatatctctaacatggatatc ttcgagaaggttgacgctatctttgataaacatgaagtccaggagatcaa ggagaagatcctgaacagcgactacgacgtggaggatttcttcgagggtg agttcttcaattttgttttgacccaagaaggcatcgatgtctacaatgcg ataattggtggttttgttaccgagagcggggagaaaattaagggtctgaa cgaatatatcaacttgtacaaccagaaaaccaaacaaaaactgccgaagt ttaagccgctgtacaagcaagtcttgtcggatcgtgaatcgctgagcttt tacggcgaaggctacaccagcgatgaggaggtgttggaggtgttccgcaa tacgttgaataagaactctgaaattttttccagcattaagaagctggaaa aactattcaagaacttcgacgagtatagcagcgcaggtatctttgtgaaa aacggtccggctattagcaccatctcgaaagacattttcggcgaatggaa tgttattcgtgataagtggaatgccgaatacgacgacattcatctgaaga aaaaggcggttgtaactgaaaagtacgaggacgatcgtcgtaagtcgttc aaaaagatcggctccttctctctggagcaactgcaagagtacgccgatgc cgatttgtcagtcgtggagaagctgaaagagatcatcattcaaaaagttg acgaaatctataaggtctatggtagcagtgaaaaactgtttgacgcggac ttcgtgctggagaaaagcctgaagaaaaatgacgccgtggtggcaatcat gaaagatcttctggatagcgtcaagtctttcgaaaactacatcaaagcgt ttttcggtgaaggcaaggaaacgaatcgtgacgagagcttctatggtgat ttcgtcctagcctatgatatcctgcttaaggtggatcacatctatgatgc catccgcaactatgttacccagaaaccgtactcaaaggacaagttcaagt tatacttccagaatccgcagtttatgggtggctgggataaagataaggaa accgactatcgcgccaccattttacgttacggtagtaagtactatctggc aatcatggataaaaaatatgcgaaatgcctgcaaaagatcgacaaggacg atgttaacggcaattatgagaagatcaactacaaactgctgccgggccca aataagatgctgccgaaggtgtttttcagcaaaaaatggatggcgtatta caatccgagcgaggacatccaaaagatctacaaaaacggtacgtttaaga agggtgatatgttcaacctcaacgattgtcataaacttattgacttcttc aaggatagcatatctcgttatccgaagtggagcaacgcgtatgactttaa ctttagcgaaaccgagaaatacaaagatatcgcgggtttctatcgtgaag ttgaagaacagggttacaaagtgtccttcgagtccgcgagcaagaaggag gtagacaagctggtcgaggagggtaagttgtacatgtttcagatttacaa taaggacttttccgacaagtcccatggtacaccgaatttgcacaccatgt atttcaagcttctgttcgacgagaacaaccacggccagatccgtctgagc ggtggtgcagagctgttcatgcgtagagctagcctgaagaaagaagagtt ggtcgttcatccggctaattcgccgatcgcgaacaaaaatccagataacc ctaaaaagactacgaccctgagctatgatgtgtataaagacaaacgcttt agcgaagaccagtatgagttacacattccgatcgctatcaacaagtgccc gaagaatattttcaagatcaacaccgaagtgcgtgttcttttgaagcacg atgacaacccgtatgtgattggtattgctcgtggtgaacgtaatctgctg tacattgtggttgtggacggcaaaggaaacatcgtggaacagtacagcct gaacgaaatcattaacaatttcaacggcattcgcattaagacggattacc attctttgctggacaaaaaggagaaagagcgtttcgaggcccgtcagaac tggacctccatcgagaacattaaggagctgaaggcgggttacatcagcca ggtggtgcacaaaatctgcgaactggtggagaagtacgacgcggtgattg ctttggcggatttgaactccggttttaagaacagccgcgttaaagtggaa aagcaggtttatcagaaattcgaaaaaatgctgattgataaattgaatta catggttgacaaaaagtctaacccgtgtgcaaccggcggtgcgctgaagg gctaccaaatcaccaataagtttgaaagctttaagagcatgagcacgcaa aatggcttcattttttacattccggcgtggctgaccagcaagatcgatcc gtcaaccggctttgttaatttactgaagacgaagtatacctctattgccg actctaaaaaatttattagttccttcgatagaatcatgtatgttccggaa gaggacctgttcgaatttgcactggactacaagaactttagccgtaccga tgctgattatataaagaaatggaaactctacagctatggcaaccgcatcc gtatctttcgcaacccgaaaaaaaacaacgtgttcgactgggaagaggta tgtctgacttcagcgtacaaggagcttttcaataaatatggtatcaacta ccagcagggtgatatccgtgcactgctttgcgagcaaagcgataaagcgt tctattcaagcttcatggcgctgatgagcctgatgctgcaaatgcgcaac agcatcaccggtcgtaccgatgttgcatttctgatttctccagtaaaaaa cagcgatggtatcttttacgacagccgtaattacgaggcccaagaaaatg cgattttgccgaagaacgctgacgcgaatggtgcatacaacattgcaagg aaagttctgtgggcaatcggccaatttaaaaaagcggaagatgagaagct ggacaaagtgaaaattgcgattagcaacaaggagtggctggagtatgcgc agacctccgttaaatcagggggaagtggcggaagcggtgggtctacgaac ctgagcgacattattgaaaaagaaactggtaaacagttggtgatccaaga atccattctgatgttaccggaggaagtggaagaggtgatcggcaacaagc cggagtccgacatcctggttcacaccgcgtatgatgagtcgaccgatgag aatgttatgctgctgaccagcgacgccccagagtacaaaccgtgggcgct cgtcatccaggatagcaatggcgaaaacaagatcaagatgttgtctggcg gtagcatggctccgaaaaagaagcgtaaagtaggtattcatggtgttccg gcatcaggttaa 4 Base editor A3A-Y130F- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca Cas9 gagcatggctccgaaaaadgaaacgtaaggtgggtatccacggcgttccg gcgatggaagcatcaccag ctagtggacccaggcacctgatggatccgcacatcttcacctccaatttt aataacggcatcggccgtcataagacgtacctgtgctatgaggttgaacg tttggacaacggtactagcgtcaagatggaccagcatcgtggtttccttc acaaccaagcgaaaaatctgctgtgcggtttttatggtcgtcacgccgaa ctgagattcttggatctggttccgtctctgcaactggacccggcgcagat ttatcgtgtgacctggttcatcagctggtcgccgtgctttagctggggtt gcgccggtgaagtgcgcgcatttctccaggagaacacccatgttcgtttg cgcatcttcgcggcacgtatcttcgattacgacccgctgtacaaggaggc gctgcaaatgttgcgtgatgctggcgctcaagttagcattatgacctacg acgaatttaaacactgttgggataccttcgtggatcatcagggctgtccg tttcagccatgggacggcctggacgagcacagccaggcgttatccggtcg cctgcgcgcgattctgcaaaaccagggaaactctggaagtgagacacccg ggacttcagaatccgcgaccccggagtctggaatggataaaaagtattca ataggactagctattggcaccaacagcgttggttgggcagttatcaccga tgaatataaggtcccgagcaagaagtttaaggtcctgggcaacaccgatc gccacagcataaaaaagaaccttattggtgcgctgctgttcgattctggt gagactgccgaagcgacccgtctgaagagaaccgcgcgtcgtagatacac ccggcgcaagaaccgtatctgctatctgcaagaaattttcagcaacgaga tggctaaggtcgacgactccttctttcatcgcctggaggaaagctttctg gttgaggaagacaaaaagcacgagcgtcatccgattttcggtaacattgt tgatgaagttgcctaccacgaaaaataccccacaatttatcatctgcgta aaaaactggtagactccaccgataaggcggatttacgccttatctatttg gcgctggcgcatatgattaagttccgcggtcattttttgatcgagggcga cctgaatccggataacagcgacgttgacaaactgtttatccagctggtgc agacctataaccagttgttcgaagagaacccgattaatgcgtctggcgtg gacgcgaaggcgatcctgagcgctcgtctgtccaagtcacgccgcctgga gaacttgatcgcgcaactgccgggtgagaagaaaaacggcttgttcggca atctgattgctctgtccctaggtttgaccccgaatttcaaatctaatttt gatctggcggaagatgcgaaattacagttgagcaaggacacttacgatga cgatctggacaacctgctcgctcagatcggcgatcagtatgccgatcttt tcctggccgcgaagaacctgagcgatgccatcttgctatcggacatctta cgtgttaacaccgaaatcaccaaagctccgctaagcgcgtccatgattaa acgttacgatgaacaccaccaggatctgacgctgctgaaagcgttggtgc gccagcaactgccggaaaaatacaaggaaattttcttcgaccaaagcaag aacggttatgcaggctatatcgacggtggtgcgtcgcaagaagaatttta taaattcatcaaaccgattttggagaagatggatggtaccgaggagctgc tggtaaaattgaatcgggaagacctcttgcgaaagcagcgtactttcgat aatggtagcatcccgcaccagattcatctgggcgaacttcacgcaatcct acgtcgtcaagaggatttctacccgtttctgaaggataaccgtgaaaaga tcgagaagattctgacctttcgtattccgtattatgtgggtccgctggcg agaggcaacagccgttttgcgtggatgacccgcaagtcggaagagactat cacgccgtggaatttcgaggaggtcgtggacaagggtgcatcagcgcaat cttttattgaacgtatgaccaattttgataaaaaccttccaaatgaaaaa gtgttgccgaagcacagcttgctgtacgagtatttcaccgtttacaatga actgacgaaagtcaagtacgttaccgaaggtatgcgtaagccagcctttc tgtctggggagcaaaaaaaagccattgtggatctgctgttcaagaccaat cgcaaggttaccgtcaagcaactgaaagaggattacttcaaaaaaatcga atgttttgactccgtggaaatcagcggcgttgaagaccgctttaatgcat ctctgggcacctaccacgatctactcaagatcatcaaggataaggacttc ctggacaacgaagaaaatgaggatatcttggaagatattgtgctgacttt aacgttgttcgaggatcgtgagatgattgaagaacgcctcaaaacgtacg cacatctgtttgacgataaggtgatgaaacagctaaagcgccgtcgttac accggttggggtcgtctgtctagaaagctgattaacggcattcgtgacaa acaatctggcaagaccatcctggacttcctcaaatccgacggcttcgcaa atcgtaatttcatgcaactgatccatgatgatagcctgacctttaaagaa gatattcagaaggctcaagtgtccggccagggtgactcgctgcatgagca tatcgcgaatctggctggctcccctgcgataaaaaaaggtattctccaaa cggtgaaagttgtggatgaactggttaaagtcatgggtcgtcataaaccg gaaaacatcgtgattgagatggcacgtgagaaccagaccacccagaaagg tcaaaaaaacagtcgtgagcgtatgaaacgtatcgaagaggggattaagg agttaggcagccagattctgaaggagcacccggttgagaacacccagctg caaaacgagaagctctacctgtattacctgcaaaacggccgtgacatgta tgttgaccaggagctggacatcaatcgtctcagcgactacgacgtggatg ctatcgtgccgcagagctttctaaaagatgattccatcgacaataaagtg ctcacccgtagcgacaagaaccgtggtaaaagcgacaacgtgccgagcga ggaagtagttaagaaaatgaaaaactactggcgtcagctattgaacgcca agcttatcacccagcgtaagtttgacaacttgacgaaggcagagcgtggc ggcctgagcgagctagacaaggcgggttttattaaacgccagctggtgga aactcgccagattaccaaacacgttgcgcaaatcttggactcacgcatga atacgaagtacgacgaaaacgataaattgatccgcgaggtgaaggtcata accctgaaatctaaactggttagcgatttccggaaggactttcaatttta taaagtccgggagattaacaactatcaccatgcacacgacgcttacttaa atgcggttgttggcacggccctgatcaagaagtacccgaaactggaaagc gagtttgtttatggtgactacaaggtgtatgacgttcgcaagatgattgc aaaatccgaacaagagattggtaaggcgacggctaagtattttttctaca gcaatatcatgaacttcttcaagactgaaatcaccctggcgaacggtgaa attcgtaaacgtccgttgatcgaaaccaacggtgaaaccggtgaaatcgt ttgggataaaggtagggattttgcgaccgttcgtaaggtcctgagcatgc cgcaggttaacatcgtgaaaaagaccgaagtgcagaccggcggtttctcc aaggagagtatcttaccgaagcgcaacagtgacaagctgatcgcgcgtaa aaaagactgggatccgaaaaaatacggcggctttgactccccgaccgtcg cgtacagcgtactggtcgtggctaaagtggagaaaggcaaatcgaaaaag ctgaaatccgttaaagagttgctgggtattacgattatggaacgttcgag cttcgagaaaaatccgatcgacttcctggaggccaaaggctacaaggaag ttaaaaaagacctgatcattaaactgccgaagtacagcctgttcgagctc gagaacggtcgcaaacgcatgctggcgagcgcgggtgagctccaaaaagg caacgaattggctctgccgagcaagtacgtgaacttcctgtatctggcct cccattatgaaaaactgaagggtagcccggaagataacgaacaaaagcag ctgttcgtggaacaacataaacactatctggacgagattattgagcaaat cagcgagttcagcaaacgcgtgattctggcggatgctaatctggacaagg ttctttcagcctataataaacaccgtgataagccgatccgtgaacaggca gaaaatattattcacctgttcaccctgacgaacctgggtgcgccagcagc gtttaaatacttcgacacaacgatcgaccggaagcgttataccagcacca aagaggttcttgacgccaccttgattcaccaaagcatcacgggtctgtat gaaacccgtattgacttgagccagttgggcggagattcagggggaagtgg cggaagcggtgggtctacgaacctgagcgacattattgaaaaagaaactg gtaaacagttggtgatccaagaatccattctgatgttaccggaggaagtg gaagaggtgatcggcaacaagccggagtccgacatcctggttcacaccgc gtatgatgagtcgaccgatgagaatgttatgctgctgaccagcgacgccc cagagtacaaaccgtgggcgctcgtcatccaggatagcaatggcgaaaac aagatcaagatgttgtctggcggtagcatggctccgaaaaagaagcgtaa agtaggtattcatggtgttccggcatcaggttaa 5 Base editor A3A-Y130F- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaagcatcaccagctagtggacccaggcacctgatggatccgcac atcttcacctccaattttaataacggcatcggccgtcataagacgtacct gtgctatgaggttgaacgtttggacaacggtactagcgtcaagatggacc agcatcgtggtttccttcacaaccaagcgaaaaatctgctgtgcggtttt tatggtcgtcacgccgaactgagattcttggatctggttccgtctctgca actggacccggcgcagatttatcgtgtgacctggttcatcagctggtcgc cgtgctttagctggggttgcgccggtgaagtgcgcgcatttctccaggag aacacccatgttcgtttgcgcatcttcgcggcacgtatcttcgattacga cccgctgtacaaggaggcgctgcaaatgttgcgtgatgctggcgctcaag ttagcattatgacctacgacgaatttaaacactgttgggataccttcgtg gatcatcagggctgtccgtttcagccatgggacggcctggacgagcacag ccaggcgttatccggtcgcctgcgcgcgattctgcaaaaccagggaaact ctggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga atgccaaaacccgctgtagagtcagaattttcaaaagttttgaaaaagca ctttccgggagaacgtttccgctcgagctatatgaaaagaggcggtaaga tcctggctgcccaaggcgaagaggcagttgttgcgtatctacagggcaag tccgaggaggagcctccgaacttccagccaccggcgaagtgccacgtggt gaccaaatcccgtgacttcgcggaatggccgatcatgaaggcgtcggaag cgattcaacgttatatctatgcactgtcgaccaccgaacgcgcggcctgt aaaccgggcaaaagtagtgagagccatgcagcgtggttcgccgctaccgg tgtcagcaaccacggctacagccacgttcagggtctgaacctgatttttg atcataccttgggccgttacgatggtgttctgaaaaaggtccaactgcgc aacgaaaaggcgagagcgcgtttagagagcattaacgcgtctagagcaga tgaaggtttaccggagattaaagccgaggaggaagaagtggctacgaacg aaaccggccacctgttgcaaccgccgggtatcaatccgagcttttacgtg tatcagaccattagcccgcaggcataccgtccgcgtgacgagatcgtgct gccgccggagtacgcaggttacgtacgtgacccgaatgctccgattccgc tgggtgtggtgcgtaaccgttgcgatatccaaaaagggtgcccgggctac atcccggaatggcagcgtgaagcaggtaccgcgatcagcccgaaaacagg caaggccgtaactgtgccgggcctgtctccgaagaaaaacaaacgtatgc gtaggtactggcgctctgagaaggagaaagctcaagatgcgctgttggtt accgtacgcattggtaccgattgggttgtcatcgacgtgcgcggtctgtt gcgcaacgcccgttggcgcaccatcgctcccaaggacatcagcctgaatg cgctcctcgatttgtttaccggtgatccggtgatcgatgtgcgtcgcaat attgttacctttacgtacaccctcgacgcctgtggtacctacgcccgtaa atggaccttgaaaggcaaacagacgaaagcgaccctggacaaactgacgg ccactcagacggttgcgttggttgcgattgcgcttggtcagaccaacccg atttccgctggcattagccgtgttacacaagaaaatggtgcactgcaatg cgaaccgctggaccggttcaccctgccggatgacctgttgaaggacatca gcgcatatcgcattgcttgggacagaaacgaagaggaactacgcgctcgc agcgtcgaggccctgccggaggcgcaacaagcggaggtccgtgcgctgga cggggtgtccaaagaaaccgcgcgtacccaactgtgcgcagatttcggcc tggacccgaaacgtctgccgtgggataaaatgagctccaatactaccttt atcagcgaagccttgctgtctaacagcgtgagccgtgatcaggttttttt cactccggctccgaagaagggtgctaagaaaaaagcgcctgttgaagtta tgcgtaaagaccgcacttgggcacgtgcgtacaagccgcgtctgagcgtc gaagctcagaaactgaagaacgaagccctgtgggcacttaagcgcacctc cccggagtatttgaagctgagccgtcgcaaagaggagctgtgtcgtcgta gcatcaactatgttatcgaaaagacccgtcgccgtacgcaatgtcagatt gtgatcccggtgatcgaggatctgaatgttcgcttctttcatggttctgg taagagactgcccggttgggataatttcttcaccgctaaaaaagagaacc gttggttcatccagggcctgcacaaagcgtttagcgatctgcgtacgcac cgttccttctatgtttttgaagttcgtccggagcgcacctctattacctg tccaaagtgcggtcattgcgaggtgggtaatcgtgacggtgaggcgtttc agtgcctgagctgcggcaagacgtgcaacgcagatcttgacgtcgcgacc cataatctgacccaagtggcgttgaccggtaagaccatgccgaagcgcga ggagccgcgtgacgctcagggtacagcgccagcgcgcaagactaagaagg cgagcaaatcaaaggcgccaccggcggagcgcgaagaccagaccccggcg caagagccaagccagaccagttctggaggtagcgggggtagcggtggtag cactaacttaagtgatattatcgagaaagaaaccgggaaacagctggtga tccaagaaagcattctgatgctgcccgaagaagttgaagaagtgattggt aacaagcctgagtcggacatcttagtgcacaccgcgtacgatgaaagcac ggatgagaatgtgatgctgctcacctctgatgcccccgaatacaagccgt gggctctggtgatccaggactctaacggagaaaacaaaattaagatgctc tctggcggctccatggcgcctaaaaaaaaacgcaaagtggggattcacgg ggttccggcgtaa 6 Base editor A3A-Y130F- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaagcatcaccagctagtggacccaggcacctgatggatccgcac atcttcacctccaattttaataacggcatcggccgtcataagacgtacct gtgctatgaggttgaacgtttggacaacggtactagcgtcaagatggacc agcatcgtggtttccttcacaaccaagcgaaaaatctgctgtgcggtttt tatggtcgtcacgccgaactgagattcttggatctggttccgtctctgca actggacccggcgcagatttatcgtgtgacctggttcatcagctggtcgc cgtgctttagctggggttgcgccggtgaagtgcgcgcatttctccaggag aacacccatgttcgtttgcgcatcttcgcggcacgtatcttcgattacga cccgctgtacaaggaggcgctgcaaatgttgcgtgatgctggcgctcaag ttagcattatgacctacgacgaatttaaacactgttgggataccttcgtg gatcatcagggctgtccgtttcagccatgggacggcctggacgagcacag ccaggcgttatccggtcgcctgcgcgcgattctgcaaaaccagggaaact ctggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga atgtcaaaactagaaaagtttacaaattgttactccctgtcgaaaaccct gagattcaaagcgatcccggtgggtaaaactcaagagaacattgataaca aacgtctgctggttgaggacgaaaagcgcgcggaggattacaaaggcgtt aaaaagctgttggaccgttattacctgtcctttattaatgatgttctgca cagcattaaattaaagaacctaaacaattacatctccctcttccgtaaaa agacccgcaccgaaaaggaaaataaagaactggagaaccttgagattaat ctgcgtaaagaaatcgctaaagcgtttaaaggcaacgagggttataaatc cttatttaaaaaagacatcatcgaaacgattctcccagaattcctggacg acaaagacgagatcgcgctggttaattccttcaacggctttaccaccgca ttcaccggcttttttgataaccgcgaaaacatgttctctgaagaggccaa aagcacctcaattgcgtttcgctgcattaacgaaaatctgacgcgttata tctctaacatggatatcttcgagaaggttgacgctatctttgataaacat gaagtccaggagatcaaggagaagatcctgaacagcgactacgacgtgga ggatttcttcgagggtgagttcttcaattttgttttgacccaagaaggca tcgatgtctacaatgcgataattggtggttttgttaccgagagcggggag aaaattaagggtctgaacgaatatatcaacttgtacaaccagaaaaccaa acaaaaactgccgaagtttaagccgctgtacaagcaagtcttgtcggatc gtgaatcgctgagcttttacggcgaaggctacaccagcgatgaggaggtg ttggaggtgttccgcaatacgttgaataagaactctgaaattttttccag cattaagaagctggaaaaactattcaagaacttcgacgagtatagcagcg caggtatctttgtgaaaaacggtccggctattagcaccatctcgaaagac attttcggcgaatggaatgttattcgtgataagtggaatgccgaatacga cgacattcatctgaagaaaaaggcggttgtaactgaaaagtacgaggacg atcgtcgtaagtcgttcaaaaagatcggctccttctctctggagcaactg caagagtacgccgatgccgatttgtcagtcgtggagaagctgaaagagat catcattcaaaaagttgacgaaatctataaggtctatggtagcagtgaaa aactgtttgacgcggacttcgtgctggagaaaagcctgaagaaaaatgac gccgtggtggcaatcatgaaagatcttctggatagcgtcaagtctttcga aaactacatcaaagcgtttttcggtgaaggcaaggaaacgaatcgtgacg agagcttctatggtgatttcgtcctagcctatgatatcctgcttaaggtg gatcacatctatgatgccatccgcaactatgttacccagaaaccgtactc aaaggacaagttcaagttatacttccagaatccgcagtttatgggtggct gggataaagataaggaaaccgactatcgcgccaccattttacgttacggt agtaagtactatctggcaatcatggataaaaaatatgcgaaatgcctgca aaagatcgacaaggacgatgttaacggcaattatgagaagatcaactaca aactgctgccgggcccaaataagatgctgccgaaggtgtttttcagcaaa aaatggatggcgtattacaatccgagcgaggacatccaaaagatctacaa aaacggtacgtttaagaagggtgatatgttcaacctcaacgattgtcata aacttattgacttcttcaaggatagcatatctcgttatccgaagtggagc aacgcgtatgactttaactttagcgaaaccgagaaatacaaagatatcgc gggtttctatcgtgaagttgaagaacagggttacaaagtgtccttcgagt ccgcgagcaagaaggaggtagacaagctggtcgaggagggtaagttgtac atgtttcagatttacaataaggacttttccgacaagtcccatggtacacc gaatttgcacaccatgtatttcaagcttctgttcgacgagaacaaccacg gccagatccgtctgagcggtggtgcagagctgttcatgcgtagagctagc ctgaagaaagaagagttggtcgttcatccggctaattcgccgatcgcgaa caaaaatccagataaccctaaaaagactacgaccctgagctatgatgtgt ataaagacaaacgctttagcgaagaccagtatgagttacacattccgatc gctatcaacaagtgcccgaagaatattttcaagatcaacaccgaagtgcg tgttcttttgaagcacgatgacaacccgtatgtgattggtattgctcgtg gtgaacgtaatctgctgtacattgtggttgtggacggcaaaggaaacatc gtggaacagtacagcctgaacgaaatcattaacaatttcaacggcattcg cattaagacggattaccattctttgctggacaaaaaggagaaagagcgtt tcgaggcccgtcagaactggacctccatcgagaacattaaggagctgaag gcgggttacatcagccaggtggtgcacaaaatctgcgaactggtggagaa gtacgacgcggtgattgctttggcggatttgaactccggttttaagaaca gccgcgttaaagtggaaaagcaggtttatcagaaattcgaaaaaatgctg attgataaattgaattacatggttgacaaaaagtctaacccgtgtgcaac cggcggtgcgctgaagggctaccaaatcaccaataagtttgaaagcttta agagcatgagcacgcaaaatggcttcattttttacattccggcgtggctg accagcaagatcgatccgtcaaccggctttgttaatttactgaagacgaa gtatacctctattgccgactctaaaaaatttattagttccttcgatagaa tcatgtatgttccggaagaggacctgttcgaatttgcactggactacaag aactttagccgtaccgatgctgattatataaagaaatggaaactctacag ctatggcaaccgcatccgtatctttcgcaacccgaaaaaaaacaacgtgt tcgactgggaagaggtatgtctgacttcagcgtacaaggagcttttcaat aaatatggtatcaactaccagcagggtgatatccgtgcactgctttgcga gcaaagcgataaagcgttctattcaagcttcatggcgctgatgagcctga tgctgcaaatgcgcaacagcatcaccggtcgtaccgatgttgcatttctg atttctccagtaaaaaacagcgatggtatcttttacgacagccgtaatta cgaggcccaagaaaatgcgattttgccgaagaacgctgacgcgaatggtg catacaacattgcaaggaaagttctgtgggcaatcggccaatttaaaaaa gcggaagatgagaagctggacaaagtgaaaattgcgattagcaacaagga gtggctggagtatgcgcagacctccgttaaatcagggggaagtggcggaa gcggtgggtctacgaacctgagcgacattattgaaaaagaaactggtaaa cagttggtgatccaagaatccattctgatgttaccggaggaagtggaaga ggtgatcggcaacaagccggagtccgacatcctggttcacaccgcgtatg atgagtcgaccgatgagaatgttatgctgctgaccagcgacgccccagag tacaaaccgtgggcgctcgtcatccaggatagcaatggcgaaagttccgg catcaggttaa 7 Base editor A3B-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaaatactaaggtatttaatggatcccgacactttcaccttcaat ttcaacaacgatccattggtcttgcgccgtcgtcagacctacttgtgcta tgaggttgaacgtctggataacggtacgtgggttttaatggatcagcata tgggtttcctgtgtaatgaagcgaagaacctgctgtgcggtttttacggc cgtcatgcggaactgcgttttcttgacctggttccgagcctgcaactgga cccggctcagatttaccgtgttacctggtttatctcgtggagcccgtgtt ttagctggggctgcgcgggtgaagtgcgcgcgtttttgcaagagaacacc cacgtgcgtctccgcatcttcgccgcacgtatttacgattatgacccgct gtataaagaggccctgcaaatgctgagagatgctggcgcacaagtgagca ttatgacctacgacgagttcgagtactgctgggatacgttcgtgtatcgc caaggttgcccgtttcagccgtgggacggcctggaggagcacagccaggc gctctccggtcgtttgcgcgcgatcctgcaatctggaagtgagacacccg ggacttcagaatccgcgaccccggagtctggaatggataaaaagtattca ataggactagctattggcaccaacagcgttggttgggcagttatcaccga tgaatataaggtcccgagcaagaagtttaaggtcctgggcaacaccgatc gccacagcataaaaaagaaccttattggtgcgctgctgttcgattctggt gagactgccgaagcgacccgtctgaagagaaccgcgcgtcgtagatacac ccggcgcaagaaccgtatctgctatctgcaagaaattttcagcaacgaga tggctaaggtcgacgactccttctttcatcgcctggaggaaagctttctg gttgaggaagacaaaaagcacgagcgtcatccgattttcggtaacattgt tgatgaagttgcctaccacgaaaaataccccacaatttatcatctgcgta aaaaactggtagactccaccgataaggcggatttacgccttatctatttg gcgctggcgcatatgattaagttccgcggtcattttttgatcgagggcga cctgaatccggataacagcgacgttgacaaactgtttatccagctggtgc agacctataaccagttgttcgaagagaacccgattaatgcgtctggcgtg gacgcgaaggcgatcctgagcgctcgtctgtccaagtcacgccgcctgga gaacttgatcgcgcaactgccgggtgagaagaaaaacggcttgttcggca atctgattgctctgtccctaggtttgaccccgaatttcaaatctaatttt gatctggcggaagatgcgaaattacagttgagcaaggacacttacgatga cgatctggacaacctgctcgctcagatcggcgatcagtatgccgatcttt tcctggccgcgaagaacctgagcgatgccatcttgctatcggacatctta cgtgttaacaccgaaatcaccaaagctccgctaagcgcgtccatgattaa acgttacgatgaacaccaccaggatctgacgctgctgaaagcgttggtgc gccagcaactgccggaaaaatacaaggaaattttcttcgaccaaagcaag aacggttatgcaggctatatcgacggtggtgcgtcgcaagaagaatttta taaattcatcaaaccgattttggagaagatggatggtaccgaggagctgc tggtaaaattgaatcgggaagacctcttgcgaaagcagcgtactttcgat aatggtagcatcccgcaccagattcatctgggcgaacttcacgcaatcct acgtcgtcaagaggatttctacccgtttctgaaggataaccgtgaaaaga tcgagaagattctgacctttcgtattccgtattatgtgggtccgctggcg agaggcaacagccgttttgcgtggatgacccgcaagtcggaagagactat cacgccgtggaatttcgaggaggtcgtggacaagggtgcatcagcgcaat cttttattgaacgtatgaccaattttgataaaaaccttccaaatgaaaaa gtgttgccgaagcacagcttgctgtacgagtatttcaccgtttacaatga actgacgaaagtcaagtacgttaccgaaggtatgcgtaagccagcctttc tgtctggggagcaaaaaaaagccattgtggatctgctgttcaagaccaat cgcaaggttaccgtcaagcaactgaaagaggattacttcaaaaaaatcga atgttttgactccgtggaaatcagcggcgttgaagaccgctttaatgcat ctctgggcacctaccacgatctactcaagatcatcaaggataaggacttc ctggacaacgaagaaaatgaggatatcttggaagatattgtgctgacttt aacgttgttcgaggatcgtgagatgattgaagaacgcctcaaaacgtacg cacatctgtttgacgataaggtgatgaaacagctaaagcgccgtcgttac accggttggggtcgtctgtctagaaagctgattaacggcattcgtgacaa acaatctggcaagaccatcctggacttcctcaaatccgacggcttcgcaa atcgtaatttcatgcaactgatccatgatgatagcctgacctttaaagaa gatattcagaaggctcaagtgtccggccagggtgactcgctgcatgagca tatcgcgaatctggctggctcccctgcgataaaaaaaggtattctccaaa cggtgaaagttgtggatgaactggttaaagtcatgggtcgtcataaaccg gaaaacatcgtgattgagatggcacgtgagaaccagaccacccagaaagg tcaaaaaaacagtcgtgagcgtatgaaacgtatcgaagaggggattaagg agttaggcagccagattctgaaggagcacccggttgagaacacccagctg caaaacgagaagctctacctgtattacctgcaaaacggccgtgacatgta tgttgaccaggagctggacatcaatcgtctcagcgactacgacgtggatg ctatcgtgccgcagagctttctaaaagatgattccatcgacaataaagtg ctcacccgtagcgacaagaaccgtggtaaaagcgacaacgtgccgagcga ggaagtagttaagaaaatgaaaaactactggcgtcagctattgaacgcca agcttatcacccagcgtaagtttgacaacttgacgaaggcagagcgtggc ggcctgagcgagctagacaaggcgggttttattaaacgccagctggtgga aactcgccagattaccaaacacgttgcgcaaatcttggactcacgcatga atacgaagtacgacgaaaacgataaattgatccgcgaggtgaaggtcata accctgaaatctaaactggttagcgatttccggaaggactttcaatttta taaagtccgggagattaacaactatcaccatgcacacgacgcttacttaa atgcggttgttggcacggccctgatcaagaagtacccgaaactggaaagc gagtttgtttatggtgactacaaggtgtatgacgttcgcaagatgattgc aaaatccgaacaagagattggtaaggcgacggctaagtattttttctaca gcaatatcatgaacttcttcaagactgaaatcaccctggcgaacggtgaa attcgtaaacgtccgttgatcgaaaccaacggtgaaaccggtgaaatcgt ttgggataaaggtagggattttgcgaccgttcgtaaggtcctgagcatgc cgcaggttaacatcgtgaaaaagaccgaagtgcagaccggcggtttctcc aaggagagtatcttaccgaagcgcaacagtgacaagctgatcgcgcgtaa aaaagactgggatccgaaaaaatacggcggctttgactccccgaccgtcg cgtacagcgtactggtcgtggctaaagtggagaaaggcaaatcgaaaaag ctgaaatccgttaaagagttgctgggtattacgattatggaacgttcgag cttcgagaaaaatccgatcgacttcctggaggccaaaggctacaaggaag ttaaaaaagacctgatcattaaactgccgaagtacagcctgttcgagctc gagaacggtcgcaaacgcatgctggcgagcgcgggtgagctccaaaaagg caacgaattggctctgccgagcaagtacgtgaacttcctgtatctggcct cccattatgaaaaactgaagggtagcccggaagataacgaacaaaagcag ctgttcgtggaacaacataaacactatctggacgagattattgagcaaat cagcgagttcagcaaacgcgtgattctggcggatgctaatctggacaagg ttctttcagcctataataaacaccgtgataagccgatccgtgaacaggca gaaaatattattcacctgttcaccctgacgaacctgggtgcgccagcagc gtttaaatacttcgacacaacgatcgaccggaagcgttataccagcacca aagaggttcttgacgccaccttgattcaccaaagcatcacgggtctgtat gaaacccgtattgacttgagccagttgggcggagattcagggggaagtgg cggaagcggtgggtctacgaacctgagcgacattattgaaaaagaaactg gtaaacagttggtgatccaagaatccattctgatgttaccggaggaagtg gaagaggtgatcggcaacaagccggagtccgacatcctggttcacaccgc gtatgatgagtcgaccgatgagaatgttatgctgctgaccagcgacgccc cagagtacaaaccgtgggcgctcgtcatccaggatagcaatggcgaaaac aagatcaagatgttgtctggcggtagcatggctccgaaaaagaagcgtaa agtaggtattcatggtgttccggcatcaggttaa 8 Base editor A3B-dCasPhi-2 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaaatactaaggtatttaatggatcccgacactttcaccttcaat ttcaacaacgatccattggtcttgcgccgtcgtcagacctacttgtgcta tgaggttgaacgtctggataacggtacgtgggttttaatggatcagcata tgggtttcctgtgtaatgaagcgaagaacctgctgtgcggtttttacggc cgtcatgcggaactgcgttttcttgacctggttccgagcctgcaactgga cccggctcagatttaccgtgttacctggtttatctcgtggagcccgtgtt ttagctggggctgcgcgggtgaagtgcgcgcgtttttgcaagagaacacc cacgtgcgtctccgcatcttcgccgcacgtatttacgattatgacccgct gtataaagaggccctgcaaatgctgagagatgctggcgcacaagtgagca ttatgacctacgacgagttcgagtactgctgggatacgttcgtgtatcgc caaggttgcccgtttcagccgtgggacggcctggaggagcacagccaggc gctctccggtcgtttgcgcgcgatcctgcaatctggaagtgagacacccg ggacttcagaatccgcgaccccggagtctggaatgccaaaacccgctgta gagtcagaattttcaaaagttttgaaaaagcactttccgggagaacgttt ccgctcgagctatatgaaaagaggcggtaagatcctggctgcccaaggcg aagaggcagttgttgcgtatctacagggcaagtccgaggaggagcctccg aacttccagccaccggcgaagtgccacgtggtgaccaaatcccgtgactt cgcggaatggccgatcatgaaggcgtcggaagcgattcaacgttatatct atgcactgtcgaccaccgaacgcgcggcctgtaaaccgggcaaaagtagt gagagccatgcagcgtggttcgccgctaccggtgtcagcaaccacggcta cagccacgttcagggtctgaacctgatttttgatcataccttgggccgtt acgatggtgttctgaaaaaggtccaactgcgcaacgaaaaggcgagagcg cgtttagagagcattaacgcgtctagagcagatgaaggtttaccggagat taaagccgaggaggaagaagtggctacgaacgaaaccggccacctgttgc aaccgccgggtatcaatccgagcttttacgtgtatcagaccattagcccg caggcataccgtccgcgtgacgagatcgtgctgccgccggagtacgcagg ttacgtacgtgacccgaatgctccgattccgctgggtgtggtgcgtaacc gttgcgatatccaaaaagggtgcccgggctacatcccggaatggcagcgt gaagcaggtaccgcgatcagcccgaaaacaggcaaggccgtaactgtgcc gggcctgtctccgaagaaaaacaaacgtatgcgtaggtactggcgctctg agaaggagaaagctcaagatgcgctgttggttaccgtacgcattggtacc gattgggttgtcatcgacgtgcgcggtctgttgcgcaacgcccgttggcg caccatcgctcccaaggacatcagcctgaatgcgctcctcgatttgttta ccggtgatccggtgatcgatgtgcgtcgcaatattgttacctttacgtac accctcgacgcctgtggtacctacgcccgtaaatggaccttgaaaggcaa acagacgaaagcgaccctggacaaactgacggccactcagacggttgcgt tggttgcgattgcgcttggtcagaccaacccgatttccgctggcattagc cgtgttacacaagaaaatggtgcactgcaatgcgaaccgctggaccggtt caccctgccggatgacctgttgaaggacatcagcgcatatcgcattgctt gggacagaaacgaagaggaactacgcgctcgcagcgtcgaggccctgccg gaggcgcaacaagcggaggtccgtgcgctggacggggtgtccaaagaaac cgcgcgtacccaactgtgcgcagatttcggcctggacccgaaacgtctgc cgtgggataaaatgagctccaatactacctttatcagcgaagccttgctg tctaacagcgtgagccgtgatcaggtttttttcactccggctccgaagaa gggtgctaagaaaaaagcgcctgttgaagttatgcgtaaagaccgcactt gggcacgtgcgtacaagccgcgtctgagcgtcgaagctcagaaactgaag aacgaagccctgtgggcacttaagcgcacctccccggagtatttgaagct gagccgtcgcaaagaggagctgtgtcgtcgtagcatcaactatgttatcg aaaagacccgtcgccgtacgcaatgtcagattgtgatcccggtgatcgag gatctgaatgttcgcttctttcatggttctggtaagagactgcccggttg ggataatttcttcaccgctaaaaaagagaaccgttggttcatccagggcc tgcacaaagcgtttagcgatctgcgtacgcaccgttccttctatgttttt gaagttcgtccggagcgcacctctattacctgtccaaagtgcggtcattg cgaggtgggtaatcgtgacggtgaggcgtttcagtgcctgagctgcggca agacgtgcaacgcagatcttgacgtcgcgacccataatctgacccaagtg gcgttgaccggtaagaccatgccgaagcgcgaggagccgcgtgacgctca gggtacagcgccagcgcgcaagactaagaaggcgagcaaatcaaaggcgc caccggcggagcgcgaagaccagaccccggcgcaagagccaagccagacc agttctggaggtagcgggggtagcggtggtagcactaacttaagtgatat tatcgagaaagaaaccgggaaacagctggtgatccaagaaagcattctga tgctgcccgaagaagttgaagaagtgattggtaacaagcctgagtcggac atcttagtgcacaccgcgtacgatgaaagcacggatgagaatgtgatgct gctcacctctgatgcccccgaatacaagccgtgggctctggtgatccagg actctaacggagaaaacaaaattaagatgctctctggcggctccatggcg cctaaaaaaaaacgcaaagtggggattcacggggttccggcgtaa 9 Base editor A3B-dLbCas12a atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaaatactaaggtatttaatggatcccgacactttcaccttcaat ttcaacaacgatccattggtcttgcgccgtcgtcagacctacttgtgcta tgaggttgaacgtctggataacggtacgtgggttttaatggatcagcata tgggtttcctgtgtaatgaagcgaagaacctgctgtgcggtttttacggc cgtcatgcggaactgcgttttcttgacctggttccgagcctgcaactgga cccggctcagatttaccgtgttacctggtttatctcgtggagcccgtgtt ttagctggggctgcgcgggtgaagtgcgcgcgtttttgcaagagaacacc cacgtgcgtctccgcatcttcgccgcacgtatttacgattatgacccgct gtataaagaggccctgcaaatgctgagagatgctggcgcacaagtgagca ttatgacctacgacgagttcgagtactgctgggatacgttcgtgtatcgc caaggttgcccgtttcagccgtgggacggcctggaggagcacagccaggc gctctccggtcgtttgcgcgcgatcctgcaatctggaagtgagacacccg ggacttcagaatccgcgaccccggagtctggaatgtcaaaactagaaaag tttacaaattgttactccctgtcgaaaaccctgagattcaaagcgatccc ggtgggtaaaactcaagagaacattgataacaaacgtctgctggttgagg acgaaaagcgcgcggaggattacaaaggcgttaaaaagctgttggaccgt tattacctgtcctttattaatgatgttctgcacagcattaaattaaagaa cctaaacaattacatctccctcttccgtaaaaagacccgcaccgaaaagg aaaataaagaactggagaaccttgagattaatctgcgtaaagaaatcgct aaagcgtttaaaggcaacgagggttataaatccttatttaaaaaagacat catcgaaacgattctcccagaattcctggacgacaaagacgagatcgcgc tggttaattccttcaacggctttaccaccgcattcaccggcttttttgat aaccgcgaaaacatgttctctgaagaggccaaaagcacctcaattgcgtt tcgctgcattaacgaaaatctgacgcgttatatctctaacatggatatct tcgagaaggttgacgctatctttgataaacatgaagtccaggagatcaag gagaagatcctgaacagcgactacgacgtggaggatttcttcgagggtga gttcttcaattttgttttgacccaagaaggcatcgatgtctacaatgcga taattggtggttttgttaccgagagcggggagaaaattaagggtctgaac gaatatatcaacttgtacaaccagaaaaccaaacaaaaactgccgaagtt taagccgctgtacaagcaagtcttgtcggatcgtgaatcgctgagctttt acggcgaaggctacaccagcgatgaggaggtgttggaggtgttccgcaat acgttgaataagaactctgaaattttttccagcattaagaagctggaaaa actattcaagaacttcgacgagtatagcagcgcaggtatctttgtgaaaa acggtccggctattagcaccatctcgaaagacattttcggcgaatggaat gttattcgtgataagtggaatgccgaatacgacgacattcatctgaagaa aaaggcggttgtaactgaaaagtacgaggacgatcgtcgtaagtcgttca aaaagatcggctccttctctctggagcaactgcaagagtacgccgatgcc gatttgtcagtcgtggagaagctgaaagagatcatcattcaaaaagttga cgaaatctataaggtctatggtagcagtgaaaaactgtttgacgcggact tcgtgctggagaaaagcctgaagaaaaatgacgccgtggtggcaatcatg aaagatcttctggatagcgtcaagtctttcgaaaactacatcaaagcgtt tttcggtgaaggcaaggaaacgaatcgtgacgagagcttctatggtgatt tcgtcctagcctatgatatcctgcttaaggtggatcacatctatgatgcc atccgcaactatgttacccagaaaccgtactcaaaggacaagttcaagtt atacttccagaatccgcagtttatgggtggctgggataaagataaggaaa ccgactatcgcgccaccattttacgttacggtagtaagtactatctggca atcatggataaaaaatatgcgaaatgcctgcaaaagatcgacaaggacga tgttaacggcaattatgagaagatcaactacaaactgctgccgggcccaa ataagatgctgccgaaggtgtttttcagcaaaaaatggatggcgtattac aatccgagcgaggacatccaaaagatctacaaaaacggtacgtttaagaa gggtgatatgttcaacctcaacgattgtcataaacttattgacttcttca aggatagcatatctcgttatccgaagtggagcaacgcgtatgactttaac tttagcgaaaccgagaaatacaaagatatcgcgggtttctatcgtgaagt tgaagaacagggttacaaagtgtccttcgagtccgcgagcaagaaggagg tagacaagctggtcgaggagggtaagttgtacatgtttcagatttacaat aaggacttttccgacaagtcccatggtacaccgaatttgcacaccatgta tttcaagcttctgttcgacgagaacaaccacggccagatccgtctgagcg gtggtgcagagctgttcatgcgtagagctagcctgaagaaagaagagttg gtcgttcatccggctaattcgccgatcgcgaacaaaaatccagataaccc taaaaagactacgaccctgagctatgatgtgtataaagacaaacgcttta gcgaagaccagtatgagttacacattccgatcgctatcaacaagtgcccg aagaatattttcaagatcaacaccgaagtgcgtgttcttttgaagcacga tgacaacccgtatgtgattggtattgctcgtggtgaacgtaatctgctgt acattgtggttgtggacggcaaaggaaacatcgtggaacagtacagcctg aacgaaatcattaacaatttcaacggcattcgcattaagacggattacca ttctttgctggacaaaaaggagaaagagcgtttcgaggcccgtcagaact ggacctccatcgagaacattaaggagctgaaggcgggttacatcagccag gtggtgcacaaaatctgcgaactggtggagaagtacgacgcggtgattgc tttggcggatttgaactccggttttaagaacagccgcgttaaagtggaaa agcaggtttatcagaaattcgaaaaaatgctgattgataaattgaattac atggttgacaaaaagtctaacccgtgtgcaaccggcggtgcgctgaaggg ctaccaaatcaccaataagtttgaaagctttaagagcatgagcacgcaaa atggcttcattttttacattccggcgtggctgaccagcaagatcgatccg tcaaccggctttgttaatttactgaagacgaagtatacctctattgccga ctctaaaaaatttattagttccttcgatagaatcatgtatgttccggaag aggacctgttcgaatttgcactggactacaagaactttagccgtaccgat gctgattatataaagaaatggaaactctacagctatggcaaccgcatccg tatctttcgcaacccgaaaaaaaacaacgtgttcgactgggaagaggtat gtctgacttcagcgtacaaggagcttttcaataaatatggtatcaactac cagcagggtgatatccgtgcactgctttgcgagcaaagcgataaagcgtt ctattcaagcttcatggcgctgatgagcctgatgctgcaaatgcgcaaca gcatcaccggtcgtaccgatgttgcatttctgatttctccagtaaaaaac agcgatggtatcttttacgacagccgtaattacgaggcccaagaaaatgc gattttgccgaagaacgctgacgcgaatggtgcatacaacattgcaagga aagttctgtgggcaatcggccaatttaaaaaagcggaagatgagaagctg gacaaagtgaaaattgcgattagcaacaaggagtggctggagtatgcgca gacctccgttaaatcagggggaagtggcggaagcggtgggtctacgaacc tgagcgacattattgaaaaagaaactggtaaacagttggtgatccaagaa tccattctgatgttaccggaggaagtggaagaggtgatcggcaacaagcc ggagtccgacatcctggttcacaccgcgtatgatgagtcgaccgatgaga atgttatgctgctgaccagcgacgccccagagtacaaaccgtgggcgctc gtcatccaggatagcaatggcgaaaacaagatcaagatgttgtctggcgg tagcatggctccgaaaaagaagcgtaaagtaggtattcatggtgttccgg catcaggttaa 10 Base editor AID-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggattcactattaatgaataggagaaaattcctgtatcagtttaag aacgtccgttgggctaaaggtcgtcgtgagacgtatttatgctacgtggt gaaacgtcgcgacagcgcaacctccttcagcctggacttcggctatctgc gtaacaaaaacggctgccacgtggagctgctgtttttgcgctacattagc gactgggatttggacccaggtcgctgctatcgtgttacctggtttacgag ctggtcgccgtgttacgactgtgcgcgtcatgtcgcggattttctgcgcg gtaatccgaatctgtccctgcgtatttttaccgcacgtctctacttctgc gaagatcgtaaggcggaaccggaaggcttgcgtcgcctgcatagagcggg tgttcagatcgctatcatgaccttcaaagattatttctactgctggaata ccttcgtggagaaccacgagcgtactttcaaggcctgggaaggccttcac gaaaacagcgttcgcttgtctcgtcaactgcgccgcatcctgctgccgct gtacgaggttgatgatctcagagacgcgtttcgtaccctgggtttgtctg gaagtgagacacccgggacttcagaatccgcgaccccggagtctggaatg gataaaaagtattcaataggactagctattggcaccaacagcgttggttg ggcagttatcaccgatgaatataaggtcccgagcaagaagtttaaggtcc tgggcaacaccgatcgccacagcataaaaaagaaccttattggtgcgctg ctgttcgattctggtgagactgccgaagcgacccgtctgaagagaaccgc gcgtcgtagatacacccggcgcaagaaccgtatctgctatctgcaagaaa ttttcagcaacgagatggctaaggtcgacgactccttctttcatcgcctg gaggaaagctttctggttgaggaagacaaaaagcacgagcgtcatccgat tttcggtaacattgttgatgaagttgcctaccacgaaaaataccccacaa tttatcatctgcgtaaaaaactggtagactccaccgataaggcggattta cgccttatctatttggcgctggcgcatatgattaagttccgcggtcattt tttgatcgagggcgacctgaatccggataacagcgacgttgacaaactgt ttatccagctggtgcagacctataaccagttgttcgaagagaacccgatt aatgcgtctggcgtggacgcgaaggcgatcctgagcgctcgtctgtccaa gtcacgccgcctggagaacttgatcgcgcaactgccgggtgagaagaaaa acggcttgttcggcaatctgattgctctgtccctaggtttgaccccgaat ttcaaatctaattttgatctggcggaagatgcgaaattacagttgagcaa ggacacttacgatgacgatctggacaacctgctcgctcagatcggcgatc agtatgccgatcttttcctggccgcgaagaacctgagcgatgccatcttg ctatcggacatcttacgtgttaacaccgaaatcaccaaagctccgctaag cgcgtccatgattaaacgttacgatgaacaccaccaggatctgacgctgc tgaaagcgttggtgcgccagcaactgccggaaaaatacaaggaaattttc ttcgaccaaagcaagaacggttatgcaggctatatcgacggtggtgcgtc gcaagaagaattttataaattcatcaaaccgattttggagaagatggatg gtaccgaggagctgctggtaaaattgaatcgggaagacctcttgcgaaag cagcgtactttcgataatggtagcatcccgcaccagattcatctgggcga acttcacgcaatcctacgtcgtcaagaggatttctacccgtttctgaagg ataaccgtgaaaagatcgagaagattctgacctttcgtattccgtattat gtgggtccgctggcgagaggcaacagccgttttgcgtggatgacccgcaa gtcggaagagactatcacgccgtggaatttcgaggaggtcgtggacaagg gtgcatcagcgcaatcttttattgaacgtatgaccaattttgataaaaac cttccaaatgaaaaagtgttgccgaagcacagcttgctgtacgagtattt caccgtttacaatgaactgacgaaagtcaagtacgttaccgaaggtatgc gtaagccagcctttctgtctggggagcaaaaaaaagccattgtggatctg ctgttcaagaccaatcgcaaggttaccgtcaagcaactgaaagaggatta cttcaaaaaaatcgaatgttttgactccgtggaaatcagcggcgttgaag accgctttaatgcatctctgggcacctaccacgatctactcaagatcatc aaggataaggacttcctggacaacgaagaaaatgaggatatcttggaaga tattgtgctgactttaacgttgttcgaggatcgtgagatgattgaagaac gcctcaaaacgtacgcacatctgtttgacgataaggtgatgaaacagcta aagcgccgtcgttacaccggttggggtcgtctgtctagaaagctgattaa cggcattcgtgacaaacaatctggcaagaccatcctggacttcctcaaat ccgacggcttcgcaaatcgtaatttcatgcaactgatccatgatgatagc ctgacctttaaagaagatattcagaaggctcaagtgtccggccagggtga ctcgctgcatgagcatatcgcgaatctggctggctcccctgcgataaaaa aaggtattctccaaacggtgaaagttgtggatgaactggttaaagtcatg ggtcgtcataaaccggaaaacatcgtgattgagatggcacgtgagaacca gaccacccagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgtatcg aagaggggattaaggagttaggcagccagattctgaaggagcacccggtt gagaacacccagctgcaaaacgagaagctctacctgtattacctgcaaaa cggccgtgacatgtatgttgaccaggagctggacatcaatcgtctcagcg actacgacgtggatgctatcgtgccgcagagctttctaaaagatgattcc atcgacaataaagtgctcacccgtagcgacaagaaccgtggtaaaagcga caacgtgccgagcgaggaagtagttaagaaaatgaaaaactactggcgtc agctattgaacgccaagcttatcacccagcgtaagtttgacaacttgacg aaggcagagcgtggcggcctgagcgagctagacaaggcgggttttattaa acgccagctggtggaaactcgccagattaccaaacacgttgcgcaaatct tggactcacgcatgaatacgaagtacgacgaaaacgataaattgatccgc gaggtgaaggtcataaccctgaaatctaaactggttagcgatttccggaa ggactttcaattttataaagtccgggagattaacaactatcaccatgcac acgacgcttacttaaatgcggttgttggcacggccctgatcaagaagtac ccgaaactggaaagcgagtttgtttatggtgactacaaggtgtatgacgt tcgcaagatgattgcaaaatccgaacaagagattggtaaggcgacggcta agtattttttctacagcaatatcatgaacttcttcaagactgaaatcacc ctggcgaacggtgaaattcgtaaacgtccgttgatcgaaaccaacggtga aaccggtgaaatcgtttgggataaaggtagggattttgcgaccgttcgta aggtcctgagcatgccgcaggttaacatcgtgaaaaagaccgaagtgcag accggcggtttctccaaggagagtatcttaccgaagcgcaacagtgacaa gctgatcgcgcgtaaaaaagactgggatccgaaaaaatacggcggctttg actccccgaccgtcgcgtacagcgtactggtcgtggctaaagtggagaaa ggcaaatcgaaaaagctgaaatccgttaaagagttgctgggtattacgat tatggaacgttcgagcttcgagaaaaatccgatcgacttcctggaggcca aaggctacaaggaagttaaaaaagacctgatcattaaactgccgaagtac agcctgttcgagctcgagaacggtcgcaaacgcatgctggcgagcgcggg tgagctccaaaaaggcaacgaattggctctgccgagcaagtacgtgaact tcctgtatctggcctcccattatgaaaaactgaagggtagcccggaagat aacgaacaaaagcagctgttcgtggaacaacataaacactatctggacga gattattgagcaaatcagcgagttcagcaaacgcgtgattctggcggatg ctaatctggacaaggttctttcagcctataataaacaccgtgataagccg atccgtgaacaggcagaaaatattattcacctgttcaccctgacgaacct gggtgcgccagcagcgtttaaatacttcgacacaacgatcgaccggaagc gttataccagcaccaaagaggttcttgacgccaccttgattcaccaaagc atcacgggtctgtatgaaacccgtattgacttgagccagttgggcggaga ttcagggggaagtggcggaagcggtgggtctacgaacctgagcgacatta ttgaaaaagaaactggtaaacagttggtgatccaagaatccattctgatg ttaccggaggaagtggaagaggtgatcggcaacaagccggagtccgacat cctggttcacaccgcgtatgatgagtcgaccgatgagaatgttatgctgc tgaccagcgacgccccagagtacaaaccgtgggcgctcgtcatccaggat agcaatggcgaaaacaagatcaagatgttgtctggcggtagcatggctcc gaaaaagaagcgtaaagtaggtattcatggtgttccggcatcaggttaa 11 Base editor AID-dCasPhi-2 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggattcactattaatgaataggagaaaattcctgtatcagtttaag aacgtccgttgggctaaaggtcgtcgtgagacgtatttatgctacgtggt gaaacgtcgcgacagcgcaacctccttcagcctggacttcggctatctgc gtaacaaaaacggctgccacgtggagctgctgtttttgcgctacattagc gactgggatttggacccaggtcgctgctatcgtgttacctggtttacgag ctggtcgccgtgttacgactgtgcgcgtcatgtcgcggattttctgcgcg gtaatccgaatctgtccctgcgtatttttaccgcacgtctctacttctgc gaagatcgtaaggcggaaccggaaggcttgcgtcgcctgcatagagcggg tgttcagatcgctatcatgaccttcaaagattatttctactgctggaata ccttcgtggagaaccacgagcgtactttcaaggcctgggaaggccttcac gaaaacagcgttcgcttgtctcgtcaactgcgccgcatcctgctgccgct gtacgaggttgatgatctcagagacgcgtttcgtaccctgggtttgtctg gaagtgagacacccgggacttcagaatccgcgaccccggagtctggaatg ccaaaacccgctgtagagtcagaattttcaaaagttttgaaaaagcactt tccgggagaacgtttccgctcgagctatatgaaaagaggcggtaagatcc tggctgcccaaggcgaagaggcagttgttgcgtatctacagggcaagtcc gaggaggagcctccgaacttccagccaccggcgaagtgccacgtggtgac caaatcccgtgacttcgcggaatggccgatcatgaaggcgtcggaagcga ttcaacgttatatctatgcactgtcgaccaccgaacgcgcggcctgtaaa ccgggcaaaagtagtgagagccatgcagcgtggttcgccgctaccggtgt cagcaaccacggctacagccacgttcagggtctgaacctgatttttgatc ataccttgggccgttacgatggtgttctgaaaaaggtccaactgcgcaac gaaaaggcgagagcgcgtttagagagcattaacgcgtctagagcagatga aggtttaccggagattaaagccgaggaggaagaagtggctacgaacgaaa ccggccacctgttgcaaccgccgggtatcaatccgagcttttacgtgtat cagaccattagcccgcaggcataccgtccgcgtgacgagatcgtgctgcc gccggagtacgcaggttacgtacgtgacccgaatgctccgattccgctgg gtgtggtgcgtaaccgttgcgatatccaaaaagggtgcccgggctacatc ccggaatggcagcgtgaagcaggtaccgcgatcagcccgaaaacaggcaa ggccgtaactgtgccgggcctgtctccgaagaaaaacaaacgtatgcgta ggtactggcgctctgagaaggagaaagctcaagatgcgctgttggttacc gtacgcattggtaccgattgggttgtcatcgacgtgcgcggtctgttgcg caacgcccgttggcgcaccatcgctcccaaggacatcagcctgaatgcgc tcctcgatttgtttaccggtgatccggtgatcgatgtgcgtcgcaatatt gttacctttacgtacaccctcgacgcctgtggtacctacgcccgtaaatg gaccttgaaaggcaaacagacgaaagcgaccctggacaaactgacggcca ctcagacggttgcgttggttgcgattgcgcttggtcagaccaacccgatt tccgctggcattagccgtgttacacaagaaaatggtgcactgcaatgcga accgctggaccggttcaccctgccggatgacctgttgaaggacatcagcg catatcgcattgcttgggacagaaacgaagaggaactacgcgctcgcagc gtcgaggccctgccggaggcgcaacaagcggaggtccgtgcgctggacgg ggtgtccaaagaaaccgcgcgtacccaactgtgcgcagatttcggcctgg acccgaaacgtctgccgtgggataaaatgagctccaatactacctttatc agcgaagccttgctgtctaacagcgtgagccgtgatcaggtttttttcac tccggctccgaagaagggtgctaagaaaaaagcgcctgttgaagttatgc gtaaagaccgcacttgggcacgtgcgtacaagccgcgtctgagcgtcgaa gctcagaaactgaagaacgaagccctgtgggcacttaagcgcacctcccc ggagtatttgaagctgagccgtcgcaaagaggagctgtgtcgtcgtagca tcaactatgttatcgaaaagacccgtcgccgtacgcaatgtcagattgtg atcccggtgatcgaggatctgaatgttcgcttctttcatggttctggtaa gagactgcccggttgggataatttcttcaccgctaaaaaagagaaccgtt ggttcatccagggcctgcacaaagcgtttagcgatctgcgtacgcaccgt tccttctatgtttttgaagttcgtccggagcgcacctctattacctgtcc aaagtgcggtcattgcgaggtgggtaatcgtgacggtgaggcgtttcagt gcctgagctgcggcaagacgtgcaacgcagatcttgacgtcgcgacccat aatctgacccaagtggcgttgaccggtaagaccatgccgaagcgcgagga gccgcgtgacgctcagggtacagcgccagcgcgcaagactaagaaggcga gcaaatcaaaggcgccaccggcggagcgcgaagaccagaccccggcgcaa gagccaagccagaccagttctggaggtagcgggggtagcggtggtagcac taacttaagtgatattatcgagaaagaaaccgggaaacagctggtgatcc aagaaagcattctgatgctgcccgaagaagttgaagaagtgattggtaac aagcctgagtcggacatcttagtgcacaccgcgtacgatgaaagcacgga tgagaatgtgatgctgctcacctctgatgcccccgaatacaagccgtggg ctctggtgatccaggactctaacggagaaaacaaaattaagatgctctct ggcggctccatggcgcctaaaaaaaaacgcaaagtggggattcacggggt tccggcgtaa 12 Base editor AID-dLbCas12a atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggattcactattaatgaataggagaaaattcctgtatcagtttaag aacgtccgttgggctaaaggtcgtcgtgagacgtatttatgctacgtggt gaaacgtcgcgacagcgcaacctccttcagcctggacttcggctatctgc gtaacaaaaacggctgccacgtggagctgctgtttttgcgctacattagc gactgggatttggacccaggtcgctgctatcgtgttacctggtttacgag ctggtcgccgtgttacgactgtgcgcgtcatgtcgcggattttctgcgcg gtaatccgaatctgtccctgcgtatttttaccgcacgtctctacttctgc gaagatcgtaaggcggaaccggaaggcttgcgtcgcctgcatagagcggg tgttcagatcgctatcatgaccttcaaagattatttctactgctggaata ccttcgtggagaaccacgagcgtactttcaaggcctgggaaggccttcac gaaaacagcgttcgcttgtctcgtcaactgcgccgcatcctgctgccgct gtacgaggttgatgatctcagagacgcgtttcgtaccctgggtttgtctg gaagtgagacacccgggacttcagaatccgcgaccccggagtctggaatg tcaaaactagaaaagtttacaaattgttactccctgtcgaaaaccctgag attcaaagcgatcccggtgggtaaaactcaagagaacattgataacaaac gtctgctggttgaggacgaaaagcgcgcggaggattacaaaggcgttaaa aagctgttggaccgttattacctgtcctttattaatgatgttctgcacag cattaaattaaagaacctaaacaattacatctccctcttccgtaaaaaga cccgcaccgaaaaggaaaataaagaactggagaaccttgagattaatctg cgtaaagaaatcgctaaagcgtttaaaggcaacgagggttataaatcctt atttaaaaaagacatcatcgaaacgattctcccagaattcctggacgaca aagacgagatcgcgctggttaattccttcaacggctttaccaccgcattc accggcttttttgataaccgcgaaaacatgttctctgaagaggccaaaag cacctcaattgcgtttcgctgcattaacgaaaatctgacgcgttatatct ctaacatggatatcttcgagaaggttgacgctatctttgataaacatgaa gtccaggagatcaaggagaagatcctgaacagcgactacgacgtggagga tttcttcgagggtgagttcttcaattttgttttgacccaagaaggcatcg atgtctacaatgcgataattggtggttttgttaccgagagcggggagaaa attaagggtctgaacgaatatatcaacttgtacaaccagaaaaccaaaca aaaactgccgaagtttaagccgctgtacaagcaagtcttgtcggatcgtg aatcgctgagcttttacggcgaaggctacaccagcgatgaggaggtgttg gaggtgttccgcaatacgttgaataagaactctgaaattttttccagcat taagaagctggaaaaactattcaagaacttcgacgagtatagcagcgcag gtatctttgtgaaaaacggtccggctattagcaccatctcgaaagacatt ttcggcgaatggaatgttattcgtgataagtggaatgccgaatacgacga cattcatctgaagaaaaaggcggttgtaactgaaaagtacgaggacgatc gtcgtaagtcgttcaaaaagatcggctccttctctctggagcaactgcaa gagtacgccgatgccgatttgtcagtcgtggagaagctgaaagagatcat cattcaaaaagttgacgaaatctataaggtctatggtagcagtgaaaaac tgtttgacgcggacttcgtgctggagaaaagcctgaagaaaaatgacgcc gtggtggcaatcatgaaagatcttctggatagcgtcaagtctttcgaaaa ctacatcaaagcgtttttcggtgaaggcaaggaaacgaatcgtgacgaga gcttctatggtgatttcgtcctagcctatgatatcctgcttaaggtggat cacatctatgatgccatccgcaactatgttacccagaaaccgtactcaaa ggacaagttcaagttatacttccagaatccgcagtttatgggtggctggg ataaagataaggaaaccgactatcgcgccaccattttacgttacggtagt aagtactatctggcaatcatggataaaaaatatgcgaaatgcctgcaaaa gatcgacaaggacgatgttaacggcaattatgagaagatcaactacaaac tgctgccgggcccaaataagatgctgccgaaggtgtttttcagcaaaaaa tggatggcgtattacaatccgagcgaggacatccaaaagatctacaaaaa cggtacgtttaagaagggtgatatgttcaacctcaacgattgtcataaac ttattgacttcttcaaggatagcatatctcgttatccgaagtggagcaac gcgtatgactttaactttagcgaaaccgagaaatacaaagatatcgcggg tttctatcgtgaagttgaagaacagggttacaaagtgtccttcgagtccg cgagcaagaaggaggtagacaagctggtcgaggagggtaagttgtacatg tttcagatttacaataaggacttttccgacaagtcccatggtacaccgaa tttgcacaccatgtatttcaagcttctgttcgacgagaacaaccacggcc agatccgtctgagcggtggtgcagagctgttcatgcgtagagctagcctg aagaaagaagagttggtcgttcatccggctaattcgccgatcgcgaacaa aaatccagataaccctaaaaagactacgaccctgagctatgatgtgtata aagacaaacgctttagcgaagaccagtatgagttacacattccgatcgct atcaacaagtgcccgaagaatattttcaagatcaacaccgaagtgcgtgt tcttttgaagcacgatgacaacccgtatgtgattggtattgctcgtggtg aacgtaatctgctgtacattgtggttgtggacggcaaaggaaacatcgtg gaacagtacagcctgaacgaaatcattaacaatttcaacggcattcgcat taagacggattaccattctttgctggacaaaaaggagaaagagcgtttcg aggcccgtcagaactggacctccatcgagaacattaaggagctgaaggcg ggttacatcagccaggtggtgcacaaaatctgcgaactggtggagaagta cgacgcggtgattgctttggcggatttgaactccggttttaagaacagcc gcgttaaagtggaaaagcaggtttatcagaaattcgaaaaaatgctgatt gataaattgaattacatggttgacaaaaagtctaacccgtgtgcaaccgg cggtgcgctgaagggctaccaaatcaccaataagtttgaaagctttaaga gcatgagcacgcaaaatggcttcattttttacattccggcgtggctgacc agcaagatcgatccgtcaaccggctttgttaatttactgaagacgaagta tacctctattgccgactctaaaaaatttattagttccttcgatagaatca tgtatgttccggaagaggacctgttcgaatttgcactggactacaagaac tttagccgtaccgatgctgattatataaagaaatggaaactctacagcta tggcaaccgcatccgtatctttcgcaacccgaaaaaaaacaacgtgttcg actgggaagaggtatgtctgacttcagcgtacaaggagcttttcaataaa tatggtatcaactaccagcagggtgatatccgtgcactgctttgcgagca aagcgataaagcgttctattcaagcttcatggcgctgatgagcctgatgc tgcaaatgcgcaacagcatcaccggtcgtaccgatgttgcatttctgatt tctccagtaaaaaacagcgatggtatcttttacgacagccgtaattacga ggcccaagaaaatgcgattttgccgaagaacgctgacgcgaatggtgcat acaacattgcaaggaaagttctgtgggcaatcggccaatttaaaaaagcg gaagatgagaagctggacaaagtgaaaattgcgattagcaacaaggagtg gctggagtatgcgcagacctccgttaaatcagggggaagtggcggaagcg gtgggtctacgaacctgagcgacattattgaaaaagaaactggtaaacag ttggtgatccaagaatccattctgatgttaccggaggaagtggaagaggt gatcggcaacaagccggagtccgacatcctggttcacaccgcgtatgatg agtcgaccgatgagaatgttatgctgctgaccagcgacgccccagagtac aaaccgtgggcgctcgtcatccaggatagcaatggcgaaaacaagatcaa gatgttgtctggcggtagcatggctccgaaaaagaagcgtaaagtaggta ttcatggtgttccggcatcaggttaa 13 Base editor AmA1-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggctgattcaagtgaaaaaatgaggggacaatatatcagccgtgac acctttgagaaaaactacaaaccgattgacggcacgaaagaggcgcatct gctgtgcgaaattaaatggggtaagtacggcaagccgtggctgcattggt gtcaaaaccaacgtatgaatatccatgctgaagactacttcatgaacaac atcttcaaagccaaaaagcatccggtgcactgctacgtgacctggtattt gtcctggtcaccgtgcgcggattgtgcgagcaagatcgttaagttcctgg aggagcgtccttatctgaaactgaccatttatgttgcacagctgtattat cacactgaagaggagaaccgtaaaggtctgcgtttgctgcgttcgaagaa ggtgattatccgcgtgatggatatctctgattacaactactgctggaaag tctttgttagcaatcagaacggtaatgaagactactggccgctgcaattc gatccgtgggttaaggagaactacagccgcctcttggacattttctggga aagcaagtgccgttccccaaatccgtggtctggaagtgagacacccggga cttcagaatccgcgaccccggagtctggaatggataaaaagtattcaata ggactagctattggcaccaacagcgttggttgggcagttatcaccgatga atataaggtcccgagcaagaagtttaaggtcctgggcaacaccgatcgcc acagcataaaaaagaaccttattggtgcgctgctgttcgattctggtgag actgccgaagcgacccgtctgaagagaaccgcgcgtcgtagatacacccg gcgcaagaaccgtatctgctatctgcaagaaattttcagcaacgagatgg ctaaggtcgacgactccttctttcatcgcctggaggaaagctttctggtt gaggaagacaaaaagcacgagcgtcatccgattttcggtaacattgttga tgaagttgcctaccacgaaaaataccccacaatttatcatctgcgtaaaa aactggtagactccaccgataaggcggatttacgccttatctatttggcg ctggcgcatatgattaagttccgcggtcattttttgatcgagggcgacct gaatccggataacagcgacgttgacaaactgtttatccagctggtgcaga cctataaccagttgttcgaagagaacccgattaatgcgtctggcgtggac gcgaaggcgatcctgagcgctcgtctgtccaagtcacgccgcctggagaa cttgatcgcgcaactgccgggtgagaagaaaaacggcttgttcggcaatc tgattgctctgtccctaggtttgaccccgaatttcaaatctaattttgat ctggcggaagatgcgaaattacagttgagcaaggacacttacgatgacga tctggacaacctgctcgctcagatcggcgatcagtatgccgatcttttcc tggccgcgaagaacctgagcgatgccatcttgctatcggacatcttacgt gttaacaccgaaatcaccaaagctccgctaagcgcgtccatgattaaacg ttacgatgaacaccaccaggatctgacgctgctgaaagcgttggtgcgcc agcaactgccggaaaaatacaaggaaattttcttcgaccaaagcaagaac ggttatgcaggctatatcgacggtggtgcgtcgcaagaagaattttataa attcatcaaaccgattttggagaagatggatggtaccgaggagctgctgg taaaattgaatcgggaagacctcttgcgaaagcagcgtactttcgataat ggtagcatcccgcaccagattcatctgggcgaacttcacgcaatcctacg tcgtcaagaggatttctacccgtttctgaaggataaccgtgaaaagatcg agaagattctgacctttcgtattccgtattatgtgggtccgctggcgaga ggcaacagccgttttgcgtggatgacccgcaagtcggaagagactatcac gccgtggaatttcgaggaggtcgtggacaagggtgcatcagcgcaatctt ttattgaacgtatgaccaattttgataaaaaccttccaaatgaaaaagtg ttgccgaagcacagcttgctgtacgagtatttcaccgtttacaatgaact gacgaaagtcaagtacgttaccgaaggtatgcgtaagccagcctttctgt ctggggagcaaaaaaaagccattgtggatctgctgttcaagaccaatcgc aaggttaccgtcaagcaactgaaagaggattacttcaaaaaaatcgaatg ttttgactccgtggaaatcagcggcgttgaagaccgctttaatgcatctc tgggcacctaccacgatctactcaagatcatcaaggataaggacttcctg gacaacgaagaaaatgaggatatcttggaagatattgtgctgactttaac gttgttcgaggatcgtgagatgattgaagaacgcctcaaaacgtacgcac atctgtttgacgataaggtgatgaaacagctaaagcgccgtcgttacacc ggttggggtcgtctgtctagaaagctgattaacggcattcgtgacaaaca atctggcaagaccatcctggacttcctcaaatccgacggcttcgcaaatc gtaatttcatgcaactgatccatgatgatagcctgacctttaaagaagat attcagaaggctcaagtgtccggccagggtgactcgctgcatgagcatat cgcgaatctggctggctcccctgcgataaaaaaaggtattctccaaacgg tgaaagttgtggatgaactggttaaagtcatgggtcgtcataaaccggaa aacatcgtgattgagatggcacgtgagaaccagaccacccagaaaggtca aaaaaacagtcgtgagcgtatgaaacgtatcgaagaggggattaaggagt taggcagccagattctgaaggagcacccggttgagaacacccagctgcaa aacgagaagctctacctgtattacctgcaaaacggccgtgacatgtatgt tgaccaggagctggacatcaatcgtctcagcgactacgacgtggatgcta tcgtgccgcagagctttctaaaagatgattccatcgacaataaagtgctc acccgtagcgacaagaaccgtggtaaaagcgacaacgtgccgagcgagga agtagttaagaaaatgaaaaactactggcgtcagctattgaacgccaagc ttatcacccagcgtaagtttgacaacttgacgaaggcagagcgtggcggc ctgagcgagctagacaaggcgggttttattaaacgccagctggtggaaac tcgccagattaccaaacacgttgcgcaaatcttggactcacgcatgaata cgaagtacgacgaaaacgataaattgatccgcgaggtgaaggtcataacc ctgaaatctaaactggttagcgatttccggaaggactttcaattttataa agtccgggagattaacaactatcaccatgcacacgacgcttacttaaatg cggttgttggcacggccctgatcaagaagtacccgaaactggaaagcgag tttgtttatggtgactacaaggtgtatgacgttcgcaagatgattgcaaa atccgaacaagagattggtaaggcgacggctaagtattttttctacagca atatcatgaacttcttcaagactgaaatcaccctggcgaacggtgaaatt cgtaaacgtccgttgatcgaaaccaacggtgaaaccggtgaaatcgtttg ggataaaggtagggattttgcgaccgttcgtaaggtcctgagcatgccgc aggttaacatcgtgaaaaagaccgaagtgcagaccggcggtttctccaag gagagtatcttaccgaagcgcaacagtgacaagctgatcgcgcgtaaaaa agactgggatccgaaaaaatacggcggctttgactccccgaccgtcgcgt acagcgtactggtcgtggctaaagtggagaaaggcaaatcgaaaaagctg aaatccgttaaagagttgctgggtattacgattatggaacgttcgagctt cgagaaaaatccgatcgacttcctggaggccaaaggctacaaggaagtta aaaaagacctgatcattaaactgccgaagtacagcctgttcgagctcgag aacggtcgcaaacgcatgctggcgagcgcgggtgagctccaaaaaggcaa cgaattggctctgccgagcaagtacgtgaacttcctgtatctggcctccc attatgaaaaactgaagggtagcccggaagataacgaacaaaagcagctg ttcgtggaacaacataaacactatctggacgagattattgagcaaatcag cgagttcagcaaacgcgtgattctggcggatgctaatctggacaaggttc tttcagcctataataaacaccgtgataagccgatccgtgaacaggcagaa aatattattcacctgttcaccctgacgaacctgggtgcgccagcagcgtt taaatacttcgacacaacgatcgaccggaagcgttataccagcaccaaag aggttcttgacgccaccttgattcaccaaagcatcacgggtctgtatgaa acccgtattgacttgagccagttgggcggagattcagggggaagtggcgg aagcggtgggtctacgaacctgagcgacattattgaaaaagaaactggta aacagttggtgatccaagaatccattctgatgttaccggaggaagtggaa gaggtgatcggcaacaagccggagtccgacatcctggttcacaccgcgta tgatgagtcgaccgatgagaatgttatgctgctgaccagcgacgccccag agtacaaaccgtgggcgctcgtcatccaggatagcaatggcgaaaacaag atcaagatgttgtctggcggtagcatggctccgaaaaagaagcgtaaagt aggtattcatggtgttccggcatcaggttaa 14 Base editor AmA1-dCasPhi-2 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggctgattcaagtgaaaaaatgaggggacaatatatcagccgtgac acctttgagaaaaactacaaaccgattgacggcacgaaagaggcgcatct gctgtgcgaaattaaatggggtaagtacggcaagccgtggctgcattggt gtcaaaaccaacgtatgaatatccatgctgaagactacttcatgaacaac atcttcaaagccaaaaagcatccggtgcactgctacgtgacctggtattt gtcctggtcaccgtgcgcggattgtgcgagcaagatcgttaagttcctgg aggagcgtccttatctgaaactgaccatttatgttgcacagctgtattat cacactgaagaggagaaccgtaaaggtctgcgtttgctgcgttcgaagaa ggtgattatccgcgtgatggatatctctgattacaactactgctggaaag tctttgttagcaatcagaacggtaatgaagactactggccgctgcaattc gatccgtgggttaaggagaactacagccgcctcttggacattttctggga aagcaagtgccgttccccaaatccgtggtctggaagtgagacacccggga cttcagaatccgcgaccccggagtctggaatgccaaaacccgctgtagag tcagaattttcaaaagttttgaaaaagcactttccgggagaacgtttccg ctcgagctatatgaaaagaggcggtaagatcctggctgcccaaggcgaag aggcagttgttgcgtatctacagggcaagtccgaggaggagcctccgaac ttccagccaccggcgaagtgccacgtggtgaccaaatcccgtgacttcgc ggaatggccgatcatgaaggcgtcggaagcgattcaacgttatatctatg cactgtcgaccaccgaacgcgcggcctgtaaaccgggcaaaagtagtgag agccatgcagcgtggttcgccgctaccggtgtcagcaaccacggctacag ccacgttcagggtctgaacctgatttttgatcataccttgggccgttacg atggtgttctgaaaaaggtccaactgcgcaacgaaaaggcgagagcgcgt ttagagagcattaacgcgtctagagcagatgaaggtttaccggagattaa agccgaggaggaagaagtggctacgaacgaaaccggccacctgttgcaac cgccgggtatcaatccgagcttttacgtgtatcagaccattagcccgcag gcataccgtccgcgtgacgagatcgtgctgccgccggagtacgcaggtta cgtacgtgacccgaatgctccgattccgctgggtgtggtgcgtaaccgtt gcgatatccaaaaagggtgcccgggctacatcccggaatggcagcgtgaa gcaggtaccgcgatcagcccgaaaacaggcaaggccgtaactgtgccggg cctgtctccgaagaaaaacaaacgtatgcgtaggtactggcgctctgaga aggagaaagctcaagatgcgctgttggttaccgtacgcattggtaccgat tgggttgtcatcgacgtgcgcggtctgttgcgcaacgcccgttggcgcac catcgctcccaaggacatcagcctgaatgcgctcctcgatttgtttaccg gtgatccggtgatcgatgtgcgtcgcaatattgttacctttacgtacacc ctcgacgcctgtggtacctacgcccgtaaatggaccttgaaaggcaaaca gacgaaagcgaccctggacaaactgacggccactcagacggttgcgttgg ttgcgattgcgcttggtcagaccaacccgatttccgctggcattagccgt gttacacaagaaaatggtgcactgcaatgcgaaccgctggaccggttcac cctgccggatgacctgttgaaggacatcagcgcatatcgcattgcttggg acagaaacgaagaggaactacgcgctcgcagcgtcgaggccctgccggag gcgcaacaagcggaggtccgtgcgctggacggggtgtccaaagaaaccgc gcgtacccaactgtgcgcagatttcggcctggacccgaaacgtctgccgt gggataaaatgagctccaatactacctttatcagcgaagccttgctgtct aacagcgtgagccgtgatcaggtttttttcactccggctccgaagaaggg tgctaagaaaaaagcgcctgttgaagttatgcgtaaagaccgcacttggg cacgtgcgtacaagccgcgtctgagcgtcgaagctcagaaactgaagaac gaagccctgtgggcacttaagcgcacctccccggagtatttgaagctgag ccgtcgcaaagaggagctgtgtcgtcgtagcatcaactatgttatcgaaa agacccgtcgccgtacgcaatgtcagattgtgatcccggtgatcgaggat ctgaatgttcgcttctttcatggttctggtaagagactgcccggttggga taatttcttcaccgctaaaaaagagaaccgttggttcatccagggcctgc acaaagcgtttagcgatctgcgtacgcaccgttccttctatgtttttgaa gttcgtccggagcgcacctctattacctgtccaaagtgcggtcattgcga ggtgggtaatcgtgacggtgaggcgtttcagtgcctgagctgcggcaaga cgtgcaacgcagatcttgacgtcgcgacccataatctgacccaagtggcg ttgaccggtaagaccatgccgaagcgcgaggagccgcgtgacgctcaggg tacagcgccagcgcgcaagactaagaaggcgagcaaatcaaaggcgccac cggcggagcgcgaagaccagaccccggcgcaagagccaagccagaccagt tctggaggtagcgggggtagcggtggtagcactaacttaagtgatattat cgagaaagaaaccgggaaacagctggtgatccaagaaagcattctgatgc tgcccgaagaagttgaagaagtgattggtaacaagcctgagtcggacatc ttagtgcacaccgcgtacgatgaaagcacggatgagaatgtgatgctgct cacctctgatgcccccgaatacaagccgtgggctctggtgatccaggact ctaacggagaaaacaaaattaagatgctctctggcggctccatggcgcct aaaaaaaaacgcaaagtggggattcacggggttccggcgtaa 15 Base editor AmA1-dLbCas12a atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggctgattcaagtgaaaaaatgaggggacaatatatcagccgtgac acctttgagaaaaactacaaaccgattgacggcacgaaagaggcgcatct gctgtgcgaaattaaatggggtaagtacggcaagccgtggctgcattggt gtcaaaaccaacgtatgaatatccatgctgaagactacttcatgaacaac atcttcaaagccaaaaagcatccggtgcactgctacgtgacctggtattt gtcctggtcaccgtgcgcggattgtgcgagcaagatcgttaagttcctgg aggagcgtccttatctgaaactgaccatttatgttgcacagctgtattat cacactgaagaggagaaccgtaaaggtctgcgtttgctgcgttcgaagaa ggtgattatccgcgtgatggatatctctgattacaactactgctggaaag tctttgttagcaatcagaacggtaatgaagactactggccgctgcaattc gatccgtgggttaaggagaactacagccgcctcttggacattttctggga aagcaagtgccgttccccaaatccgtggtctggaagtgagacacccggga cttcagaatccgcgaccccggagtctggaatgtcaaaactagaaaagttt acaaattgttactccctgtcgaaaaccctgagattcaaagcgatcccggt gggtaaaactcaagagaacattgataacaaacgtctgctggttgaggacg aaaagcgcgcggaggattacaaaggcgttaaaaagctgttggaccgttat tacctgtcctttattaatgatgttctgcacagcattaaattaaagaacct aaacaattacatctccctcttccgtaaaaagacccgcaccgaaaaggaaa ataaagaactggagaaccttgagattaatctgcgtaaagaaatcgctaaa gcgtttaaaggcaacgagggttataaatccttatttaaaaaagacatcat cgaaacgattctcccagaattcctggacgacaaagacgagatcgcgctgg ttaattccttcaacggctttaccaccgcattcaccggcttttttgataac cgcgaaaacatgttctctgaagaggccaaaagcacctcaattgcgtttcg ctgcattaacgaaaatctgacgcgttatatctctaacatggatatcttcg agaaggttgacgctatctttgataaacatgaagtccaggagatcaaggag aagatcctgaacagcgactacgacgtggaggatttcttcgagggtgagtt cttcaattttgttttgacccaagaaggcatcgatgtctacaatgcgataa ttggtggttttgttaccgagagcggggagaaaattaagggtctgaacgaa tatatcaacttgtacaaccagaaaaccaaacaaaaactgccgaagtttaa gccgctgtacaagcaagtcttgtcggatcgtgaatcgctgagcttttacg gcgaaggctacaccagcgatgaggaggtgttggaggtgttccgcaatacg ttgaataagaactctgaaattttttccagcattaagaagctggaaaaact attcaagaacttcgacgagtatagcagcgcaggtatctttgtgaaaaacg gtccggctattagcaccatctcgaaagacattttcggcgaatggaatgtt attcgtgataagtggaatgccgaatacgacgacattcatctgaagaaaaa ggcggttgtaactgaaaagtacgaggacgatcgtcgtaagtcgttcaaaa agatcggctccttctctctggagcaactgcaagagtacgccgatgccgat ttgtcagtcgtggagaagctgaaagagatcatcattcaaaaagttgacga aatctataaggtctatggtagcagtgaaaaactgtttgacgcggacttcg tgctggagaaaagcctgaagaaaaatgacgccgtggtggcaatcatgaaa gatcttctggatagcgtcaagtctttcgaaaactacatcaaagcgttttt cggtgaaggcaaggaaacgaatcgtgacgagagcttctatggtgatttcg tcctagcctatgatatcctgcttaaggtggatcacatctatgatgccatc cgcaactatgttacccagaaaccgtactcaaaggacaagttcaagttata cttccagaatccgcagtttatgggtggctgggataaagataaggaaaccg actatcgcgccaccattttacgttacggtagtaagtactatctggcaatc atggataaaaaatatgcgaaatgcctgcaaaagatcgacaaggacgatgt taacggcaattatgagaagatcaactacaaactgctgccgggcccaaata agatgctgccgaaggtgtttttcagcaaaaaatggatggcgtattacaat ccgagcgaggacatccaaaagatctacaaaaacggtacgtttaagaaggg tgatatgttcaacctcaacgattgtcataaacttattgacttcttcaagg atagcatatctcgttatccgaagtggagcaacgcgtatgactttaacttt agcgaaaccgagaaatacaaagatatcgcgggtttctatcgtgaagttga agaacagggttacaaagtgtccttcgagtccgcgagcaagaaggaggtag acaagctggtcgaggagggtaagttgtacatgtttcagatttacaataag gacttttccgacaagtcccatggtacaccgaatttgcacaccatgtattt caagcttctgttcgacgagaacaaccacggccagatccgtctgagcggtg gtgcagagctgttcatgcgtagagctagcctgaagaaagaagagttggtc gttcatccggctaattcgccgatcgcgaacaaaaatccagataaccctaa aaagactacgaccctgagctatgatgtgtataaagacaaacgctttagcg aagaccagtatgagttacacattccgatcgctatcaacaagtgcccgaag aatattttcaagatcaacaccgaagtgcgtgttcttttgaagcacgatga caacccgtatgtgattggtattgctcgtggtgaacgtaatctgctgtaca ttgtggttgtggacggcaaaggaaacatcgtggaacagtacagcctgaac gaaatcattaacaatttcaacggcattcgcattaagacggattaccattc tttgctggacaaaaaggagaaagagcgtttcgaggcccgtcagaactgga cctccatcgagaacattaaggagctgaaggcgggttacatcagccaggtg gtgcacaaaatctgcgaactggtggagaagtacgacgcggtgattgcttt ggcggatttgaactccggttttaagaacagccgcgttaaagtggaaaagc aggtttatcagaaattcgaaaaaatgctgattgataaattgaattacatg gttgacaaaaagtctaacccgtgtgcaaccggcggtgcgctgaagggcta ccaaatcaccaataagtttgaaagctttaagagcatgagcacgcaaaatg gcttcattttttacattccggcgtggctgaccagcaagatcgatccgtca accggctttgttaatttactgaagacgaagtatacctctattgccgactc taaaaaatttattagttccttcgatagaatcatgtatgttccggaagagg acctgttcgaatttgcactggactacaagaactttagccgtaccgatgct gattatataaagaaatggaaactctacagctatggcaaccgcatccgtat ctttcgcaacccgaaaaaaaacaacgtgttcgactgggaagaggtatgtc tgacttcagcgtacaaggagcttttcaataaatatggtatcaactaccag cagggtgatatccgtgcactgctttgcgagcaaagcgataaagcgttcta ttcaagcttcatggcgctgatgagcctgatgctgcaaatgcgcaacagca tcaccggtcgtaccgatgttgcatttctgatttctccagtaaaaaacagc gatggtatcttttacgacagccgtaattacgaggcccaagaaaatgcgat tttgccgaagaacgctgacgcgaatggtgcatacaacattgcaaggaaag ttctgtgggcaatcggccaatttaaaaaagcggaagatgagaagctggac aaagtgaaaattgcgattagcaacaaggagtggctggagtatgcgcagac ctccgttaaatcagggggaagtggcggaagcggtgggtctacgaacctga gcgacattattgaaaaagaaactggtaaacagttggtgatccaagaatcc attctgatgttaccggaggaagtggaagaggtgatcggcaacaagccgga gtccgacatcctggttcacaccgcgtatgatgagtcgaccgatgagaatg ttatgctgctgaccagcgacgccccagagtacaaaccgtgggcgctcgtc atccaggatagcaatggcgaaaacaagatcaagatgttgtctggcggtag catggctccgaaaaagaagcgtaaagtaggtattcatggtgttccggcat caggttaa 16 Base editor Anc-rA1-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgacgctgcgccgt cgtattgagccgcacgagttcgaggttttttttgatccgcgtgaactccg caaggagacatgcttgctgtacgagatcaaatggggcacttcacacaaaa tctggcgccacagcagcaagaacaccaccaagcacgtggaagtgaacttc atcgagaaattcacgtctgaacgtcacttttgtccgtccaccagctgtag cattacctggtttctatcctggagcccgtgcggtgaatgttccaaggcga ttaccgaattcttgtcgcaacatccgaacgtgactcttgttatttatgtg gcccgtttgtaccatcacatggatcagcagaatcgtcaaggcttgcgcga cctggttaacagcggtgttaccatccagatcatgaccgcaccggaatacg actactgctggcgtaatttcgtcaactatccgccgggcaaggaggcgcat tggccgcgttatccgccgctgtggatgaaactgtacgctctggaactgca tgcgggtattttaggcctgccaccgtgcttgaatattctgagacgcaagc agcctcagctgacctttttcacgatcgcgctgcaaagctgtcattatcaa cgtctgccgccacacatcctgtgggctaccggtctgaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatggataaaa agtattcaataggactagctattggcaccaacagcgttggttgggcagtt atcaccgatgaatataaggtcccgagcaagaagtttaaggtcctgggcaa caccgatcgccacagcataaaaaagaaccttattggtgcgctgctgttcg attctggtgagactgccgaagcgacccgtctgaagagaaccgcgcgtcgt agatacacccggcgcaagaaccgtatctgctatctgcaagaaattttcag caacgagatggctaaggtcgacgactccttctttcatcgcctggaggaaa gctttctggttgaggaagacaaaaagcacgagcgtcatccgattttcggt aacattgttgatgaagttgcctaccacgaaaaataccccacaatttatca tctgcgtaaaaaactggtagactccaccgataaggcggatttacgcctta tctatttggcgctggcgcatatgattaagttccgcggtcattttttgatc gagggcgacctgaatccggataacagcgacgttgacaaactgtttatcca gctggtgcagacctataaccagttgttcgaagagaacccgattaatgcgt ctggcgtggacgcgaaggcgatcctgagcgctcgtctgtccaagtcacgc cgcctggagaacttgatcgcgcaactgccgggtgagaagaaaaacggctt gttcggcaatctgattgctctgtccctaggtttgaccccgaatttcaaat ctaattttgatctggcggaagatgcgaaattacagttgagcaaggacact tacgatgacgatctggacaacctgctcgctcagatcggcgatcagtatgc cgatcttttcctggccgcgaagaacctgagcgatgccatcttgctatcgg acatcttacgtgttaacaccgaaatcaccaaagctccgctaagcgcgtcc atgattaaacgttacgatgaacaccaccaggatctgacgctgctgaaagc gttggtgcgccagcaactgccggaaaaatacaaggaaattttcttcgacc aaagcaagaacggttatgcaggctatatcgacggtggtgcgtcgcaagaa gaattttataaattcatcaaaccgattttggagaagatggatggtaccga ggagctgctggtaaaattgaatcgggaagacctcttgcgaaagcagcgta ctttcgataatggtagcatcccgcaccagattcatctgggcgaacttcac gcaatcctacgtcgtcaagaggatttctacccgtttctgaaggataaccg tgaaaagatcgagaagattctgacctttcgtattccgtattatgtgggtc cgctggcgagaggcaacagccgttttgcgtggatgacccgcaagtcggaa gagactatcacgccgtggaatttcgaggaggtcgtggacaagggtgcatc agcgcaatcttttattgaacgtatgaccaattttgataaaaaccttccaa atgaaaaagtgttgccgaagcacagcttgctgtacgagtatttcaccgtt tacaatgaactgacgaaagtcaagtacgttaccgaaggtatgcgtaagcc agcctttctgtctggggagcaaaaaaaagccattgtggatctgctgttca agaccaatcgcaaggttaccgtcaagcaactgaaagaggattacttcaaa aaaatcgaatgttttgactccgtggaaatcagcggcgttgaagaccgctt taatgcatctctgggcacctaccacgatctactcaagatcatcaaggata aggacttcctggacaacgaagaaaatgaggatatcttggaagatattgtg ctgactttaacgttgttcgaggatcgtgagatgattgaagaacgcctcaa aacgtacgcacatctgtttgacgataaggtgatgaaacagctaaagcgcc gtcgttacaccggttggggtcgtctgtctagaaagctgattaacggcatt cgtgacaaacaatctggcaagaccatcctggacttcctcaaatccgacgg cttcgcaaatcgtaatttcatgcaactgatccatgatgatagcctgacct ttaaagaagatattcagaaggctcaagtgtccggccagggtgactcgctg catgagcatatcgcgaatctggctggctcccctgcgataaaaaaaggtat tctccaaacggtgaaagttgtggatgaactggttaaagtcatgggtcgtc ataaaccggaaaacatcgtgattgagatggcacgtgagaaccagaccacc cagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgtatcgaagaggg gattaaggagttaggcagccagattctgaaggagcacccggttgagaaca cccagctgcaaaacgagaagctctacctgtattacctgcaaaacggccgt gacatgtatgttgaccaggagctggacatcaatcgtctcagcgactacga cgtggatgctatcgtgccgcagagctttctaaaagatgattccatcgaca ataaagtgctcacccgtagcgacaagaaccgtggtaaaagcgacaacgtg ccgagcgaggaagtagttaagaaaatgaaaaactactggcgtcagctatt gaacgccaagcttatcacccagcgtaagtttgacaacttgacgaaggcag agcgtggcggcctgagcgagctagacaaggcgggttttattaaacgccag ctggtggaaactcgccagattaccaaacacgttgcgcaaatcttggactc acgcatgaatacgaagtacgacgaaaacgataaattgatccgcgaggtga aggtcataaccctgaaatctaaactggttagcgatttccggaaggacttt caattttataaagtccgggagattaacaactatcaccatgcacacgacgc ttacttaaatgcggttgttggcacggccctgatcaagaagtacccgaaac tggaaagcgagtttgtttatggtgactacaaggtgtatgacgttcgcaag atgattgcaaaatccgaacaagagattggtaaggcgacggctaagtattt tttctacagcaatatcatgaacttcttcaagactgaaatcaccctggcga acggtgaaattcgtaaacgtccgttgatcgaaaccaacggtgaaaccggt gaaatcgtttgggataaaggtagggattttgcgaccgttcgtaaggtcct gagcatgccgcaggttaacatcgtgaaaaagaccgaagtgcagaccggcg gtttctccaaggagagtatcttaccgaagcgcaacagtgacaagctgatc gcgcgtaaaaaagactgggatccgaaaaaatacggcggctttgactcccc gaccgtcgcgtacagcgtactggtcgtggctaaagtggagaaaggcaaat cgaaaaagctgaaatccgttaaagagttgctgggtattacgattatggaa cgttcgagcttcgagaaaaatccgatcgacttcctggaggccaaaggcta caaggaagttaaaaaagacctgatcattaaactgccgaagtacagcctgt tcgagctcgagaacggtcgcaaacgcatgctggcgagcgcgggtgagctc caaaaaggcaacgaattggctctgccgagcaagtacgtgaacttcctgta tctggcctcccattatgaaaaactgaagggtagcccggaagataacgaac aaaagcagctgttcgtggaacaacataaacactatctggacgagattatt gagcaaatcagcgagttcagcaaacgcgtgattctggcggatgctaatct ggacaaggttctttcagcctataataaacaccgtgataagccgatccgtg aacaggcagaaaatattattcacctgttcaccctgacgaacctgggtgcg ccagcagcgtttaaatacttcgacacaacgatcgaccggaagcgttatac cagcaccaaagaggttcttgacgccaccttgattcaccaaagcatcacgg gtctgtatgaaacccgtattgacttgagccagttgggcggagattcaggg ggaagtggcggaagcggtgggtctacgaacctgagcgacattattgaaaa agaaactggtaaacagttggtgatccaagaatccattctgatgttaccgg aggaagtggaagaggtgatcggcaacaagccggagtccgacatcctggtt cacaccgcgtatgatgagtcgaccgatgagaatgttatgctgctgaccag cgacgccccagagtacaaaccgtgggcgctcgtcatccaggatagcaatg gcgaaaacaagatcaagatgttgtctggcggtagcatggctccgaaaaag aagcgtaaagtaggtattcatggtgttccggcatcaggttaa 17 Base editor Anc-rA1- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgacgctgcgccgt cgtattgagccgcacgagttcgaggttttttttgatccgcgtgaactccg caaggagacatgcttgctgtacgagatcaaatggggcacttcacacaaaa tctggcgccacagcagcaagaacaccaccaagcacgtggaagtgaacttc atcgagaaattcacgtctgaacgtcacttttgtccgtccaccagctgtag cattacctggtttctatcctggagcccgtgcggtgaatgttccaaggcga ttaccgaattcttgtcgcaacatccgaacgtgactcttgttatttatgtg gcccgtttgtaccatcacatggatcagcagaatcgtcaaggcttgcgcga cctggttaacagcggtgttaccatccagatcatgaccgcaccggaatacg actactgctggcgtaatttcgtcaactatccgccgggcaaggaggcgcat tggccgcgttatccgccgctgtggatgaaactgtacgctctggaactgca tgcgggtattttaggcctgccaccgtgcttgaatattctgagacgcaagc agcctcagctgacctttttcacgatcgcgctgcaaagctgtcattatcaa cgtctgccgccacacatcctgtgggctaccggtctgaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatgccaaaac ccgctgtagagtcagaattttcaaaagttttgaaaaagcactttccggga gaacgtttccgctcgagctatatgaaaagaggcggtaagatcctggctgc ccaaggcgaagaggcagttgttgcgtatctacagggcaagtccgaggagg agcctccgaacttccagccaccggcgaagtgccacgtggtgaccaaatcc cgtgacttcgcggaatggccgatcatgaaggcgtcggaagcgattcaacg ttatatctatgcactgtcgaccaccgaacgcgcggcctgtaaaccgggca aaagtagtgagagccatgcagcgtggttcgccgctaccggtgtcagcaac cacggctacagccacgttcagggtctgaacctgatttttgatcatacctt gggccgttacgatggtgttctgaaaaaggtccaactgcgcaacgaaaagg cgagagcgcgtttagagagcattaacgcgtctagagcagatgaaggttta ccggagattaaagccgaggaggaagaagtggctacgaacgaaaccggcca cctgttgcaaccgccgggtatcaatccgagcttttacgtgtatcagacca ttagcccgcaggcataccgtccgcgtgacgagatcgtgctgccgccggag tacgcaggttacgtacgtgacccgaatgctccgattccgctgggtgtggt gcgtaaccgttgcgatatccaaaaagggtgcccgggctacatcccggaat ggcagcgtgaagcaggtaccgcgatcagcccgaaaacaggcaaggccgta actgtgccgggcctgtctccgaagaaaaacaaacgtatgcgtaggtactg gcgctctgagaaggagaaagctcaagatgcgctgttggttaccgtacgca ttggtaccgattgggttgtcatcgacgtgcgcggtctgttgcgcaacgcc cgttggcgcaccatcgctcccaaggacatcagcctgaatgcgctcctcga tttgtttaccggtgatccggtgatcgatgtgcgtcgcaatattgttacct ttacgtacaccctcgacgcctgtggtacctacgcccgtaaatggaccttg aaaggcaaacagacgaaagcgaccctggacaaactgacggccactcagac ggttgcgttggttgcgattgcgcttggtcagaccaacccgatttccgctg gcattagccgtgttacacaagaaaatggtgcactgcaatgcgaaccgctg gaccggttcaccctgccggatgacctgttgaaggacatcagcgcatatcg cattgcttgggacagaaacgaagaggaactacgcgctcgcagcgtcgagg ccctgccggaggcgcaacaagcggaggtccgtgcgctggacggggtgtcc aaagaaaccgcgcgtacccaactgtgcgcagatttcggcctggacccgaa acgtctgccgtgggataaaatgagctccaatactacctttatcagcgaag ccttgctgtctaacagcgtgagccgtgatcaggtttttttcactccggct ccgaagaagggtgctaagaaaaaagcgcctgttgaagttatgcgtaaaga ccgcacttgggcacgtgcgtacaagccgcgtctgagcgtcgaagctcaga aactgaagaacgaagccctgtgggcacttaagcgcacctccccggagtat ttgaagctgagccgtcgcaaagaggagctgtgtcgtcgtagcatcaacta tgttatcgaaaagacccgtcgccgtacgcaatgtcagattgtgatcccgg tgatcgaggatctgaatgttcgcttctttcatggttctggtaagagactg cccggttgggataatttcttcaccgctaaaaaagagaaccgttggttcat ccagggcctgcacaaagcgtttagcgatctgcgtacgcaccgttccttct atgtttttgaagttcgtccggagcgcacctctattacctgtccaaagtgc ggtcattgcgaggtgggtaatcgtgacggtgaggcgtttcagtgcctgag ctgcggcaagacgtgcaacgcagatcttgacgtcgcgacccataatctga cccaagtggcgttgaccggtaagaccatgccgaagcgcgaggagccgcgt gacgctcagggtacagcgccagcgcgcaagactaagaaggcgagcaaatc aaaggcgccaccggcggagcgcgaagaccagaccccggcgcaagagccaa gccagaccagttctggaggtagcgggggtagcggtggtagcactaactta agtgatattatcgagaaagaaaccgggaaacagctggtgatccaagaaag cattctgatgctgcccgaagaagttgaagaagtgattggtaacaagcctg agtcggacatcttagtgcacaccgcgtacgatgaaagcacggatgagaat gtgatgctgctcacctctgatgcccccgaatacaagccgtgggctctggt gatccaggactctaacggagaaaacaaaattaagatgctctctggcggct ccatggcgcctaaaaaaaaacgcaaagtggggattcacggggttccggcg taa 18 Base editor Anc-rA1- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgacgctgcgccgt cgtattgagccgcacgagttcgaggttttttttgatccgcgtgaactccg caaggagacatgcttgctgtacgagatcaaatggggcacttcacacaaaa tctggcgccacagcagcaagaacaccaccaagcacgtggaagtgaacttc atcgagaaattcacgtctgaacgtcacttttgtccgtccaccagctgtag cattacctggtttctatcctggagcccgtgcggtgaatgttccaaggcga ttaccgaattcttgtcgcaacatccgaacgtgactcttgttatttatgtg gcccgtttgtaccatcacatggatcagcagaatcgtcaaggcttgcgcga cctggttaacagcggtgttaccatccagatcatgaccgcaccggaatacg actactgctggcgtaatttcgtcaactatccgccgggcaaggaggcgcat tggccgcgttatccgccgctgtggatgaaactgtacgctctggaactgca tgcgggtattttaggcctgccaccgtgcttgaatattctgagacgcaagc agcctcagctgacctttttcacgatcgcgctgcaaagctgtcattatcaa cgtctgccgccacacatcctgtgggctaccggtctgaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatgtcaaaac tagaaaagtttacaaattgttactccctgtcgaaaaccctgagattcaaa gcgatcccggtgggtaaaactcaagagaacattgataacaaacgtctgct ggttgaggacgaaaagcgcgcggaggattacaaaggcgttaaaaagctgt tggaccgttattacctgtcctttattaatgatgttctgcacagcattaaa ttaaagaacctaaacaattacatctccctcttccgtaaaaagacccgcac cgaaaaggaaaataaagaactggagaaccttgagattaatctgcgtaaag aaatcgctaaagcgtttaaaggcaacgagggttataaatccttatttaaa aaagacatcatcgaaacgattctcccagaattcctggacgacaaagacga gatcgcgctggttaattccttcaacggctttaccaccgcattcaccggct tttttgataaccgcgaaaacatgttctctgaagaggccaaaagcacctca attgcgtttcgctgcattaacgaaaatctgacgcgttatatctctaacat ggatatcttcgagaaggttgacgctatctttgataaacatgaagtccagg agatcaaggagaagatcctgaacagcgactacgacgtggaggatttcttc gagggtgagttcttcaattttgttttgacccaagaaggcatcgatgtcta caatgcgataattggtggttttgttaccgagagcggggagaaaattaagg gtctgaacgaatatatcaacttgtacaaccagaaaaccaaacaaaaactg ccgaagtttaagccgctgtacaagcaagtcttgtcggatcgtgaatcgct gagcttttacggcgaaggctacaccagcgatgaggaggtgttggaggtgt tccgcaatacgttgaataagaactctgaaattttttccagcattaagaag ctggaaaaactattcaagaacttcgacgagtatagcagcgcaggtatctt tgtgaaaaacggtccggctattagcaccatctcgaaagacattttcggcg aatggaatgttattcgtgataagtggaatgccgaatacgacgacattcat ctgaagaaaaaggcggttgtaactgaaaagtacgaggacgatcgtcgtaa gtcgttcaaaaagatcggctccttctctctggagcaactgcaagagtacg ccgatgccgatttgtcagtcgtggagaagctgaaagagatcatcattcaa aaagttgacgaaatctataaggtctatggtagcagtgaaaaactgtttga cgcggacttcgtgctggagaaaagcctgaagaaaaatgacgccgtggtgg caatcatgaaagatcttctggatagcgtcaagtctttcgaaaactacatc aaagcgtttttcggtgaaggcaaggaaacgaatcgtgacgagagcttcta tggtgatttcgtcctagcctatgatatcctgcttaaggtggatcacatct atgatgccatccgcaactatgttacccagaaaccgtactcaaaggacaag ttcaagttatacttccagaatccgcagtttatgggtggctgggataaaga taaggaaaccgactatcgcgccaccattttacgttacggtagtaagtact atctggcaatcatggataaaaaatatgcgaaatgcctgcaaaagatcgac aaggacgatgttaacggcaattatgagaagatcaactacaaactgctgcc gggcccaaataagatgctgccgaaggtgtttttcagcaaaaaatggatgg cgtattacaatccgagcgaggacatccaaaagatctacaaaaacggtacg tttaagaagggtgatatgttcaacctcaacgattgtcataaacttattga cttcttcaaggatagcatatctcgttatccgaagtggagcaacgcgtatg actttaactttagcgaaaccgagaaatacaaagatatcgcgggtttctat cgtgaagttgaagaacagggttacaaagtgtccttcgagtccgcgagcaa gaaggaggtagacaagctggtcgaggagggtaagttgtacatgtttcaga tttacaataaggacttttccgacaagtcccatggtacaccgaatttgcac accatgtatttcaagcttctgttcgacgagaacaaccacggccagatccg tctgagcggtggtgcagagctgttcatgcgtagagctagcctgaagaaag aagagttggtcgttcatccggctaattcgccgatcgcgaacaaaaatcca gataaccctaaaaagactacgaccctgagctatgatgtgtataaagacaa acgctttagcgaagaccagtatgagttacacattccgatcgctatcaaca agtgcccgaagaatattttcaagatcaacaccgaagtgcgtgttcttttg aagcacgatgacaacccgtatgtgattggtattgctcgtggtgaacgtaa tctgctgtacattgtggttgtggacggcaaaggaaacatcgtggaacagt acagcctgaacgaaatcattaacaatttcaacggcattcgcattaagacg gattaccattctttgctggacaaaaaggagaaagagcgtttcgaggcccg tcagaactggacctccatcgagaacattaaggagctgaaggcgggttaca tcagccaggtggtgcacaaaatctgcgaactggtggagaagtacgacgcg gtgattgctttggcggatttgaactccggttttaagaacagccgcgttaa agtggaaaagcaggtttatcagaaattcgaaaaaatgctgattgataaat tgaattacatggttgacaaaaagtctaacccgtgtgcaaccggcggtgcg ctgaagggctaccaaatcaccaataagtttgaaagctttaagagcatgag cacgcaaaatggcttcattttttacattccggcgtggctgaccagcaaga tcgatccgtcaaccggctttgttaatttactgaagacgaagtatacctct attgccgactctaaaaaatttattagttccttcgatagaatcatgtatgt tccggaagaggacctgttcgaatttgcactggactacaagaactttagcc gtaccgatgctgattatataaagaaatggaaactctacagctatggcaac cgcatccgtatctttcgcaacccgaaaaaaaacaacgtgttcgactggga agaggtatgtctgacttcagcgtacaaggagcttttcaataaatatggta tcaactaccagcagggtgatatccgtgcactgctttgcgagcaaagcgat aaagcgttctattcaagcttcatggcgctgatgagcctgatgctgcaaat gcgcaacagcatcaccggtcgtaccgatgttgcatttctgatttctccag taaaaaacagcgatggtatcttttacgacagccgtaattacgaggcccaa gaaaatgcgattttgccgaagaacgctgacgcgaatggtgcatacaacat tgcaaggaaagttctgtgggcaatcggccaatttaaaaaagcggaagatg agaagctggacaaagtgaaaattgcgattagcaacaaggagtggctggag tatgcgcagacctccgttaaatcagggggaagtggcggaagcggtgggtc tacgaacctgagcgacattattgaaaaagaaactggtaaacagttggtga tccaagaatccattctgatgttaccggaggaagtggaagaggtgatcggc aacaagccggagtccgacatcctggttcacaccgcgtatgatgagtcgac cgatgagaatgttatgctgctgaccagcgacgccccagagtacaaaccgt gggcgctcgtcatccaggatagcaatggcgaaaacaagatcaagatgttg tctggcggtagcatggctccgaaaaagaagcgtaaagtaggtattcatgg tgttccggcatcaggttaa 19 Base editor eA3A-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaagcaagtcccgcttcaggaccaaggcacctgatggacccacat attttcaccagtaattttaacaacggcatcggccgtcacaagacctacct gtgttatgaggtcgaacgtctggataatggcacttccgtgaaaatggatc agcatcgtggtttcctgcatggtcaggctaagaatctgctttgcggtttc tatggtcgccacgccgaactgcgttttttggacctggttccgtccctcca actggacccggcgcaaatctatcgtgttacctggtttatcagctggtcgc cgtgtttcagctggggttgcgcaggcgaagtacgtgcgttcttacaagag aacacccatgtgcgcttgcgcatcttcgccgcacgtatttacgactacga cccgctgtataaagaggcgttgcaaatgctgcgcgatgctggcgcacagg ttagcattatgacgtacgacgaatttaagcactgctgggataccttcgtg gatcaccagggctgcccgtttcagccgtgggatggtttggacgagcactc tcaggcgctgagcggtcgtctcagagcgattctgcaaaaccagggaaact ctggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga atggataaaaagtattcaataggactagctattggcaccaacagcgttgg ttgggcagttatcaccgatgaatataaggtcccgagcaagaagtttaagg tcctgggcaacaccgatcgccacagcataaaaaagaaccttattggtgcg ctgctgttcgattctggtgagactgccgaagcgacccgtctgaagagaac cgcgcgtcgtagatacacccggcgcaagaaccgtatctgctatctgcaag aaattttcagcaacgagatggctaaggtcgacgactccttctttcatcgc ctggaggaaagctttctggttgaggaagacaaaaagcacgagcgtcatcc gattttcggtaacattgttgatgaagttgcctaccacgaaaaatacccca caatttatcatctgcgtaaaaaactggtagactccaccgataaggcggat ttacgccttatctatttggcgctggcgcatatgattaagttccgcggtca ttttttgatcgagggcgacctgaatccggataacagcgacgttgacaaac tgtttatccagctggtgcagacctataaccagttgttcgaagagaacccg attaatgcgtctggcgtggacgcgaaggcgatcctgagcgctcgtctgtc caagtcacgccgcctggagaacttgatcgcgcaactgccgggtgagaaga aaaacggcttgttcggcaatctgattgctctgtccctaggtttgaccccg aatttcaaatctaattttgatctggcggaagatgcgaaattacagttgag caaggacacttacgatgacgatctggacaacctgctcgctcagatcggcg atcagtatgccgatcttttcctggccgcgaagaacctgagcgatgccatc ttgctatcggacatcttacgtgttaacaccgaaatcaccaaagctccgct aagcgcgtccatgattaaacgttacgatgaacaccaccaggatctgacgc tgctgaaagcgttggtgcgccagcaactgccggaaaaatacaaggaaatt ttcttcgaccaaagcaagaacggttatgcaggctatatcgacggtggtgc gtcgcaagaagaattttataaattcatcaaaccgattttggagaagatgg atggtaccgaggagctgctggtaaaattgaatcgggaagacctcttgcga aagcagcgtactttcgataatggtagcatcccgcaccagattcatctggg cgaacttcacgcaatcctacgtcgtcaagaggatttctacccgtttctga aggataaccgtgaaaagatcgagaagattctgacctttcgtattccgtat tatgtgggtccgctggcgagaggcaacagccgttttgcgtggatgacccg caagtcggaagagactatcacgccgtggaatttcgaggaggtcgtggaca agggtgcatcagcgcaatcttttattgaacgtatgaccaattttgataaa aaccttccaaatgaaaaagtgttgccgaagcacagcttgctgtacgagta tttcaccgtttacaatgaactgacgaaagtcaagtacgttaccgaaggta tgcgtaagccagcctttctgtctggggagcaaaaaaaagccattgtggat ctgctgttcaagaccaatcgcaaggttaccgtcaagcaactgaaagagga ttacttcaaaaaaatcgaatgttttgactccgtggaaatcagcggcgttg aagaccgctttaatgcatctctgggcacctaccacgatctactcaagatc atcaaggataaggacttcctggacaacgaagaaaatgaggatatcttgga agatattgtgctgactttaacgttgttcgaggatcgtgagatgattgaag aacgcctcaaaacgtacgcacatctgtttgacgataaggtgatgaaacag ctaaagcgccgtcgttacaccggttggggtcgtctgtctagaaagctgat taacggcattcgtgacaaacaatctggcaagaccatcctggacttcctca aatccgacggcttcgcaaatcgtaatttcatgcaactgatccatgatgat agcctgacctttaaagaagatattcagaaggctcaagtgtccggccaggg tgactcgctgcatgagcatatcgcgaatctggctggctcccctgcgataa aaaaaggtattctccaaacggtgaaagttgtggatgaactggttaaagtc atgggtcgtcataaaccggaaaacatcgtgattgagatggcacgtgagaa ccagaccacccagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgta tcgaagaggggattaaggagttaggcagccagattctgaaggagcacccg gttgagaacacccagctgcaaaacgagaagctctacctgtattacctgca aaacggccgtgacatgtatgttgaccaggagctggacatcaatcgtctca gcgactacgacgtggatgctatcgtgccgcagagctttctaaaagatgat tccatcgacaataaagtgctcacccgtagcgacaagaaccgtggtaaaag cgacaacgtgccgagcgaggaagtagttaagaaaatgaaaaactactggc gtcagctattgaacgccaagcttatcacccagcgtaagtttgacaacttg acgaaggcagagcgtggcggcctgagcgagctagacaaggcgggttttat taaacgccagctggtggaaactcgccagattaccaaacacgttgcgcaaa tcttggactcacgcatgaatacgaagtacgacgaaaacgataaattgatc cgcgaggtgaaggtcataaccctgaaatctaaactggttagcgatttccg gaaggactttcaattttataaagtccgggagattaacaactatcaccatg cacacgacgcttacttaaatgcggttgttggcacggccctgatcaagaag tacccgaaactggaaagcgagtttgtttatggtgactacaaggtgtatga cgttcgcaagatgattgcaaaatccgaacaagagattggtaaggcgacgg ctaagtattttttctacagcaatatcatgaacttcttcaagactgaaatc accctggcgaacggtgaaattcgtaaacgtccgttgatcgaaaccaacgg tgaaaccggtgaaatcgtttgggataaaggtagggattttgcgaccgttc gtaaggtcctgagcatgccgcaggttaacatcgtgaaaaagaccgaagtg cagaccggcggtttctccaaggagagtatcttaccgaagcgcaacagtga caagctgatcgcgcgtaaaaaagactgggatccgaaaaaatacggcggct ttgactccccgaccgtcgcgtacagcgtactggtcgtggctaaagtggag aaaggcaaatcgaaaaagctgaaatccgttaaagagttgctgggtattac gattatggaacgttcgagcttcgagaaaaatccgatcgacttcctggagg ccaaaggctacaaggaagttaaaaaagacctgatcattaaactgccgaag tacagcctgttcgagctcgagaacggtcgcaaacgcatgctggcgagcgc gggtgagctccaaaaaggcaacgaattggctctgccgagcaagtacgtga acttcctgtatctggcctcccattatgaaaaactgaagggtagcccggaa gataacgaacaaaagcagctgttcgtggaacaacataaacactatctgga cgagattattgagcaaatcagcgagttcagcaaacgcgtgattctggcgg atgctaatctggacaaggttctttcagcctataataaacaccgtgataag ccgatccgtgaacaggcagaaaatattattcacctgttcaccctgacgaa cctgggtgcgccagcagcgtttaaatacttcgacacaacgatcgaccgga agcgttataccagcaccaaagaggttcttgacgccaccttgattcaccaa agcatcacgggtctgtatgaaacccgtattgacttgagccagttgggcgg agattcagggggaagtggcggaagcggtgggtctacgaacctgagcgaca ttattgaaaaagaaactggtaaacagttggtgatccaagaatccattctg atgttaccggaggaagtggaagaggtgatcggcaacaagccggagtccga catcctggttcacaccgcgtatgatgagtcgaccgatgagaatgttatgc tgctgaccagcgacgccccagagtacaaaccgtgggcgctcgtcatccag gatagcaatggcgaaaacaagatcaagatgttgtctggcggtagcatggc tccgaaaaagaagcgtaaagtaggtattcatggtgttccggcatcaggtt aa 20 Base editor eA3A- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaagcaagtcccgcttcaggaccaaggcacctgatggacccacat attttcaccagtaattttaacaacggcatcggccgtcacaagacctacct gtgttatgaggtcgaacgtctggataatggcacttccgtgaaaatggatc agcatcgtggtttcctgcatggtcaggctaagaatctgctttgcggtttc tatggtcgccacgccgaactgcgttttttggacctggttccgtccctcca actggacccggcgcaaatctatcgtgttacctggtttatcagctggtcgc cgtgtttcagctggggttgcgcaggcgaagtacgtgcgttcttacaagag aacacccatgtgcgcttgcgcatcttcgccgcacgtatttacgactacga cccgctgtataaagaggcgttgcaaatgctgcgcgatgctggcgcacagg ttagcattatgacgtacgacgaatttaagcactgctgggataccttcgtg gatcaccagggctgcccgtttcagccgtgggatggtttggacgagcactc tcaggcgctgagcggtcgtctcagagcgattctgcaaaaccagggaaact ctggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga atgccaaaacccgctgtagagtcagaattttcaaaagttttgaaaaagca ctttccgggagaacgtttccgctcgagctatatgaaaagaggcggtaaga tcctggctgcccaaggcgaagaggcagttgttgcgtatctacagggcaag tccgaggaggagcctccgaacttccagccaccggcgaagtgccacgtggt gaccaaatcccgtgacttcgcggaatggccgatcatgaaggcgtcggaag cgattcaacgttatatctatgcactgtcgaccaccgaacgcgcggcctgt aaaccgggcaaaagtagtgagagccatgcagcgtggttcgccgctaccgg tgtcagcaaccacggctacagccacgttcagggtctgaacctgatttttg atcataccttgggccgttacgatggtgttctgaaaaaggtccaactgcgc aacgaaaaggcgagagcgcgtttagagagcattaacgcgtctagagcaga tgaaggtttaccggagattaaagccgaggaggaagaagtggctacgaacg aaaccggccacctgttgcaaccgccgggtatcaatccgagcttttacgtg tatcagaccattagcccgcaggcataccgtccgcgtgacgagatcgtgct gccgccggagtacgcaggttacgtacgtgacccgaatgctccgattccgc tgggtgtggtgcgtaaccgttgcgatatccaaaaagggtgcccgggctac atcccggaatggcagcgtgaagcaggtaccgcgatcagcccgaaaacagg caaggccgtaactgtgccgggcctgtctccgaagaaaaacaaacgtatgc gtaggtactggcgctctgagaaggagaaagctcaagatgcgctgttggtt accgtacgcattggtaccgattgggttgtcatcgacgtgcgcggtctgtt gcgcaacgcccgttggcgcaccatcgctcccaaggacatcagcctgaatg cgctcctcgatttgtttaccggtgatccggtgatcgatgtgcgtcgcaat attgttacctttacgtacaccctcgacgcctgtggtacctacgcccgtaa atggaccttgaaaggcaaacagacgaaagcgaccctggacaaactgacgg ccactcagacggttgcgttggttgcgattgcgcttggtcagaccaacccg atttccgctggcattagccgtgttacacaagaaaatggtgcactgcaatg cgaaccgctggaccggttcaccctgccggatgacctgttgaaggacatca gcgcatatcgcattgcttgggacagaaacgaagaggaactacgcgctcgc agcgtcgaggccctgccggaggcgcaacaagcggaggtccgtgcgctgga cggggtgtccaaagaaaccgcgcgtacccaactgtgcgcagatttcggcc tggacccgaaacgtctgccgtgggataaaatgagctccaatactaccttt atcagcgaagccttgctgtctaacagcgtgagccgtgatcaggttttttt cactccggctccgaagaagggtgctaagaaaaaagcgcctgttgaagtta tgcgtaaagaccgcacttgggcacgtgcgtacaagccgcgtctgagcgtc gaagctcagaaactgaagaacgaagccctgtgggcacttaagcgcacctc cccggagtatttgaagctgagccgtcgcaaagaggagctgtgtcgtcgta gcatcaactatgttatcgaaaagacccgtcgccgtacgcaatgtcagatt gtgatcccggtgatcgaggatctgaatgttcgcttctttcatggttctgg taagagactgcccggttgggataatttcttcaccgctaaaaaagagaacc gttggttcatccagggcctgcacaaagcgtttagcgatctgcgtacgcac cgttccttctatgtttttgaagttcgtccggagcgcacctctattacctg tccaaagtgcggtcattgcgaggtgggtaatcgtgacggtgaggcgtttc agtgcctgagctgcggcaagacgtgcaacgcagatcttgacgtcgcgacc cataatctgacccaagtggcgttgaccggtaagaccatgccgaagcgcga ggagccgcgtgacgctcagggtacagcgccagcgcgcaagactaagaagg cgagcaaatcaaaggcgccaccggcggagcgcgaagaccagaccccggcg caagagccaagccagaccagttctggaggtagcgggggtagcggtggtag cactaacttaagtgatattatcgagaaagaaaccgggaaacagctggtga tccaagaaagcattctgatgctgcccgaagaagttgaagaagtgattggt aacaagcctgagtcggacatcttagtgcacaccgcgtacgatgaaagcac ggatgagaatgtgatgctgctcacctctgatgcccccgaatacaagccgt gggctctggtgatccaggactctaacggagaaaacaaaattaagatgctc tctggcggctccatggcgcctaaaaaaaaacgcaaagtggggattcacgg ggttccggcgtaa 21 Base editor eA3A- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaagcaagtcccgcttcaggaccaaggcacctgatggacccacat attttcaccagtaattttaacaacggcatcggccgtcacaagacctacct gtgttatgaggtcgaacgtctggataatggcacttccgtgaaaatggatc agcatcgtggtttcctgcatggtcaggctaagaatctgctttgcggtttc tatggtcgccacgccgaactgcgttttttggacctggttccgtccctcca actggacccggcgcaaatctatcgtgttacctggtttatcagctggtcgc cgtgtttcagctggggttgcgcaggcgaagtacgtgcgttcttacaagag aacacccatgtgcgcttgcgcatcttcgccgcacgtatttacgactacga cccgctgtataaagaggcgttgcaaatgctgcgcgatgctggcgcacagg ttagcattatgacgtacgacgaatttaagcactgctgggataccttcgtg gatcaccagggctgcccgtttcagccgtgggatggtttggacgagcactc tcaggcgctgagcggtcgtctcagagcgattctgcaaaaccagggaaact ctggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga atgtcaaaactagaaaagtttacaaattgttactccctgtcgaaaaccct gagattcaaagcgatcccggtgggtaaaactcaagagaacattgataaca aacgtctgctggttgaggacgaaaagcgcgcggaggattacaaaggcgtt aaaaagctgttggaccgttattacctgtcctttattaatgatgttctgca cagcattaaattaaagaacctaaacaattacatctccctcttccgtaaaa agacccgcaccgaaaaggaaaataaagaactggagaaccttgagattaat ctgcgtaaagaaatcgctaaagcgtttaaaggcaacgagggttataaatc cttatttaaaaaagacatcatcgaaacgattctcccagaattcctggacg acaaagacgagatcgcgctggttaattccttcaacggctttaccaccgca ttcaccggcttttttgataaccgcgaaaacatgttctctgaagaggccaa aagcacctcaattgcgtttcgctgcattaacgaaaatctgacgcgttata tctctaacatggatatcttcgagaaggttgacgctatctttgataaacat gaagtccaggagatcaaggagaagatcctgaacagcgactacgacgtgga ggatttcttcgagggtgagttcttcaattttgttttgacccaagaaggca tcgatgtctacaatgcgataattggtggttttgttaccgagagcggggag aaaattaagggtctgaacgaatatatcaacttgtacaaccagaaaaccaa acaaaaactgccgaagtttaagccgctgtacaagcaagtcttgtcggatc gtgaatcgctgagcttttacggcgaaggctacaccagcgatgaggaggtg ttggaggtgttccgcaatacgttgaataagaactctgaaattttttccag cattaagaagctggaaaaactattcaagaacttcgacgagtatagcagcg caggtatctttgtgaaaaacggtccggctattagcaccatctcgaaagac attttcggcgaatggaatgttattcgtgataagtggaatgccgaatacga cgacattcatctgaagaaaaaggcggttgtaactgaaaagtacgaggacg atcgtcgtaagtcgttcaaaaagatcggctccttctctctggagcaactg caagagtacgccgatgccgatttgtcagtcgtggagaagctgaaagagat catcattcaaaaagttgacgaaatctataaggtctatggtagcagtgaaa aactgtttgacgcggacttcgtgctggagaaaagcctgaagaaaaatgac gccgtggtggcaatcatgaaagatcttctggatagcgtcaagtctttcga aaactacatcaaagcgtttttcggtgaaggcaaggaaacgaatcgtgacg agagcttctatggtgatttcgtcctagcctatgatatcctgcttaaggtg gatcacatctatgatgccatccgcaactatgttacccagaaaccgtactc aaaggacaagttcaagttatacttccagaatccgcagtttatgggtggct gggataaagataaggaaaccgactatcgcgccaccattttacgttacggt agtaagtactatctggcaatcatggataaaaaatatgcgaaatgcctgca aaagatcgacaaggacgatgttaacggcaattatgagaagatcaactaca aactgctgccgggcccaaataagatgctgccgaaggtgtttttcagcaaa aaatggatggcgtattacaatccgagcgaggacatccaaaagatctacaa aaacggtacgtttaagaagggtgatatgttcaacctcaacgattgtcata aacttattgacttcttcaaggatagcatatctcgttatccgaagtggagc aacgcgtatgactttaactttagcgaaaccgagaaatacaaagatatcgc gggtttctatcgtgaagttgaagaacagggttacaaagtgtccttcgagt ccgcgagcaagaaggaggtagacaagctggtcgaggagggtaagttgtac atgtttcagatttacaataaggacttttccgacaagtcccatggtacacc gaatttgcacaccatgtatttcaagcttctgttcgacgagaacaaccacg gccagatccgtctgagcggtggtgcagagctgttcatgcgtagagctagc ctgaagaaagaagagttggtcgttcatccggctaattcgccgatcgcgaa caaaaatccagataaccctaaaaagactacgaccctgagctatgatgtgt ataaagacaaacgctttagcgaagaccagtatgagttacacattccgatc gctatcaacaagtgcccgaagaatattttcaagatcaacaccgaagtgcg tgttcttttgaagcacgatgacaacccgtatgtgattggtattgctcgtg gtgaacgtaatctgctgtacattgtggttgtggacggcaaaggaaacatc gtggaacagtacagcctgaacgaaatcattaacaatttcaacggcattcg cattaagacggattaccattctttgctggacaaaaaggagaaagagcgtt tcgaggcccgtcagaactggacctccatcgagaacattaaggagctgaag gcgggttacatcagccaggtggtgcacaaaatctgcgaactggtggagaa gtacgacgcggtgattgctttggcggatttgaactccggttttaagaaca gccgcgttaaagtggaaaagcaggtttatcagaaattcgaaaaaatgctg attgataaattgaattacatggttgacaaaaagtctaacccgtgtgcaac cggcggtgcgctgaagggctaccaaatcaccaataagtttgaaagcttta agagcatgagcacgcaaaatggcttcattttttacattccggcgtggctg accagcaagatcgatccgtcaaccggctttgttaatttactgaagacgaa gtatacctctattgccgactctaaaaaatttattagttccttcgatagaa tcatgtatgttccggaagaggacctgttcgaatttgcactggactacaag aactttagccgtaccgatgctgattatataaagaaatggaaactctacag ctatggcaaccgcatccgtatctttcgcaacccgaaaaaaaacaacgtgt tcgactgggaagaggtatgtctgacttcagcgtacaaggagcttttcaat aaatatggtatcaactaccagcagggtgatatccgtgcactgctttgcga gcaaagcgataaagcgttctattcaagcttcatggcgctgatgagcctga tgctgcaaatgcgcaacagcatcaccggtcgtaccgatgttgcatttctg atttctccagtaaaaaacagcgatggtatcttttacgacagccgtaatta cgaggcccaagaaaatgcgattttgccgaagaacgctgacgcgaatggtg catacaacattgcaaggaaagttctgtgggcaatcggccaatttaaaaaa gcggaagatgagaagctggacaaagtgaaaattgcgattagcaacaagga gtggctggagtatgcgcagacctccgttaaatcagggggaagtggcggaa gcggtgggtctacgaacctgagcgacattattgaaaaagaaactggtaaa cagttggtgatccaagaatccattctgatgttaccggaggaagtggaaga ggtgatcggcaacaagccggagtccgacatcctggttcacaccgcgtatg atgagtcgaccgatgagaatgttatgctgctgaccagcgacgccccagag tacaaaccgtgggcgctcgtcatccaggatagcaatggcgaaaacaagat caagatgttgtctggcggtagcatggctccgaaaaagaagcgtaaagtag gtattcatggtgttccggcatcaggttaa 22 Base editor evoAPOBEC1- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCas9 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaagtaaaacaggacccgttgctgtagatccgacgctgagacgt cgcatcgagccgcacgaattcgaggtgttttttgatccgcgtgaactgcg caaggagacgtgcctgctgtatgagatcaactggggtggccgtcacagca tttggcgtcacacctcccaaaacacgaacaaacacgtggaagtcaatttc atcgaaaaattcaccaccgaacgttacttctgcccgaacacccgttgttc catcacctggttcctgtcttggagcccgtgtggtgagtgcagccgcgcaa ttactgagttcctgagccgttacccgaatgttaccctgtttatctatatc gcccgtttgtaccatctggcgaacccgcgcaaccgtcagggtttacgcga cttaattagctctggcgttaccattcagattatgaccgagcaagagagcg gttattgctggcataactttgtaaactatagcccgagcaatgaaagccat tggcctcgctacccgcacctgtgggttcgtttgtacgtgctggaactgta ctgcatcatccttggtttgccaccgtgcttgaatattttgagacgtaagc agtcgcaactgaccagttttacgatcgcgctacagagctgtcattatcag cgtctcccgccacacattctgtgggctaccggcctgaaaagcggcggtag cagcggtggctccagcggctcggaaactccgggcacctccgagtcagcga ccccggaatctggaagtgagacacccgggacttcagaatccgcgaccccg gagtctggaatggataaaaagtattcaataggactagctattggcaccaa cagcgttggttgggcagttatcaccgatgaatataaggtcccgagcaaga agtttaaggtcctgggcaacaccgatcgccacagcataaaaaagaacctt attggtgcgctgctgttcgattctggtgagactgccgaagcgacccgtct gaagagaaccgcgcgtcgtagatacacccggcgcaagaaccgtatctgct atctgcaagaaattttcagcaacgagatggctaaggtcgacgactccttc tttcatcgcctggaggaaagctttctggttgaggaagacaaaaagcacga gcgtcatccgattttcggtaacattgttgatgaagttgcctaccacgaaa aataccccacaatttatcatctgcgtaaaaaactggtagactccaccgat aaggcggatttacgccttatctatttggcgctggcgcatatgattaagtt ccgcggtcattttttgatcgagggcgacctgaatccggataacagcgacg ttgacaaactgtttatccagctggtgcagacctataaccagttgttcgaa gagaacccgattaatgcgtctggcgtggacgcgaaggcgatcctgagcgc tcgtctgtccaagtcacgccgcctggagaacttgatcgcgcaactgccgg gtgagaagaaaaacggcttgttcggcaatctgattgctctgtccctaggt ttgaccccgaatttcaaatctaattttgatctggcggaagatgcgaaatt acagttgagcaaggacacttacgatgacgatctggacaacctgctcgctc agatcggcgatcagtatgccgatcttttcctggccgcgaagaacctgagc gatgccatcttgctatcggacatcttacgtgttaacaccgaaatcaccaa agctccgctaagcgcgtccatgattaaacgttacgatgaacaccaccagg atctgacgctgctgaaagcgttggtgcgccagcaactgccggaaaaatac aaggaaattttcttcgaccaaagcaagaacggttatgcaggctatatcga cggtggtgcgtcgcaagaagaattttataaattcatcaaaccgattttgg agaagatggatggtaccgaggagctgctggtaaaattgaatcgggaagac ctcttgcgaaagcagcgtactttcgataatggtagcatcccgcaccagat tcatctgggcgaacttcacgcaatcctacgtcgtcaagaggatttctacc cgtttctgaaggataaccgtgaaaagatcgagaagattctgacctttcgt attccgtattatgtgggtccgctggcgagaggcaacagccgttttgcgtg gatgacccgcaagtcggaagagactatcacgccgtggaatttcgaggagg tcgtggacaagggtgcatcagcgcaatcttttattgaacgtatgaccaat tttgataaaaaccttccaaatgaaaaagtgttgccgaagcacagcttgct gtacgagtatttcaccgtttacaatgaactgacgaaagtcaagtacgtta ccgaaggtatgcgtaagccagcctttctgtctggggagcaaaaaaaagcc attgtggatctgctgttcaagaccaatcgcaaggttaccgtcaagcaact gaaagaggattacttcaaaaaaatcgaatgttttgactccgtggaaatca gcggcgttgaagaccgctttaatgcatctctgggcacctaccacgatcta ctcaagatcatcaaggataaggacttcctggacaacgaagaaaatgagga tatcttggaagatattgtgctgactttaacgttgttcgaggatcgtgaga tgattgaagaacgcctcaaaacgtacgcacatctgtttgacgataaggtg atgaaacagctaaagcgccgtcgttacaccggttggggtcgtctgtctag aaagctgattaacggcattcgtgacaaacaatctggcaagaccatcctgg acttcctcaaatccgacggcttcgcaaatcgtaatttcatgcaactgatc catgatgatagcctgacctttaaagaagatattcagaaggctcaagtgtc cggccagggtgactcgctgcatgagcatatcgcgaatctggctggctccc ctgcgataaaaaaaggtattctccaaacggtgaaagttgtggatgaactg gttaaagtcatgggtcgtcataaaccggaaaacatcgtgattgagatggc acgtgagaaccagaccacccagaaaggtcaaaaaaacagtcgtgagcgta tgaaacgtatcgaagaggggattaaggagttaggcagccagattctgaag gagcacccggttgagaacacccagctgcaaaacgagaagctctacctgta ttacctgcaaaacggccgtgacatgtatgttgaccaggagctggacatca atcgtctcagcgactacgacgtggatgctatcgtgccgcagagctttcta aaagatgattccatcgacaataaagtgctcacccgtagcgacaagaaccg tggtaaaagcgacaacgtgccgagcgaggaagtagttaagaaaatgaaaa actactggcgtcagctattgaacgccaagcttatcacccagcgtaagttt gacaacttgacgaaggcagagcgtggcggcctgagcgagctagacaaggc gggttttattaaacgccagctggtggaaactcgccagattaccaaacacg ttgcgcaaatcttggactcacgcatgaatacgaagtacgacgaaaacgat aaattgatccgcgaggtgaaggtcataaccctgaaatctaaactggttag cgatttccggaaggactttcaattttataaagtccgggagattaacaact atcaccatgcacacgacgcttacttaaatgcggttgttggcacggccctg atcaagaagtacccgaaactggaaagcgagtttgtttatggtgactacaa ggtgtatgacgttcgcaagatgattgcaaaatccgaacaagagattggta aggcgacggctaagtattttttctacagcaatatcatgaacttcttcaag actgaaatcaccctggcgaacggtgaaattcgtaaacgtccgttgatcga aaccaacggtgaaaccggtgaaatcgtttgggataaaggtagggattttg cgaccgttcgtaaggtcctgagcatgccgcaggttaacatcgtgaaaaag accgaagtgcagaccggcggtttctccaaggagagtatcttaccgaagcg caacagtgacaagctgatcgcgcgtaaaaaagactgggatccgaaaaaat acggcggctttgactccccgaccgtcgcgtacagcgtactggtcgtggct aaagtggagaaaggcaaatcgaaaaagctgaaatccgttaaagagttgct gggtattacgattatggaacgttcgagcttcgagaaaaatccgatcgact tcctggaggccaaaggctacaaggaagttaaaaaagacctgatcattaaa ctgccgaagtacagcctgttcgagctcgagaacggtcgcaaacgcatgct ggcgagcgcgggtgagctccaaaaaggcaacgaattggctctgccgagca agtacgtgaacttcctgtatctggcctcccattatgaaaaactgaagggt agcccggaagataacgaacaaaagcagctgttcgtggaacaacataaaca ctatctggacgagattattgagcaaatcagcgagttcagcaaacgcgtga ttctggcggatgctaatctggacaaggttctttcagcctataataaacac cgtgataagccgatccgtgaacaggcagaaaatattattcacctgttcac cctgacgaacctgggtgcgccagcagcgtttaaatacttcgacacaacga tcgaccggaagcgttataccagcaccaaagaggttcttgacgccaccttg attcaccaaagcatcacgggtctgtatgaaacccgtattgacttgagcca gttgggcggagattcagggggaagtggcggaagcggtgggtctacgaacc tgagcgacattattgaaaaagaaactggtaaacagttggtgatccaagaa tccattctgatgttaccggaggaagtggaagaggtgatcggcaacaagcc ggagtccgacatcctggttcacaccgcgtatgatgagtcgaccgatgaga atgttatgctgctgaccagcgacgccccagagtacaaaccgtgggcgctc gtcatccaggatagcaatggcgaaaacaagatcaagatgttgtctggcgg tagcatggctccgaaaaagaagcgtaaagtaggtattcatggtgttccgg catcaggttaa 23 Base editor evo APOBEC1- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaagtaaaacaggacccgttgctgtagatccgacgctgagacgt cgcatcgagccgcacgaattcgaggtgttttttgatccgcgtgaactgcg caaggagacgtgcctgctgtatgagatcaactggggtggccgtcacagca tttggcgtcacacctcccaaaacacgaacaaacacgtggaagtcaatttc atcgaaaaattcaccaccgaacgttacttctgcccgaacacccgttgttc catcacctggttcctgtcttggagcccgtgtggtgagtgcagccgcgcaa ttactgagttcctgagccgttacccgaatgttaccctgtttatctatatc gcccgtttgtaccatctggcgaacccgcgcaaccgtcagggtttacgcga cttaattagctctggcgttaccattcagattatgaccgagcaagagagcg gttattgctggcataactttgtaaactatagcccgagcaatgaaagccat tggcctcgctacccgcacctgtgggttcgtttgtacgtgctggaactgta ctgcatcatccttggtttgccaccgtgcttgaatattttgagacgtaagc agtcgcaactgaccagttttacgatcgcgctacagagctgtcattatcag cgtctcccgccacacattctgtgggctaccggcctgaaaagcggcggtag cagcggtggctccagcggctcggaaactccgggcacctccgagtcagcga ccccggaatctggaagtgagacacccgggacttcagaatccgcgaccccg gagtctggaatgccaaaacccgctgtagagtcagaattttcaaaagtttt gaaaaagcactttccgggagaacgtttccgctcgagctatatgaaaagag gcggtaagatcctggctgcccaaggcgaagaggcagttgttgcgtatcta cagggcaagtccgaggaggagcctccgaacttccagccaccggcgaagtg ccacgtggtgaccaaatcccgtgacttcgcggaatggccgatcatgaagg cgtcggaagcgattcaacgttatatctatgcactgtcgaccaccgaacgc gcggcctgtaaaccgggcaaaagtagtgagagccatgcagcgtggttcgc cgctaccggtgtcagcaaccacggctacagccacgttcagggtctgaacc tgatttttgatcataccttgggccgttacgatggtgttctgaaaaaggtc caactgcgcaacgaaaaggcgagagcgcgtttagagagcattaacgcgtc tagagcagatgaaggtttaccggagattaaagccgaggaggaagaagtgg ctacgaacgaaaccggccacctgttgcaaccgccgggtatcaatccgagc ttttacgtgtatcagaccattagcccgcaggcataccgtccgcgtgacga gatcgtgctgccgccggagtacgcaggttacgtacgtgacccgaatgctc cgattccgctgggtgtggtgcgtaaccgttgcgatatccaaaaagggtgc ccgggctacatcccggaatggcagcgtgaagcaggtaccgcgatcagccc gaaaacaggcaaggccgtaactgtgccgggcctgtctccgaagaaaaaca aacgtatgcgtaggtactggcgctctgagaaggagaaagctcaagatgcg ctgttggttaccgtacgcattggtaccgattgggttgtcatcgacgtgcg cggtctgttgcgcaacgcccgttggcgcaccatcgctcccaaggacatca gcctgaatgcgctcctcgatttgtttaccggtgatccggtgatcgatgtg cgtcgcaatattgttacctttacgtacaccctcgacgcctgtggtaccta cgcccgtaaatggaccttgaaaggcaaacagacgaaagcgaccctggaca aactgacggccactcagacggttgcgttggttgcgattgcgcttggtcag accaacccgatttccgctggcattagccgtgttacacaagaaaatggtgc actgcaatgcgaaccgctggaccggttcaccctgccggatgacctgttga aggacatcagcgcatatcgcattgcttgggacagaaacgaagaggaacta cgcgctcgcagcgtcgaggccctgccggaggcgcaacaagcggaggtccg tgcgctggacggggtgtccaaagaaaccgcgcgtacccaactgtgcgcag atttcggcctggacccgaaacgtctgccgtgggataaaatgagctccaat actacctttatcagcgaagccttgctgtctaacagcgtgagccgtgatca ggtttttttcactccggctccgaagaagggtgctaagaaaaaagcgcctg ttgaagttatgcgtaaagaccgcacttgggcacgtgcgtacaagccgcgt ctgagcgtcgaagctcagaaactgaagaacgaagccctgtgggcacttaa gcgcacctccccggagtatttgaagctgagccgtcgcaaagaggagctgt gtcgtcgtagcatcaactatgttatcgaaaagacccgtcgccgtacgcaa tgtcagattgtgatcccggtgatcgaggatctgaatgttcgcttctttca tggttctggtaagagactgcccggttgggataatttcttcaccgctaaaa aagagaaccgttggttcatccagggcctgcacaaagcgtttagcgatctg cgtacgcaccgttccttctatgtttttgaagttcgtccggagcgcacctc tattacctgtccaaagtgcggtcattgcgaggtgggtaatcgtgacggtg aggcgtttcagtgcctgagctgcggcaagacgtgcaacgcagatcttgac gtcgcgacccataatctgacccaagtggcgttgaccggtaagaccatgcc gaagcgcgaggagccgcgtgacgctcagggtacagcgccagcgcgcaaga ctaagaaggcgagcaaatcaaaggcgccaccggcggagcgcgaagaccag accccggcgcaagagccaagccagaccagttctggaggtagcgggggtag cggtggtagcactaacttaagtgatattatcgagaaagaaaccgggaaac agctggtgatccaagaaagcattctgatgctgcccgaagaagttgaagaa gtgattggtaacaagcctgagtcggacatcttagtgcacaccgcgtacga tgaaagcacggatgagaatgtgatgctgctcacctctgatgcccccgaat acaagccgtgggctctggtgatccaggactctaacggagaaaacaaaatt aagatgctctctggcggctccatggcgcctaaaaaaaaacgcaaagtggg gattcacggggttccggcgtaa 24 Base editor evo APOBEC1- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaagtaaaacaggacccgttgctgtagatccgacgctgagacgt cgcatcgagccgcacgaattcgaggtgttttttgatccgcgtgaactgcg caaggagacgtgcctgctgtatgagatcaactggggtggccgtcacagca tttggcgtcacacctcccaaaacacgaacaaacacgtggaagtcaatttc atcgaaaaattcaccaccgaacgttacttctgcccgaacacccgttgttc catcacctggttcctgtcttggagcccgtgtggtgagtgcagccgcgcaa ttactgagttcctgagccgttacccgaatgttaccctgtttatctatatc gcccgtttgtaccatctggcgaacccgcgcaaccgtcagggtttacgcga cttaattagctctggcgttaccattcagattatgaccgagcaagagagcg gttattgctggcataactttgtaaactatagcccgagcaatgaaagccat tggcctcgctacccgcacctgtgggttcgtttgtacgtgctggaactgta ctgcatcatccttggtttgccaccgtgcttgaatattttgagacgtaagc agtcgcaactgaccagttttacgatcgcgctacagagctgtcattatcag cgtctcccgccacacattctgtgggctaccggcctgaaaagcggcggtag cagcggtggctccagcggctcggaaactccgggcacctccgagtcagcga ccccggaatctggaagtgagacacccgggacttcagaatccgcgaccccg gagtctggaatgtcaaaactagaaaagtttacaaattgttactccctgtc gaaaaccctgagattcaaagcgatcccggtgggtaaaactcaagagaaca ttgataacaaacgtctgctggttgaggacgaaaagcgcgcggaggattac aaaggcgttaaaaagctgttggaccgttattacctgtcctttattaatga tgttctgcacagcattaaattaaagaacctaaacaattacatctccctct tccgtaaaaagacccgcaccgaaaaggaaaataaagaactggagaacctt gagattaatctgcgtaaagaaatcgctaaagcgtttaaaggcaacgaggg ttataaatccttatttaaaaaagacatcatcgaaacgattctcccagaat tcctggacgacaaagacgagatcgcgctggttaattccttcaacggcttt accaccgcattcaccggcttttttgataaccgcgaaaacatgttctctga agaggccaaaagcacctcaattgcgtttcgctgcattaacgaaaatctga cgcgttatatctctaacatggatatcttcgagaaggttgacgctatcttt gataaacatgaagtccaggagatcaaggagaagatcctgaacagcgacta cgacgtggaggatttcttcgagggtgagttcttcaattttgttttgaccc aagaaggcatcgatgtctacaatgcgataattggtggttttgttaccgag agcggggagaaaattaagggtctgaacgaatatatcaacttgtacaacca gaaaaccaaacaaaaactgccgaagtttaagccgctgtacaagcaagtct tgtcggatcgtgaatcgctgagcttttacggcgaaggctacaccagcgat gaggaggtgttggaggtgttccgcaatacgttgaataagaactctgaaat tttttccagcattaagaagctggaaaaactattcaagaacttcgacgagt atagcagcgcaggtatctttgtgaaaaacggtccggctattagcaccatc tcgaaagacattttcggcgaatggaatgttattcgtgataagtggaatgc cgaatacgacgacattcatctgaagaaaaaggcggttgtaactgaaaagt acgaggacgatcgtcgtaagtcgttcaaaaagatcggctccttctctctg gagcaactgcaagagtacgccgatgccgatttgtcagtcgtggagaagct gaaagagatcatcattcaaaaagttgacgaaatctataaggtctatggta gcagtgaaaaactgtttgacgcggacttcgtgctggagaaaagcctgaag aaaaatgacgccgtggtggcaatcatgaaagatcttctggatagcgtcaa gtctttcgaaaactacatcaaagcgtttttcggtgaaggcaaggaaacga atcgtgacgagagcttctatggtgatttcgtcctagcctatgatatcctg cttaaggtggatcacatctatgatgccatccgcaactatgttacccagaa accgtactcaaaggacaagttcaagttatacttccagaatccgcagttta tgggtggctgggataaagataaggaaaccgactatcgcgccaccatttta cgttacggtagtaagtactatctggcaatcatggataaaaaatatgcgaa atgcctgcaaaagatcgacaaggacgatgttaacggcaattatgagaaga tcaactacaaactgctgccgggcccaaataagatgctgccgaaggtgttt ttcagcaaaaaatggatggcgtattacaatccgagcgaggacatccaaaa gatctacaaaaacggtacgtttaagaagggtgatatgttcaacctcaacg attgtcataaacttattgacttcttcaaggatagcatatctcgttatccg aagtggagcaacgcgtatgactttaactttagcgaaaccgagaaatacaa agatatcgcgggtttctatcgtgaagttgaagaacagggttacaaagtgt ccttcgagtccgcgagcaagaaggaggtagacaagctggtcgaggagggt aagttgtacatgtttcagatttacaataaggacttttccgacaagtccca tggtacaccgaatttgcacaccatgtatttcaagcttctgttcgacgaga acaaccacggccagatccgtctgagcggtggtgcagagctgttcatgcgt agagctagcctgaagaaagaagagttggtcgttcatccggctaattcgcc gatcgcgaacaaaaatccagataaccctaaaaagactacgaccctgagct atgatgtgtataaagacaaacgctttagcgaagaccagtatgagttacac attccgatcgctatcaacaagtgcccgaagaatattttcaagatcaacac cgaagtgcgtgttcttttgaagcacgatgacaacccgtatgtgattggta ttgctcgtggtgaacgtaatctgctgtacattgtggttgtggacggcaaa ggaaacatcgtggaacagtacagcctgaacgaaatcattaacaatttcaa cggcattcgcattaagacggattaccattctttgctggacaaaaaggaga aagagcgtttcgaggcccgtcagaactggacctccatcgagaacattaag gagctgaaggcgggttacatcagccaggtggtgcacaaaatctgcgaact ggtggagaagtacgacgcggtgattgctttggcggatttgaactccggtt ttaagaacagccgcgttaaagtggaaaagcaggtttatcagaaattcgaa aaaatgctgattgataaattgaattacatggttgacaaaaagtctaaccc gtgtgcaaccggcggtgcgctgaagggctaccaaatcaccaataagtttg aaagctttaagagcatgagcacgcaaaatggcttcattttttacattccg gcgtggctgaccagcaagatcgatccgtcaaccggctttgttaatttact gaagacgaagtatacctctattgccgactctaaaaaatttattagttcct tcgatagaatcatgtatgttccggaagaggacctgttcgaatttgcactg gactacaagaactttagccgtaccgatgctgattatataaagaaatggaa actctacagctatggcaaccgcatccgtatctttcgcaacccgaaaaaaa acaacgtgttcgactgggaagaggtatgtctgacttcagcgtacaaggag cttttcaataaatatggtatcaactaccagcagggtgatatccgtgcact gctttgcgagcaaagcgataaagcgttctattcaagcttcatggcgctga tgagcctgatgctgcaaatgcgcaacagcatcaccggtcgtaccgatgtt gcatttctgatttctccagtaaaaaacagcgatggtatcttttacgacag ccgtaattacgaggcccaagaaaatgcgattttgccgaagaacgctgacg cgaatggtgcatacaacattgcaaggaaagttctgtgggcaatcggccaa tttaaaaaagcggaagatgagaagctggacaaagtgaaaattgcgattag caacaaggagtggctggagtatgcgcagacctccgttaaatcagggggaa gtggcggaagcggtgggtctacgaacctgagcgacattattgaaaaagaa actggtaaacagttggtgatccaagaatccattctgatgttaccggagga agtggaagaggtgatcggcaacaagccggagtccgacatcctggttcaca ccgcgtatgatgagtcgaccgatgagaatgttatgctgctgaccagcgac gccccagagtacaaaccgtgggcgctcgtcatccaggatagcaatggcga aaacaagatcaagatgttgtctggcggtagcatggctccgaaaaagaagc gtaaagtaggtattcatggtgttccggcatcaggttaa 25 Base editor evoCDA1-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaacagatgctgaatatgtaaggatacacgagaagctggacatc tacacctttaaaaagcagttctccaacaataaaaaatctgtcagccatcg ttgctacgtgttgtttgaactcaagcgtcgtggcgaacgccgtgcgtgct tttggggttacgctgtgaacaaaccgcagagcggtacggaacgtggtatt catgcggagatcttcagcatccgcaaggtggaagagtatctgcgcgataa cccgggtcaattcaccattaactggtacagcagctggtcaccgtgcgccg actgtgctgagaagattttggagtggtataaccaagaattgcgcggtaat ggccatactctgaagatctgggtgtgtaaactttattacgaaaagaacgc gcgtaatcaaattggtctgtggaatctgagagataacggcgttggtctga atgttatggtttccgagcactatcagtgctgccgtaaaatcttcattcag tccagccacaaccaactgaacgagaaccgttggctggaaaagaccctgaa gcgcgcggagaaacgtcgtagcgagctgagcattatgtttcaggttaaaa tcttacacaccaccaaatcgccggcagtctctggcggttcctcgggcggc agctctggctccgaaaccccaggtacgagcgagagcgcaaccccggaatc tggaagtgagacacccgggacttcagaatccgcgaccccggagtctggaa tggataaaaagtattcaataggactagctattggcaccaacagcgttggt tgggcagttatcaccgatgaatataaggtcccgagcaagaagtttaaggt cctgggcaacaccgatcgccacagcataaaaaagaaccttattggtgcgc tgctgttcgattctggtgagactgccgaagcgacccgtctgaagagaacc gcgcgtcgtagatacacccggcgcaagaaccgtatctgctatctgcaaga aattttcagcaacgagatggctaaggtcgacgactccttctttcatcgcc tggaggaaagctttctggttgaggaagacaaaaagcacgagcgtcatccg attttcggtaacattgttgatgaagttgcctaccacgaaaaataccccac aatttatcatctgcgtaaaaaactggtagactccaccgataaggcggatt tacgccttatctatttggcgctggcgcatatgattaagttccgcggtcat tttttgatcgagggcgacctgaatccggataacagcgacgttgacaaact gtttatccagctggtgcagacctataaccagttgttcgaagagaacccga ttaatgcgtctggcgtggacgcgaaggcgatcctgagcgctcgtctgtcc aagtcacgccgcctggagaacttgatcgcgcaactgccgggtgagaagaa aaacggcttgttcggcaatctgattgctctgtccctaggtttgaccccga atttcaaatctaattttgatctggcggaagatgcgaaattacagttgagc aaggacacttacgatgacgatctggacaacctgctcgctcagatcggcga tcagtatgccgatcttttcctggccgcgaagaacctgagcgatgccatct tgctatcggacatcttacgtgttaacaccgaaatcaccaaagctccgcta agcgcgtccatgattaaacgttacgatgaacaccaccaggatctgacgct gctgaaagcgttggtgcgccagcaactgccggaaaaatacaaggaaattt tcttcgaccaaagcaagaacggttatgcaggctatatcgacggtggtgcg tcgcaagaagaattttataaattcatcaaaccgattttggagaagatgga tggtaccgaggagctgctggtaaaattgaatcgggaagacctcttgcgaa agcagcgtactttcgataatggtagcatcccgcaccagattcatctgggc gaacttcacgcaatcctacgtcgtcaagaggatttctacccgtttctgaa ggataaccgtgaaaagatcgagaagattctgacctttcgtattccgtatt atgtgggtccgctggcgagaggcaacagccgttttgcgtggatgacccgc aagtcggaagagactatcacgccgtggaatttcgaggaggtcgtggacaa gggtgcatcagcgcaatcttttattgaacgtatgaccaattttgataaaa accttccaaatgaaaaagtgttgccgaagcacagcttgctgtacgagtat ttcaccgtttacaatgaactgacgaaagtcaagtacgttaccgaaggtat gcgtaagccagcctttctgtctggggagcaaaaaaaagccattgtggatc tgctgttcaagaccaatcgcaaggttaccgtcaagcaactgaaagaggat tacttcaaaaaaatcgaatgttttgactccgtggaaatcagcggcgttga agaccgctttaatgcatctctgggcacctaccacgatctactcaagatca tcaaggataaggacttcctggacaacgaagaaaatgaggatatcttggaa gatattgtgctgactttaacgttgttcgaggatcgtgagatgattgaaga acgcctcaaaacgtacgcacatctgtttgacgataaggtgatgaaacagc taaagcgccgtcgttacaccggttggggtcgtctgtctagaaagctgatt aacggcattcgtgacaaacaatctggcaagaccatcctggacttcctcaa atccgacggcttcgcaaatcgtaatttcatgcaactgatccatgatgata gcctgacctttaaagaagatattcagaaggctcaagtgtccggccagggt gactcgctgcatgagcatatcgcgaatctggctggctcccctgcgataaa aaaaggtattctccaaacggtgaaagttgtggatgaactggttaaagtca tgggtcgtcataaaccggaaaacatcgtgattgagatggcacgtgagaac cagaccacccagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgtat cgaagaggggattaaggagttaggcagccagattctgaaggagcacccgg ttgagaacacccagctgcaaaacgagaagctctacctgtattacctgcaa aacggccgtgacatgtatgttgaccaggagctggacatcaatcgtctcag cgactacgacgtggatgctatcgtgccgcagagctttctaaaagatgatt ccatcgacaataaagtgctcacccgtagcgacaagaaccgtggtaaaagc gacaacgtgccgagcgaggaagtagttaagaaaatgaaaaactactggcg tcagctattgaacgccaagcttatcacccagcgtaagtttgacaacttga cgaaggcagagcgtggcggcctgagcgagctagacaaggcgggttttatt aaacgccagctggtggaaactcgccagattaccaaacacgttgcgcaaat cttggactcacgcatgaatacgaagtacgacgaaaacgataaattgatcc gcgaggtgaaggtcataaccctgaaatctaaactggttagcgatttccgg aaggactttcaattttataaagtccgggagattaacaactatcaccatgc acacgacgcttacttaaatgcggttgttggcacggccctgatcaagaagt acccgaaactggaaagcgagtttgtttatggtgactacaaggtgtatgac gttcgcaagatgattgcaaaatccgaacaagagattggtaaggcgacggc taagtattttttctacagcaatatcatgaacttcttcaagactgaaatca ccctggcgaacggtgaaattcgtaaacgtccgttgatcgaaaccaacggt gaaaccggtgaaatcgtttgggataaaggtagggattttgcgaccgttcg taaggtcctgagcatgccgcaggttaacatcgtgaaaaagaccgaagtgc agaccggcggtttctccaaggagagtatcttaccgaagcgcaacagtgac aagctgatcgcgcgtaaaaaagactgggatccgaaaaaatacggcggctt tgactccccgaccgtcgcgtacagcgtactggtcgtggctaaagtggaga aaggcaaatcgaaaaagctgaaatccgttaaagagttgctgggtattacg attatggaacgttcgagcttcgagaaaaatccgatcgacttcctggaggc caaaggctacaaggaagttaaaaaagacctgatcattaaactgccgaagt acagcctgttcgagctcgagaacggtcgcaaacgcatgctggcgagcgcg ggtgagctccaaaaaggcaacgaattggctctgccgagcaagtacgtgaa cttcctgtatctggcctcccattatgaaaaactgaagggtagcccggaag ataacgaacaaaagcagctgttcgtggaacaacataaacactatctggac gagattattgagcaaatcagcgagttcagcaaacgcgtgattctggcgga tgctaatctggacaaggttctttcagcctataataaacaccgtgataagc cgatccgtgaacaggcagaaaatattattcacctgttcaccctgacgaac ctgggtgcgccagcagcgtttaaatacttcgacacaacgatcgaccggaa gcgttataccagcaccaaagaggttcttgacgccaccttgattcaccaaa gcatcacgggtctgtatgaaacccgtattgacttgagccagttgggcgga gattcagggggaagtggcggaagcggtgggtctacgaacctgagcgacat tattgaaaaagaaactggtaaacagttggtgatccaagaatccattctga tgttaccggaggaagtggaagaggtgatcggcaacaagccggagtccgac atcctggttcacaccgcgtatgatgagtcgaccgatgagaatgttatgct gctgaccagcgacgccccagagtacaaaccgtgggcgctcgtcatccagg atagcaatggcgaaaacaagatcaagatgttgtctggcggtagcatggct ccgaaaaagaagcgtaaagtaggtattcatggtgttccggcatcaggtta a 26 Base editor evoCDA1- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaacagatgctgaatatgtaaggatacacgagaagctggacatc tacacctttaaaaagcagttctccaacaataaaaaatctgtcagccatcg ttgctacgtgttgtttgaactcaagcgtcgtggcgaacgccgtgcgtgct tttggggttacgctgtgaacaaaccgcagagcggtacggaacgtggtatt catgcggagatcttcagcatccgcaaggtggaagagtatctgcgcgataa cccgggtcaattcaccattaactggtacagcagctggtcaccgtgcgccg actgtgctgagaagattttggagtggtataaccaagaattgcgcggtaat ggccatactctgaagatctgggtgtgtaaactttattacgaaaagaacgc gcgtaatcaaattggtctgtggaatctgagagataacggcgttggtctga atgttatggtttccgagcactatcagtgctgccgtaaaatcttcattcag tccagccacaaccaactgaacgagaaccgttggctggaaaagaccctgaa gcgcgcggagaaacgtcgtagcgagctgagcattatgtttcaggttaaaa tcttacacaccaccaaatcgccggcagtctctggcggttcctcgggcggc agctctggctccgaaaccccaggtacgagcgagagcgcaaccccggaatc tggaagtgagacacccgggacttcagaatccgcgaccccggagtctggaa tgccaaaacccgctgtagagtcagaattttcaaaagttttgaaaaagcac tttccgggagaacgtttccgctcgagctatatgaaaagaggcggtaagat cctggctgcccaaggcgaagaggcagttgttgcgtatctacagggcaagt ccgaggaggagcctccgaacttccagccaccggcgaagtgccacgtggtg accaaatcccgtgacttcgcggaatggccgatcatgaaggcgtcggaagc gattcaacgttatatctatgcactgtcgaccaccgaacgcgcggcctgta aaccgggcaaaagtagtgagagccatgcagcgtggttcgccgctaccggt gtcagcaaccacggctacagccacgttcagggtctgaacctgatttttga tcataccttgggccgttacgatggtgttctgaaaaaggtccaactgcgca acgaaaaggcgagagcgcgtttagagagcattaacgcgtctagagcagat gaaggtttaccggagattaaagccgaggaggaagaagtggctacgaacga aaccggccacctgttgcaaccgccgggtatcaatccgagcttttacgtgt atcagaccattagcccgcaggcataccgtccgcgtgacgagatcgtgctg ccgccggagtacgcaggttacgtacgtgacccgaatgctccgattccgct gggtgtggtgcgtaaccgttgcgatatccaaaaagggtgcccgggctaca tcccggaatggcagcgtgaagcaggtaccgcgatcagcccgaaaacaggc aaggccgtaactgtgccgggcctgtctccgaagaaaaacaaacgtatgcg taggtactggcgctctgagaaggagaaagctcaagatgcgctgttggtta ccgtacgcattggtaccgattgggttgtcatcgacgtgcgcggtctgttg cgcaacgcccgttggcgcaccatcgctcccaaggacatcagcctgaatgc gctcctcgatttgtttaccggtgatccggtgatcgatgtgcgtcgcaata ttgttacctttacgtacaccctcgacgcctgtggtacctacgcccgtaaa tggaccttgaaaggcaaacagacgaaagcgaccctggacaaactgacggc cactcagacggttgcgttggttgcgattgcgcttggtcagaccaacccga tttccgctggcattagccgtgttacacaagaaaatggtgcactgcaatgc gaaccgctggaccggttcaccctgccggatgacctgttgaaggacatcag cgcatatcgcattgcttgggacagaaacgaagaggaactacgcgctcgca gcgtcgaggccctgccggaggcgcaacaagcggaggtccgtgcgctggac ggggtgtccaaagaaaccgcgcgtacccaactgtgcgcagatttcggcct ggacccgaaacgtctgccgtgggataaaatgagctccaatactaccttta tcagcgaagccttgctgtctaacagcgtgagccgtgatcaggtttttttc actccggctccgaagaagggtgctaagaaaaaagcgcctgttgaagttat gcgtaaagaccgcacttgggcacgtgcgtacaagccgcgtctgagcgtcg aagctcagaaactgaagaacgaagccctgtgggcacttaagcgcacctcc ccggagtatttgaagctgagccgtcgcaaagaggagctgtgtcgtcgtag catcaactatgttatcgaaaagacccgtcgccgtacgcaatgtcagattg tgatcccggtgatcgaggatctgaatgttcgcttctttcatggttctggt aagagactgcccggttgggataatttcttcaccgctaaaaaagagaaccg ttggttcatccagggcctgcacaaagcgtttagcgatctgcgtacgcacc gttccttctatgtttttgaagttcgtccggagcgcacctctattacctgt ccaaagtgcggtcattgcgaggtgggtaatcgtgacggtgaggcgtttca gtgcctgagctgcggcaagacgtgcaacgcagatcttgacgtcgcgaccc ataatctgacccaagtggcgttgaccggtaagaccatgccgaagcgcgag gagccgcgtgacgctcagggtacagcgccagcgcgcaagactaagaaggc gagcaaatcaaaggcgccaccggcggagcgcgaagaccagaccccggcgc aagagccaagccagaccagttctggaggtagcgggggtagcggtggtagc actaacttaagtgatattatcgagaaagaaaccgggaaacagctggtgat ccaagaaagcattctgatgctgcccgaagaagttgaagaagtgattggta acaagcctgagtcggacatcttagtgcacaccgcgtacgatgaaagcacg gatgagaatgtgatgctgctcacctctgatgcccccgaatacaagccgtg ggctctggtgatccaggactctaacggagaaaacaaaattaagatgctct ctggcggctccatggcgcctaaaaaaaaacgcaaagtggggattcacggg gttccggcgtaa 27 Base editor evoCDA1- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaacagatgctgaatatgtaaggatacacgagaagctggacatc tacacctttaaaaagcagttctccaacaataaaaaatctgtcagccatcg ttgctacgtgttgtttgaactcaagcgtcgtggcgaacgccgtgcgtgct tttggggttacgctgtgaacaaaccgcagagcggtacggaacgtggtatt catgcggagatcttcagcatccgcaaggtggaagagtatctgcgcgataa cccgggtcaattcaccattaactggtacagcagctggtcaccgtgcgccg actgtgctgagaagattttggagtggtataaccaagaattgcgcggtaat ggccatactctgaagatctgggtgtgtaaactttattacgaaaagaacgc gcgtaatcaaattggtctgtggaatctgagagataacggcgttggtctga atgttatggtttccgagcactatcagtgctgccgtaaaatcttcattcag tccagccacaaccaactgaacgagaaccgttggctggaaaagaccctgaa gcgcgcggagaaacgtcgtagcgagctgagcattatgtttcaggttaaaa tcttacacaccaccaaatcgccggcagtctctggcggttcctcgggcggc agctctggctccgaaaccccaggtacgagcgagagcgcaaccccggaatc tggaagtgagacacccgggacttcagaatccgcgaccccggagtctggaa tgtcaaaactagaaaagtttacaaattgttactccctgtcgaaaaccctg agattcaaagcgatcccggtgggtaaaactcaagagaacattgataacaa acgtctgctggttgaggacgaaaagcgcgcggaggattacaaaggcgtta aaaagctgttggaccgttattacctgtcctttattaatgatgttctgcac agcattaaattaaagaacctaaacaattacatctccctcttccgtaaaaa gacccgcaccgaaaaggaaaataaagaactggagaaccttgagattaatc tgcgtaaagaaatcgctaaagcgtttaaaggcaacgagggttataaatcc ttatttaaaaaagacatcatcgaaacgattctcccagaattcctggacga caaagacgagatcgcgctggttaattccttcaacggctttaccaccgcat tcaccggcttttttgataaccgcgaaaacatgttctctgaagaggccaaa agcacctcaattgcgtttcgctgcattaacgaaaatctgacgcgttatat ctctaacatggatatcttcgagaaggttgacgctatctttgataaacatg aagtccaggagatcaaggagaagatcctgaacagcgactacgacgtggag gatttcttcgagggtgagttcttcaattttgttttgacccaagaaggcat cgatgtctacaatgcgataattggtggttttgttaccgagagcggggaga aaattaagggtctgaacgaatatatcaacttgtacaaccagaaaaccaaa caaaaactgccgaagtttaagccgctgtacaagcaagtcttgtcggatcg tgaatcgctgagcttttacggcgaaggctacaccagcgatgaggaggtgt tggaggtgttccgcaatacgttgaataagaactctgaaattttttccagc attaagaagctggaaaaactattcaagaacttcgacgagtatagcagcgc aggtatctttgtgaaaaacggtccggctattagcaccatctcgaaagaca ttttcggcgaatggaatgttattcgtgataagtggaatgccgaatacgac gacattcatctgaagaaaaaggcggttgtaactgaaaagtacgaggacga tcgtcgtaagtcgttcaaaaagatcggctccttctctctggagcaactgc aagagtacgccgatgccgatttgtcagtcgtggagaagctgaaagagatc atcattcaaaaagttgacgaaatctataaggtctatggtagcagtgaaaa actgtttgacgcggacttcgtgctggagaaaagcctgaagaaaaatgacg ccgtggtggcaatcatgaaagatcttctggatagcgtcaagtctttcgaa aactacatcaaagcgtttttcggtgaaggcaaggaaacgaatcgtgacga gagcttctatggtgatttcgtcctagcctatgatatcctgcttaaggtgg atcacatctatgatgccatccgcaactatgttacccagaaaccgtactca aaggacaagttcaagttatacttccagaatccgcagtttatgggtggctg ggataaagataaggaaaccgactatcgcgccaccattttacgttacggta gtaagtactatctggcaatcatggataaaaaatatgcgaaatgcctgcaa aagatcgacaaggacgatgttaacggcaattatgagaagatcaactacaa actgctgccgggcccaaataagatgctgccgaaggtgtttttcagcaaaa aatggatggcgtattacaatccgagcgaggacatccaaaagatctacaaa aacggtacgtttaagaagggtgatatgttcaacctcaacgattgtcataa acttattgacttcttcaaggatagcatatctcgttatccgaagtggagca acgcgtatgactttaactttagcgaaaccgagaaatacaaagatatcgcg ggtttctatcgtgaagttgaagaacagggttacaaagtgtccttcgagtc cgcgagcaagaaggaggtagacaagctggtcgaggagggtaagttgtaca tgtttcagatttacaataaggacttttccgacaagtcccatggtacaccg aatttgcacaccatgtatttcaagcttctgttcgacgagaacaaccacgg ccagatccgtctgagcggtggtgcagagctgttcatgcgtagagctagcc tgaagaaagaagagttggtcgttcatccggctaattcgccgatcgcgaac aaaaatccagataaccctaaaaagactacgaccctgagctatgatgtgta taaagacaaacgctttagcgaagaccagtatgagttacacattccgatcg ctatcaacaagtgcccgaagaatattttcaagatcaacaccgaagtgcgt gttcttttgaagcacgatgacaacccgtatgtgattggtattgctcgtgg tgaacgtaatctgctgtacattgtggttgtggacggcaaaggaaacatcg tggaacagtacagcctgaacgaaatcattaacaatttcaacggcattcgc attaagacggattaccattctttgctggacaaaaaggagaaagagcgttt cgaggcccgtcagaactggacctccatcgagaacattaaggagctgaagg cgggttacatcagccaggtggtgcacaaaatctgcgaactggtggagaag tacgacgcggtgattgctttggcggatttgaactccggttttaagaacag ccgcgttaaagtggaaaagcaggtttatcagaaattcgaaaaaatgctga ttgataaattgaattacatggttgacaaaaagtctaacccgtgtgcaacc ggcggtgcgctgaagggctaccaaatcaccaataagtttgaaagctttaa gagcatgagcacgcaaaatggcttcattttttacattccggcgtggctga ccagcaagatcgatccgtcaaccggctttgttaatttactgaagacgaag tatacctctattgccgactctaaaaaatttattagttccttcgatagaat catgtatgttccggaagaggacctgttcgaatttgcactggactacaaga actttagccgtaccgatgctgattatataaagaaatggaaactctacagc tatggcaaccgcatccgtatctttcgcaacccgaaaaaaaacaacgtgtt cgactgggaagaggtatgtctgacttcagcgtacaaggagcttttcaata aatatggtatcaactaccagcagggtgatatccgtgcactgctttgcgag caaagcgataaagcgttctattcaagcttcatggcgctgatgagcctgat gctgcaaatgcgcaacagcatcaccggtcgtaccgatgttgcatttctga tttctccagtaaaaaacagcgatggtatcttttacgacagccgtaattac gaggcccaagaaaatgcgattttgccgaagaacgctgacgcgaatggtgc atacaacattgcaaggaaagttctgtgggcaatcggccaatttaaaaaag cggaagatgagaagctggacaaagtgaaaattgcgattagcaacaaggag tggctggagtatgcgcagacctccgttaaatcagggggaagtggcggaag cggtgggtctacgaacctgagcgacattattgaaaaagaaactggtaaac agttggtgatccaagaatccattctgatgttaccggaggaagtggaagag gtgatcggcaacaagccggagtccgacatcctggttcacaccgcgtatga tgagtcgaccgatgagaatgttatgctgctgaccagcgacgccccagagt acaaaccgtgggcgctcgtcatccaggatagcaatggcgaaaacaagatc aagatgttgtctggcggtagcatggctccgaaaaagaagcgtaaagtagg tattcatggtgttccggcatcaggttaa 28 Base editor evoFERNY-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcatttgagaggaattatgatcccagagaattgcgcaaagagacg tacctgctgtatgaaatcaagtggggtaaaagcggcaagctgtggcgtca ttggtgtcaaaacaaccgcacccaacacgcggaagtttatttcctcgaga atattttcaacgcccgtcgttttaacccgagcacccactgctccatcacc tggtatctttcttggtcgccgtgtgcggagtgctcgcaaaaaatcgtgga cttcctgaaagaacatccgaatgtgaacctggagatctatgttgcgagat tgtactatccggagaacgaacgtaatcgtcagggcctgcgcgacttggtc aacagcggggtgaccattcgtattatggatctgccggattacaattactg ctggaaaacctttgtttccgatcagggtggcgacgaagactactggcctg gtcactttgctccgtggattaagcagtacagcctgaagctgagcggtggt tcttccggcggtagcagtggctccgagactccaggtacgagcgagagcgc aaccccggaatctggaagtgagacacccgggacttcagaatccgcgaccc cggagtctggaatggataaaaagtattcaataggactagctattggcacc aacagcgttggttgggcagttatcaccgatgaatataaggtcccgagcaa gaagtttaaggtcctgggcaacaccgatcgccacagcataaaaaagaacc ttattggtgcgctgctgttcgattctggtgagactgccgaagcgacccgt ctgaagagaaccgcgcgtcgtagatacacccggcgcaagaaccgtatctg ctatctgcaagaaattttcagcaacgagatggctaaggtcgacgactcct tctttcatcgcctggaggaaagctttctggttgaggaagacaaaaagcac gagcgtcatccgattttcggtaacattgttgatgaagttgcctaccacga aaaataccccacaatttatcatctgcgtaaaaaactggtagactccaccg ataaggcggatttacgccttatctatttggcgctggcgcatatgattaag ttccgcggtcattttttgatcgagggcgacctgaatccggataacagcga cgttgacaaactgtttatccagctggtgcagacctataaccagttgttcg aagagaacccgattaatgcgtctggcgtggacgcgaaggcgatcctgagc gctcgtctgtccaagtcacgccgcctggagaacttgatcgcgcaactgcc gggtgagaagaaaaacggcttgttcggcaatctgattgctctgtccctag gtttgaccccgaatttcaaatctaattttgatctggcggaagatgcgaaa ttacagttgagcaaggacacttacgatgacgatctggacaacctgctcgc tcagatcggcgatcagtatgccgatcttttcctggccgcgaagaacctga gcgatgccatcttgctatcggacatcttacgtgttaacaccgaaatcacc aaagctccgctaagcgcgtccatgattaaacgttacgatgaacaccacca ggatctgacgctgctgaaagcgttggtgcgccagcaactgccggaaaaat acaaggaaattttcttcgaccaaagcaagaacggttatgcaggctatatc gacggtggtgcgtcgcaagaagaattttataaattcatcaaaccgatttt ggagaagatggatggtaccgaggagctgctggtaaaattgaatcgggaag acctcttgcgaaagcagcgtactttcgataatggtagcatcccgcaccag attcatctgggcgaacttcacgcaatcctacgtcgtcaagaggatttcta cccgtttctgaaggataaccgtgaaaagatcgagaagattctgacctttc gtattccgtattatgtgggtccgctggcgagaggcaacagccgttttgcg tggatgacccgcaagtcggaagagactatcacgccgtggaatttcgagga ggtcgtggacaagggtgcatcagcgcaatcttttattgaacgtatgacca attttgataaaaaccttccaaatgaaaaagtgttgccgaagcacagcttg ctgtacgagtatttcaccgtttacaatgaactgacgaaagtcaagtacgt taccgaaggtatgcgtaagccagcctttctgtctggggagcaaaaaaaag ccattgtggatctgctgttcaagaccaatcgcaaggttaccgtcaagcaa ctgaaagaggattacttcaaaaaaatcgaatgttttgactccgtggaaat cagcggcgttgaagaccgctttaatgcatctctgggcacctaccacgatc tactcaagatcatcaaggataaggacttcctggacaacgaagaaaatgag gatatcttggaagatattgtgctgactttaacgttgttcgaggatcgtga gatgattgaagaacgcctcaaaacgtacgcacatctgtttgacgataagg tgatgaaacagctaaagcgccgtcgttacaccggttggggtcgtctgtct agaaagctgattaacggcattcgtgacaaacaatctggcaagaccatcct ggacttcctcaaatccgacggcttcgcaaatcgtaatttcatgcaactga tccatgatgatagcctgacctttaaagaagatattcagaaggctcaagtg tccggccagggtgactcgctgcatgagcatatcgcgaatctggctggctc ccctgcgataaaaaaaggtattctccaaacggtgaaagttgtggatgaac tggttaaagtcatgggtcgtcataaaccggaaaacatcgtgattgagatg gcacgtgagaaccagaccacccagaaaggtcaaaaaaacagtcgtgagcg tatgaaacgtatcgaagaggggattaaggagttaggcagccagattctga aggagcacccggttgagaacacccagctgcaaaacgagaagctctacctg tattacctgcaaaacggccgtgacatgtatgttgaccaggagctggacat caatcgtctcagcgactacgacgtggatgctatcgtgccgcagagctttc taaaagatgattccatcgacaataaagtgctcacccgtagcgacaagaac cgtggtaaaagcgacaacgtgccgagcgaggaagtagttaagaaaatgaa aaactactggcgtcagctattgaacgccaagcttatcacccagcgtaagt ttgacaacttgacgaaggcagagcgtggcggcctgagcgagctagacaag gcgggttttattaaacgccagctggtggaaactcgccagattaccaaaca cgttgcgcaaatcttggactcacgcatgaatacgaagtacgacgaaaacg ataaattgatccgcgaggtgaaggtcataaccctgaaatctaaactggtt agcgatttccggaaggactttcaattttataaagtccgggagattaacaa ctatcaccatgcacacgacgcttacttaaatgcggttgttggcacggccc tgatcaagaagtacccgaaactggaaagcgagtttgtttatggtgactac aaggtgtatgacgttcgcaagatgattgcaaaatccgaacaagagattgg taaggcgacggctaagtattttttctacagcaatatcatgaacttcttca agactgaaatcaccctggcgaacggtgaaattcgtaaacgtccgttgatc gaaaccaacggtgaaaccggtgaaatcgtttgggataaaggtagggattt tgcgaccgttcgtaaggtcctgagcatgccgcaggttaacatcgtgaaaa agaccgaagtgcagaccggcggtttctccaaggagagtatcttaccgaag cgcaacagtgacaagctgatcgcgcgtaaaaaagactgggatccgaaaaa atacggcggctttgactccccgaccgtcgcgtacagcgtactggtcgtgg ctaaagtggagaaaggcaaatcgaaaaagctgaaatccgttaaagagttg ctgggtattacgattatggaacgttcgagcttcgagaaaaatccgatcga cttcctggaggccaaaggctacaaggaagttaaaaaagacctgatcatta aactgccgaagtacagcctgttcgagctcgagaacggtcgcaaacgcatg ctggcgagcgcgggtgagctccaaaaaggcaacgaattggctctgccgag caagtacgtgaacttcctgtatctggcctcccattatgaaaaactgaagg gtagcccggaagataacgaacaaaagcagctgttcgtggaacaacataaa cactatctggacgagattattgagcaaatcagcgagttcagcaaacgcgt gattctggcggatgctaatctggacaaggttctttcagcctataataaac accgtgataagccgatccgtgaacaggcagaaaatattattcacctgttc accctgacgaacctgggtgcgccagcagcgtttaaatacttcgacacaac gatcgaccggaagcgttataccagcaccaaagaggttcttgacgccacct tgattcaccaaagcatcacgggtctgtatgaaacccgtattgacttgagc cagttgggcggagattcagggggaagtggcggaagcggtgggtctacgaa cctgagcgacattattgaaaaagaaactggtaaacagttggtgatccaag aatccattctgatgttaccggaggaagtggaagaggtgatcggcaacaag ccggagtccgacatcctggttcacaccgcgtatgatgagtcgaccgatga gaatgttatgctgctgaccagcgacgccccagagtacaaaccgtgggcgc tcgtcatccaggatagcaatggcgaaaacaagatcaagatgttgtctggc ggtagcatggctccgaaaaagaagcgtaaagtaggtattcatggtgttcc ggcatcaggttaa 29 Base editor evoFERNY- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcatttgagaggaattatgatcccagagaattgcgcaaagagacg tacctgctgtatgaaatcaagtggggtaaaagcggcaagctgtggcgtca ttggtgtcaaaacaaccgcacccaacacgcggaagtttatttcctcgaga atattttcaacgcccgtcgttttaacccgagcacccactgctccatcacc tggtatctttcttggtcgccgtgtgcggagtgctcgcaaaaaatcgtgga cttcctgaaagaacatccgaatgtgaacctggagatctatgttgcgagat tgtactatccggagaacgaacgtaatcgtcagggcctgcgcgacttggtc aacagcggggtgaccattcgtattatggatctgccggattacaattactg ctggaaaacctttgtttccgatcagggtggcgacgaagactactggcctg gtcactttgctccgtggattaagcagtacagcctgaagctgagcggtggt tcttccggcggtagcagtggctccgagactccaggtacgagcgagagcgc aaccccggaatctggaagtgagacacccgggacttcagaatccgcgaccc cggagtctggaatgccaaaacccgctgtagagtcagaattttcaaaagtt ttgaaaaagcactttccgggagaacgtttccgctcgagctatatgaaaag aggcggtaagatcctggctgcccaaggcgaagaggcagttgttgcgtatc tacagggcaagtccgaggaggagcctccgaacttccagccaccggcgaag tgccacgtggtgaccaaatcccgtgacttcgcggaatggccgatcatgaa ggcgtcggaagcgattcaacgttatatctatgcactgtcgaccaccgaac gcgcggcctgtaaaccgggcaaaagtagtgagagccatgcagcgtggttc gccgctaccggtgtcagcaaccacggctacagccacgttcagggtctgaa cctgatttttgatcataccttgggccgttacgatggtgttctgaaaaagg tccaactgcgcaacgaaaaggcgagagcgcgtttagagagcattaacgcg tctagagcagatgaaggtttaccggagattaaagccgaggaggaagaagt ggctacgaacgaaaccggccacctgttgcaaccgccgggtatcaatccga gcttttacgtgtatcagaccattagcccgcaggcataccgtccgcgtgac gagatcgtgctgccgccggagtacgcaggttacgtacgtgacccgaatgc tccgattccgctgggtgtggtgcgtaaccgttgcgatatccaaaaagggt gcccgggctacatcccggaatggcagcgtgaagcaggtaccgcgatcagc ccgaaaacaggcaaggccgtaactgtgccgggcctgtctccgaagaaaaa caaacgtatgcgtaggtactggcgctctgagaaggagaaagctcaagatg cgctgttggttaccgtacgcattggtaccgattgggttgtcatcgacgtg cgcggtctgttgcgcaacgcccgttggcgcaccatcgctcccaaggacat cagcctgaatgcgctcctcgatttgtttaccggtgatccggtgatcgatg tgcgtcgcaatattgttacctttacgtacaccctcgacgcctgtggtacc tacgcccgtaaatggaccttgaaaggcaaacagacgaaagcgaccctgga caaactgacggccactcagacggttgcgttggttgcgattgcgcttggtc agaccaacccgatttccgctggcattagccgtgttacacaagaaaatggt gcactgcaatgcgaaccgctggaccggttcaccctgccggatgacctgtt gaaggacatcagcgcatatcgcattgcttgggacagaaacgaagaggaac tacgcgctcgcagcgtcgaggccctgccggaggcgcaacaagcggaggtc cgtgcgctggacggggtgtccaaagaaaccgcgcgtacccaactgtgcgc agatttcggcctggacccgaaacgtctgccgtgggataaaatgagctcca atactacctttatcagcgaagccttgctgtctaacagcgtgagccgtgat caggtttttttcactccggctccgaagaagggtgctaagaaaaaagcgcc tgttgaagttatgcgtaaagaccgcacttgggcacgtgcgtacaagccgc gtctgagcgtcgaagctcagaaactgaagaacgaagccctgtgggcactt aagcgcacctccccggagtatttgaagctgagccgtcgcaaagaggagct gtgtcgtcgtagcatcaactatgttatcgaaaagacccgtcgccgtacgc aatgtcagattgtgatcccggtgatcgaggatctgaatgttcgcttcttt catggttctggtaagagactgcccggttgggataatttcttcaccgctaa aaaagagaaccgttggttcatccagggcctgcacaaagcgtttagcgatc tgcgtacgcaccgttccttctatgtttttgaagttcgtccggagcgcacc tctattacctgtccaaagtgcggtcattgcgaggtgggtaatcgtgacgg tgaggcgtttcagtgcctgagctgcggcaagacgtgcaacgcagatcttg acgtcgcgacccataatctgacccaagtggcgttgaccggtaagaccatg ccgaagcgcgaggagccgcgtgacgctcagggtacagcgccagcgcgcaa gactaagaaggcgagcaaatcaaaggcgccaccggcggagcgcgaagacc agaccccggcgcaagagccaagccagaccagttctggaggtagcgggggt agcggtggtagcactaacttaagtgatattatcgagaaagaaaccgggaa acagctggtgatccaagaaagcattctgatgctgcccgaagaagttgaag aagtgattggtaacaagcctgagtcggacatcttagtgcacaccgcgtac gatgaaagcacggatgagaatgtgatgctgctcacctctgatgcccccga atacaagccgtgggctctggtgatccaggactctaacggagaaaacaaaa ttaagatgctctctggcggctccatggcgcctaaaaaaaaacgcaaagtg gggattcacggggttccggcgtaa 30 Base editor evoFERNY- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcatttgagaggaattatgatcccagagaattgcgcaaagagacg tacctgctgtatgaaatcaagtggggtaaaagcggcaagctgtggcgtca ttggtgtcaaaacaaccgcacccaacacgcggaagtttatttcctcgaga atattttcaacgcccgtcgttttaacccgagcacccactgctccatcacc tggtatctttcttggtcgccgtgtgcggagtgctcgcaaaaaatcgtgga cttcctgaaagaacatccgaatgtgaacctggagatctatgttgcgagat tgtactatccggagaacgaacgtaatcgtcagggcctgcgcgacttggtc aacagcggggtgaccattcgtattatggatctgccggattacaattactg ctggaaaacctttgtttccgatcagggtggcgacgaagactactggcctg gtcactttgctccgtggattaagcagtacagcctgaagctgagcggtggt tcttccggcggtagcagtggctccgagactccaggtacgagcgagagcgc aaccccggaatctggaagtgagacacccgggacttcagaatccgcgaccc cggagtctggaatgtcaaaactagaaaagtttacaaattgttactccctg tcgaaaaccctgagattcaaagcgatcccggtgggtaaaactcaagagaa cattgataacaaacgtctgctggttgaggacgaaaagcgcgcggaggatt acaaaggcgttaaaaagctgttggaccgttattacctgtcctttattaat gatgttctgcacagcattaaattaaagaacctaaacaattacatctccct cttccgtaaaaagacccgcaccgaaaaggaaaataaagaactggagaacc ttgagattaatctgcgtaaagaaatcgctaaagcgtttaaaggcaacgag ggttataaatccttatttaaaaaagacatcatcgaaacgattctcccaga attcctggacgacaaagacgagatcgcgctggttaattccttcaacggct ttaccaccgcattcaccggcttttttgataaccgcgaaaacatgttctct gaagaggccaaaagcacctcaattgcgtttcgctgcattaacgaaaatct gacgcgttatatctctaacatggatatcttcgagaaggttgacgctatct ttgataaacatgaagtccaggagatcaaggagaagatcctgaacagcgac tacgacgtggaggatttcttcgagggtgagttcttcaattttgttttgac ccaagaaggcatcgatgtctacaatgcgataattggtggttttgttaccg agagcggggagaaaattaagggtctgaacgaatatatcaacttgtacaac cagaaaaccaaacaaaaactgccgaagtttaagccgctgtacaagcaagt cttgtcggatcgtgaatcgctgagcttttacggcgaaggctacaccagcg atgaggaggtgttggaggtgttccgcaatacgttgaataagaactctgaa attttttccagcattaagaagctggaaaaactattcaagaacttcgacga gtatagcagcgcaggtatctttgtgaaaaacggtccggctattagcacca tctcgaaagacattttcggcgaatggaatgttattcgtgataagtggaat gccgaatacgacgacattcatctgaagaaaaaggcggttgtaactgaaaa gtacgaggacgatcgtcgtaagtcgttcaaaaagatcggctccttctctc tggagcaactgcaagagtacgccgatgccgatttgtcagtcgtggagaag ctgaaagagatcatcattcaaaaagttgacgaaatctataaggtctatgg tagcagtgaaaaactgtttgacgcggacttcgtgctggagaaaagcctga agaaaaatgacgccgtggtggcaatcatgaaagatcttctggatagcgtc aagtctttcgaaaactacatcaaagcgtttttcggtgaaggcaaggaaac gaatcgtgacgagagcttctatggtgatttcgtcctagcctatgatatcc tgcttaaggtggatcacatctatgatgccatccgcaactatgttacccag aaaccgtactcaaaggacaagttcaagttatacttccagaatccgcagtt tatgggtggctgggataaagataaggaaaccgactatcgcgccaccattt tacgttacggtagtaagtactatctggcaatcatggataaaaaatatgcg aaatgcctgcaaaagatcgacaaggacgatgttaacggcaattatgagaa gatcaactacaaactgctgccgggcccaaataagatgctgccgaaggtgt ttttcagcaaaaaatggatggcgtattacaatccgagcgaggacatccaa aagatctacaaaaacggtacgtttaagaagggtgatatgttcaacctcaa cgattgtcataaacttattgacttcttcaaggatagcatatctcgttatc cgaagtggagcaacgcgtatgactttaactttagcgaaaccgagaaatac aaagatatcgcgggtttctatcgtgaagttgaagaacagggttacaaagt gtccttcgagtccgcgagcaagaaggaggtagacaagctggtcgaggagg gtaagttgtacatgtttcagatttacaataaggacttttccgacaagtcc catggtacaccgaatttgcacaccatgtatttcaagcttctgttcgacga gaacaaccacggccagatccgtctgagcggtggtgcagagctgttcatgc gtagagctagcctgaagaaagaagagttggtcgttcatccggctaattcg ccgatcgcgaacaaaaatccagataaccctaaaaagactacgaccctgag ctatgatgtgtataaagacaaacgctttagcgaagaccagtatgagttac acattccgatcgctatcaacaagtgcccgaagaatattttcaagatcaac accgaagtgcgtgttcttttgaagcacgatgacaacccgtatgtgattgg tattgctcgtggtgaacgtaatctgctgtacattgtggttgtggacggca aaggaaacatcgtggaacagtacagcctgaacgaaatcattaacaatttc aacggcattcgcattaagacggattaccattctttgctggacaaaaagga gaaagagcgtttcgaggcccgtcagaactggacctccatcgagaacatta aggagctgaaggcgggttacatcagccaggtggtgcacaaaatctgcgaa ctggtggagaagtacgacgcggtgattgctttggcggatttgaactccgg ttttaagaacagccgcgttaaagtggaaaagcaggtttatcagaaattcg aaaaaatgctgattgataaattgaattacatggttgacaaaaagtctaac ccgtgtgcaaccggcggtgcgctgaagggctaccaaatcaccaataagtt tgaaagctttaagagcatgagcacgcaaaatggcttcattttttacattc cggcgtggctgaccagcaagatcgatccgtcaaccggctttgttaattta ctgaagacgaagtatacctctattgccgactctaaaaaatttattagttc cttcgatagaatcatgtatgttccggaagaggacctgttcgaatttgcac tggactacaagaactttagccgtaccgatgctgattatataaagaaatgg aaactctacagctatggcaaccgcatccgtatctttcgcaacccgaaaaa aaacaacgtgttcgactgggaagaggtatgtctgacttcagcgtacaagg agcttttcaataaatatggtatcaactaccagcagggtgatatccgtgca ctgctttgcgagcaaagcgataaagcgttctattcaagcttcatggcgct gatgagcctgatgctgcaaatgcgcaacagcatcaccggtcgtaccgatg ttgcatttctgatttctccagtaaaaaacagcgatggtatcttttacgac agccgtaattacgaggcccaagaaaatgcgattttgccgaagaacgctga cgcgaatggtgcatacaacattgcaaggaaagttctgtgggcaatcggcc aatttaaaaaagcggaagatgagaagctggacaaagtgaaaattgcgatt agcaacaaggagtggctggagtatgcgcagacctccgttaaatcaggggg aagtggcggaagcggtgggtctacgaacctgagcgacattattgaaaaag aaactggtaaacagttggtgatccaagaatccattctgatgttaccggag gaagtggaagaggtgatcggcaacaagccggagtccgacatcctggttca caccgcgtatgatgagtcgaccgatgagaatgttatgctgctgaccagcg acgccccagagtacaaaccgtgggcgctcgtcatccaggatagcaatggc gaaaacaagatcaagatgttgtctggcggtagcatggctccgaaaaagaa gcgtaaagtaggtattcatggtgttccggcatcaggttaa 31 Base editor hA3G-CTD-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggatcccccaacatttactttcaactttaataacgaaccgtgggtt cgcggtcgccacgaaacctacctgtgctatgaggtggaacgtatgcataa tgatacttgggttctgctgaatcaacgtagaggctttttatgcaaccaag ctccgcataaacatggttttctggaaggccgtcacgccgagctgtgcttc cttgacgtgatcccattctggaaactggacttggaccaggattatcgtgt gacctgtttcaccagctggtcgccgtgcttcagctgtgcgcaggagatgg cgaagttcatctccaaaaacaagcacgttagcttgtgcatttttaccgcg cgtatttacgatgatcaaggtcgctgccaagagggcctgcgtaccctggc agaggctggtgcgaagatctctatcatgacgtacagcgaatttaaacact gctgggacacgtttgtcgatcaccagggttgtccgttccagccgtgggac ggcttggacgaacatagccaggatttgtccggtcgtctgcgcgcaattct acagaatcaagagaactctggaagtgagacacccgggacttcagaatccg cgaccccggagtctggaatggataaaaagtattcaataggactagctatt ggcaccaacagcgttggttgggcagttatcaccgatgaatataaggtccc gagcaagaagtttaaggtcctgggcaacaccgatcgccacagcataaaaa agaaccttattggtgcgctgctgttcgattctggtgagactgccgaagcg acccgtctgaagagaaccgcgcgtcgtagatacacccggcgcaagaaccg tatctgctatctgcaagaaattttcagcaacgagatggctaaggtcgacg actccttctttcatcgcctggaggaaagctttctggttgaggaagacaaa aagcacgagcgtcatccgattttcggtaacattgttgatgaagttgccta ccacgaaaaataccccacaatttatcatctgcgtaaaaaactggtagact ccaccgataaggcggatttacgccttatctatttggcgctggcgcatatg attaagttccgcggtcattttttgatcgagggcgacctgaatccggataa cagcgacgttgacaaactgtttatccagctggtgcagacctataaccagt tgttcgaagagaacccgattaatgcgtctggcgtggacgcgaaggcgatc ctgagcgctcgtctgtccaagtcacgccgcctggagaacttgatcgcgca actgccgggtgagaagaaaaacggcttgttcggcaatctgattgctctgt ccctaggtttgaccccgaatttcaaatctaattttgatctggcggaagat gcgaaattacagttgagcaaggacacttacgatgacgatctggacaacct gctcgctcagatcggcgatcagtatgccgatcttttcctggccgcgaaga acctgagcgatgccatcttgctatcggacatcttacgtgttaacaccgaa atcaccaaagctccgctaagcgcgtccatgattaaacgttacgatgaaca ccaccaggatctgacgctgctgaaagcgttggtgcgccagcaactgccgg aaaaatacaaggaaattttcttcgaccaaagcaagaacggttatgcaggc tatatcgacggtggtgcgtcgcaagaagaattttataaattcatcaaacc gattttggagaagatggatggtaccgaggagctgctggtaaaattgaatc gggaagacctcttgcgaaagcagcgtactttcgataatggtagcatcccg caccagattcatctgggcgaacttcacgcaatcctacgtcgtcaagagga tttctacccgtttctgaaggataaccgtgaaaagatcgagaagattctga cctttcgtattccgtattatgtgggtccgctggcgagaggcaacagccgt tttgcgtggatgacccgcaagtcggaagagactatcacgccgtggaattt cgaggaggtcgtggacaagggtgcatcagcgcaatcttttattgaacgta tgaccaattttgataaaaaccttccaaatgaaaaagtgttgccgaagcac agcttgctgtacgagtatttcaccgtttacaatgaactgacgaaagtcaa gtacgttaccgaaggtatgcgtaagccagcctttctgtctggggagcaaa aaaaagccattgtggatctgctgttcaagaccaatcgcaaggttaccgtc aagcaactgaaagaggattacttcaaaaaaatcgaatgttttgactccgt ggaaatcagcggcgttgaagaccgctttaatgcatctctgggcacctacc acgatctactcaagatcatcaaggataaggacttcctggacaacgaagaa aatgaggatatcttggaagatattgtgctgactttaacgttgttcgagga tcgtgagatgattgaagaacgcctcaaaacgtacgcacatctgtttgacg ataaggtgatgaaacagctaaagcgccgtcgttacaccggttggggtcgt ctgtctagaaagctgattaacggcattcgtgacaaacaatctggcaagac catcctggacttcctcaaatccgacggcttcgcaaatcgtaatttcatgc aactgatccatgatgatagcctgacctttaaagaagatattcagaaggct caagtgtccggccagggtgactcgctgcatgagcatatcgcgaatctggc tggctcccctgcgataaaaaaaggtattctccaaacggtgaaagttgtgg atgaactggttaaagtcatgggtcgtcataaaccggaaaacatcgtgatt gagatggcacgtgagaaccagaccacccagaaaggtcaaaaaaacagtcg tgagcgtatgaaacgtatcgaagaggggattaaggagttaggcagccaga ttctgaaggagcacccggttgagaacacccagctgcaaaacgagaagctc tacctgtattacctgcaaaacggccgtgacatgtatgttgaccaggagct ggacatcaatcgtctcagcgactacgacgtggatgctatcgtgccgcaga gctttctaaaagatgattccatcgacaataaagtgctcacccgtagcgac aagaaccgtggtaaaagcgacaacgtgccgagcgaggaagtagttaagaa aatgaaaaactactggcgtcagctattgaacgccaagcttatcacccagc gtaagtttgacaacttgacgaaggcagagcgtggcggcctgagcgagcta gacaaggcgggttttattaaacgccagctggtggaaactcgccagattac caaacacgttgcgcaaatcttggactcacgcatgaatacgaagtacgacg aaaacgataaattgatccgcgaggtgaaggtcataaccctgaaatctaaa ctggttagcgatttccggaaggactttcaattttataaagtccgggagat taacaactatcaccatgcacacgacgcttacttaaatgcggttgttggca cggccctgatcaagaagtacccgaaactggaaagcgagtttgtttatggt gactacaaggtgtatgacgttcgcaagatgattgcaaaatccgaacaaga gattggtaaggcgacggctaagtattttttctacagcaatatcatgaact tcttcaagactgaaatcaccctggcgaacggtgaaattcgtaaacgtccg ttgatcgaaaccaacggtgaaaccggtgaaatcgtttgggataaaggtag ggattttgcgaccgttcgtaaggtcctgagcatgccgcaggttaacatcg tgaaaaagaccgaagtgcagaccggcggtttctccaaggagagtatctta ccgaagcgcaacagtgacaagctgatcgcgcgtaaaaaagactgggatcc gaaaaaatacggcggctttgactccccgaccgtcgcgtacagcgtactgg tcgtggctaaagtggagaaaggcaaatcgaaaaagctgaaatccgttaaa gagttgctgggtattacgattatggaacgttcgagcttcgagaaaaatcc gatcgacttcctggaggccaaaggctacaaggaagttaaaaaagacctga tcattaaactgccgaagtacagcctgttcgagctcgagaacggtcgcaaa cgcatgctggcgagcgcgggtgagctccaaaaaggcaacgaattggctct gccgagcaagtacgtgaacttcctgtatctggcctcccattatgaaaaac tgaagggtagcccggaagataacgaacaaaagcagctgttcgtggaacaa cataaacactatctggacgagattattgagcaaatcagcgagttcagcaa acgcgtgattctggcggatgctaatctggacaaggttctttcagcctata ataaacaccgtgataagccgatccgtgaacaggcagaaaatattattcac ctgttcaccctgacgaacctgggtgcgccagcagcgtttaaatacttcga cacaacgatcgaccggaagcgttataccagcaccaaagaggttcttgacg ccaccttgattcaccaaagcatcacgggtctgtatgaaacccgtattgac ttgagccagttgggcggagattcagggggaagtggcggaagcggtgggtc tacgaacctgagcgacattattgaaaaagaaactggtaaacagttggtga tccaagaatccattctgatgttaccggaggaagtggaagaggtgatcggc aacaagccggagtccgacatcctggttcacaccgcgtatgatgagtcgac cgatgagaatgttatgctgctgaccagcgacgccccagagtacaaaccgt gggcgctcgtcatccaggatagcaatggcgaaaacaagatcaagatgttg tctggcggtagcatggctccgaaaaagaagcgtaaagtaggtattcatgg tgttccggcatcaggttaa 32 Base editor hA3G-CTD-dCasPhi-2 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggatcccccaacatttactttcaactttaataacgaaccgtgggtt cgcggtcgccacgaaacctacctgtgctatgaggtggaacgtatgcataa tgatacttgggttctgctgaatcaacgtagaggctttttatgcaaccaag ctccgcataaacatggttttctggaaggccgtcacgccgagctgtgcttc cttgacgtgatcccattctggaaactggacttggaccaggattatcgtgt gacctgtttcaccagctggtcgccgtgcttcagctgtgcgcaggagatgg cgaagttcatctccaaaaacaagcacgttagcttgtgcatttttaccgcg cgtatttacgatgatcaaggtcgctgccaagagggcctgcgtaccctggc agaggctggtgcgaagatctctatcatgacgtacagcgaatttaaacact gctgggacacgtttgtcgatcaccagggttgtccgttccagccgtgggac ggcttggacgaacatagccaggatttgtccggtcgtctgcgcgcaattct acagaatcaagagaactctggaagtgagacacccgggacttcagaatccg cgaccccggagtctggaatgccaaaacccgctgtagagtcagaattttca aaagttttgaaaaagcactttccgggagaacgtttccgctcgagctatat gaaaagaggcggtaagatcctggctgcccaaggcgaagaggcagttgttg cgtatctacagggcaagtccgaggaggagcctccgaacttccagccaccg gcgaagtgccacgtggtgaccaaatcccgtgacttcgcggaatggccgat catgaaggcgtcggaagcgattcaacgttatatctatgcactgtcgacca ccgaacgcgcggcctgtaaaccgggcaaaagtagtgagagccatgcagcg tggttcgccgctaccggtgtcagcaaccacggctacagccacgttcaggg tctgaacctgatttttgatcataccttgggccgttacgatggtgttctga aaaaggtccaactgcgcaacgaaaaggcgagagcgcgtttagagagcatt aacgcgtctagagcagatgaaggtttaccggagattaaagccgaggagga agaagtggctacgaacgaaaccggccacctgttgcaaccgccgggtatca atccgagcttttacgtgtatcagaccattagcccgcaggcataccgtccg cgtgacgagatcgtgctgccgccggagtacgcaggttacgtacgtgaccc gaatgctccgattccgctgggtgtggtgcgtaaccgttgcgatatccaaa aagggtgcccgggctacatcccggaatggcagcgtgaagcaggtaccgcg atcagcccgaaaacaggcaaggccgtaactgtgccgggcctgtctccgaa gaaaaacaaacgtatgcgtaggtactggcgctctgagaaggagaaagctc aagatgcgctgttggttaccgtacgcattggtaccgattgggttgtcatc gacgtgcgcggtctgttgcgcaacgcccgttggcgcaccatcgctcccaa ggacatcagcctgaatgcgctcctcgatttgtttaccggtgatccggtga tcgatgtgcgtcgcaatattgttacctttacgtacaccctcgacgcctgt ggtacctacgcccgtaaatggaccttgaaaggcaaacagacgaaagcgac cctggacaaactgacggccactcagacggttgcgttggttgcgattgcgc ttggtcagaccaacccgatttccgctggcattagccgtgttacacaagaa aatggtgcactgcaatgcgaaccgctggaccggttcaccctgccggatga cctgttgaaggacatcagcgcatatcgcattgcttgggacagaaacgaag aggaactacgcgctcgcagcgtcgaggccctgccggaggcgcaacaagcg gaggtccgtgcgctggacggggtgtccaaagaaaccgcgcgtacccaact gtgcgcagatttcggcctggacccgaaacgtctgccgtgggataaaatga gctccaatactacctttatcagcgaagccttgctgtctaacagcgtgagc cgtgatcaggtttttttcactccggctccgaagaagggtgctaagaaaaa agcgcctgttgaagttatgcgtaaagaccgcacttgggcacgtgcgtaca agccgcgtctgagcgtcgaagctcagaaactgaagaacgaagccctgtgg gcacttaagcgcacctccccggagtatttgaagctgagccgtcgcaaaga ggagctgtgtcgtcgtagcatcaactatgttatcgaaaagacccgtcgcc gtacgcaatgtcagattgtgatcccggtgatcgaggatctgaatgttcgc ttctttcatggttctggtaagagactgcccggttgggataatttcttcac cgctaaaaaagagaaccgttggttcatccagggcctgcacaaagcgttta gcgatctgcgtacgcaccgttccttctatgtttttgaagttcgtccggag cgcacctctattacctgtccaaagtgcggtcattgcgaggtgggtaatcg tgacggtgaggcgtttcagtgcctgagctgcggcaagacgtgcaacgcag atcttgacgtcgcgacccataatctgacccaagtggcgttgaccggtaag accatgccgaagcgcgaggagccgcgtgacgctcagggtacagcgccagc gcgcaagactaagaaggcgagcaaatcaaaggcgccaccggcggagcgcg aagaccagaccccggcgcaagagccaagccagaccagttctggaggtagc gggggtagcggtggtagcactaacttaagtgatattatcgagaaagaaac cgggaaacagctggtgatccaagaaagcattctgatgctgcccgaagaag ttgaagaagtgattggtaacaagcctgagtcggacatcttagtgcacacc gcgtacgatgaaagcacggatgagaatgtgatgctgctcacctctgatgc ccccgaatacaagccgtgggctctggtgatccaggactctaacggagaaa acaaaattaagatgctctctggcggctccatggcgcctaaaaaaaaacgc aaagtggggattcacggggttccggcgtaa 33 Base editor hA3G-CTD-dLbCas12a atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggatcccccaacatttactttcaactttaataacgaaccgtgggtt cgcggtcgccacgaaacctacctgtgctatgaggtggaacgtatgcataa tgatacttgggttctgctgaatcaacgtagaggctttttatgcaaccaag ctccgcataaacatggttttctggaaggccgtcacgccgagctgtgcttc cttgacgtgatcccattctggaaactggacttggaccaggattatcgtgt gacctgtttcaccagctggtcgccgtgcttcagctgtgcgcaggagatgg cgaagttcatctccaaaaacaagcacgttagcttgtgcatttttaccgcg cgtatttacgatgatcaaggtcgctgccaagagggcctgcgtaccctggc agaggctggtgcgaagatctctatcatgacgtacagcgaatttaaacact gctgggacacgtttgtcgatcaccagggttgtccgttccagccgtgggac ggcttggacgaacatagccaggatttgtccggtcgtctgcgcgcaattct acagaatcaagagaactctggaagtgagacacccgggacttcagaatccg cgaccccggagtctggaatgtcaaaactagaaaagtttacaaattgttac tccctgtcgaaaaccctgagattcaaagcgatcccggtgggtaaaactca agagaacattgataacaaacgtctgctggttgaggacgaaaagcgcgcgg aggattacaaaggcgttaaaaagctgttggaccgttattacctgtccttt attaatgatgttctgcacagcattaaattaaagaacctaaacaattacat ctccctcttccgtaaaaagacccgcaccgaaaaggaaaataaagaactgg agaaccttgagattaatctgcgtaaagaaatcgctaaagcgtttaaaggc aacgagggttataaatccttatttaaaaaagacatcatcgaaacgattct cccagaattcctggacgacaaagacgagatcgcgctggttaattccttca acggctttaccaccgcattcaccggcttttttgataaccgcgaaaacatg ttctctgaagaggccaaaagcacctcaattgcgtttcgctgcattaacga aaatctgacgcgttatatctctaacatggatatcttcgagaaggttgacg ctatctttgataaacatgaagtccaggagatcaaggagaagatcctgaac agcgactacgacgtggaggatttcttcgagggtgagttcttcaattttgt tttgacccaagaaggcatcgatgtctacaatgcgataattggtggttttg ttaccgagagcggggagaaaattaagggtctgaacgaatatatcaacttg tacaaccagaaaaccaaacaaaaactgccgaagtttaagccgctgtacaa gcaagtcttgtcggatcgtgaatcgctgagcttttacggcgaaggctaca ccagcgatgaggaggtgttggaggtgttccgcaatacgttgaataagaac tctgaaattttttccagcattaagaagctggaaaaactattcaagaactt cgacgagtatagcagcgcaggtatctttgtgaaaaacggtccggctatta gcaccatctcgaaagacattttcggcgaatggaatgttattcgtgataag tggaatgccgaatacgacgacattcatctgaagaaaaaggcggttgtaac tgaaaagtacgaggacgatcgtcgtaagtcgttcaaaaagatcggctcct tctctctggagcaactgcaagagtacgccgatgccgatttgtcagtcgtg gagaagctgaaagagatcatcattcaaaaagttgacgaaatctataaggt ctatggtagcagtgaaaaactgtttgacgcggacttcgtgctggagaaaa gcctgaagaaaaatgacgccgtggtggcaatcatgaaagatcttctggat agcgtcaagtctttcgaaaactacatcaaagcgtttttcggtgaaggcaa ggaaacgaatcgtgacgagagcttctatggtgatttcgtcctagcctatg atatcctgcttaaggtggatcacatctatgatgccatccgcaactatgtt acccagaaaccgtactcaaaggacaagttcaagttatacttccagaatcc gcagtttatgggtggctgggataaagataaggaaaccgactatcgcgcca ccattttacgttacggtagtaagtactatctggcaatcatggataaaaaa tatgcgaaatgcctgcaaaagatcgacaaggacgatgttaacggcaatta tgagaagatcaactacaaactgctgccgggcccaaataagatgctgccga aggtgtttttcagcaaaaaatggatggcgtattacaatccgagcgaggac atccaaaagatctacaaaaacggtacgtttaagaagggtgatatgttcaa cctcaacgattgtcataaacttattgacttcttcaaggatagcatatctc gttatccgaagtggagcaacgcgtatgactttaactttagcgaaaccgag aaatacaaagatatcgcgggtttctatcgtgaagttgaagaacagggtta caaagtgtccttcgagtccgcgagcaagaaggaggtagacaagctggtcg aggagggtaagttgtacatgtttcagatttacaataaggacttttccgac aagtcccatggtacaccgaatttgcacaccatgtatttcaagcttctgtt cgacgagaacaaccacggccagatccgtctgagcggtggtgcagagctgt tcatgcgtagagctagcctgaagaaagaagagttggtcgttcatccggct aattcgccgatcgcgaacaaaaatccagataaccctaaaaagactacgac cctgagctatgatgtgtataaagacaaacgctttagcgaagaccagtatg agttacacattccgatcgctatcaacaagtgcccgaagaatattttcaag atcaacaccgaagtgcgtgttcttttgaagcacgatgacaacccgtatgt gattggtattgctcgtggtgaacgtaatctgctgtacattgtggttgtgg acggcaaaggaaacatcgtggaacagtacagcctgaacgaaatcattaac aatttcaacggcattcgcattaagacggattaccattctttgctggacaa aaaggagaaagagcgtttcgaggcccgtcagaactggacctccatcgaga acattaaggagctgaaggcgggttacatcagccaggtggtgcacaaaatc tgcgaactggtggagaagtacgacgcggtgattgctttggcggatttgaa ctccggttttaagaacagccgcgttaaagtggaaaagcaggtttatcaga aattcgaaaaaatgctgattgataaattgaattacatggttgacaaaaag tctaacccgtgtgcaaccggcggtgcgctgaagggctaccaaatcaccaa taagtttgaaagctttaagagcatgagcacgcaaaatggcttcatttttt acattccggcgtggctgaccagcaagatcgatccgtcaaccggctttgtt aatttactgaagacgaagtatacctctattgccgactctaaaaaatttat tagttccttcgatagaatcatgtatgttccggaagaggacctgttcgaat ttgcactggactacaagaactttagccgtaccgatgctgattatataaag aaatggaaactctacagctatggcaaccgcatccgtatctttcgcaaccc gaaaaaaaacaacgtgttcgactgggaagaggtatgtctgacttcagcgt acaaggagcttttcaataaatatggtatcaactaccagcagggtgatatc cgtgcactgctttgcgagcaaagcgataaagcgttctattcaagcttcat ggcgctgatgagcctgatgctgcaaatgcgcaacagcatcaccggtcgta ccgatgttgcatttctgatttctccagtaaaaaacagcgatggtatcttt tacgacagccgtaattacgaggcccaagaaaatgcgattttgccgaagaa cgctgacgcgaatggtgcatacaacattgcaaggaaagttctgtgggcaa tcggccaatttaaaaaagcggaagatgagaagctggacaaagtgaaaatt gcgattagcaacaaggagtggctggagtatgcgcagacctccgttaaatc agggggaagtggcggaagcggtgggtctacgaacctgagcgacattattg aaaaagaaactggtaaacagttggtgatccaagaatccattctgatgtta ccggaggaagtggaagaggtgatcggcaacaagccggagtccgacatcct ggttcacaccgcgtatgatgagtcgaccgatgagaatgttatgctgctga ccagcgacgccccagagtacaaaccgtgggcgctcgtcatccaggatagc aatggcgaaaacaagatcaagatgttgtctggcggtagcatggctccgaa aaagaagcgtaaagtaggtattcatggtgttccggcatcaggttaa 34 Base editor minStart-dCas9 atgggcagccaccaccaccaccaccacagcggcgagaacctgtacttcca gtccatggctccaaagaagaagagaaaggttggaatccacggagttccag cttctggaatggataaaaagtattcaataggactagctattggcaccaac agcgttggttgggcagttatcaccgatgaatataaggtcccgagcaagaa gtttaaggtcctgggcaacaccgatcgccacagcataaaaaagaacctta ttggtgcgctgctgttcgattctggtgagactgccgaagcgacccgtctg aagagaaccgcgcgtcgtagatacacccggcgcaagaaccgtatctgcta tctgcaagaaattttcagcaacgagatggctaaggtcgacgactccttct ttcatcgcctggaggaaagctttctggttgaggaagacaaaaagcacgag cgtcatccgattttcggtaacattgttgatgaagttgcctaccacgaaaa ataccccacaatttatcatctgcgtaaaaaactggtagactccaccgata aggcggatttacgccttatctatttggcgctggcgcatatgattaagttc cgcggtcattttttgatcgagggcgacctgaatccggataacagcgacgt tgacaaactgtttatccagctggtgcagacctataaccagttgttcgaag agaacccgattaatgcgtctggcgtggacgcgaaggcgatcctgagcgct cgtctgtccaagtcacgccgcctggagaacttgatcgcgcaactgccggg tgagaagaaaaacggcttgttcggcaatctgattgctctgtccctaggtt tgaccccgaatttcaaatctaattttgatctggcggaagatgcgaaatta cagttgagcaaggacacttacgatgacgatctggacaacctgctcgctca gatcggcgatcagtatgccgatcttttcctggccgcgaagaacctgagcg atgccatcttgctatcggacatcttacgtgttaacaccgaaatcaccaaa gctccgctaagcgcgtccatgattaaacgttacgatgaacaccaccagga tctgacgctgctgaaagcgttggtgcgccagcaactgccggaaaaataca aggaaattttcttcgaccaaagcaagaacggttatgcaggctatatcgac ggtggtgcgtcgcaagaagaattttataaattcatcaaaccgattttgga gaagatggatggtaccgaggagctgctggtaaaattgaatcgggaagacc tcttgcgaaagcagcgtactttcgataatggtagcatcccgcaccagatt catctgggcgaacttcacgcaatcctacgtcgtcaagaggatttctaccc gtttctgaaggataaccgtgaaaagatcgagaagattctgacctttcgta ttccgtattatgtgggtccgctggcgagaggcaacagccgttttgcgtgg atgacccgcaagtcggaagagactatcacgccgtggaatttcgaggaggt cgtggacaagggtgcatcagcgcaatcttttattgaacgtatgaccaatt ttgataaaaaccttccaaatgaaaaagtgttgccgaagcacagcttgctg tacgagtatttcaccgtttacaatgaactgacgaaagtcaagtacgttac cgaaggtatgcgtaagccagcctttctgtctggggagcaaaaaaaagcca ttgtggatctgctgttcaagaccaatcgcaaggttaccgtcaagcaactg aaagaggattacttcaaaaaaatcgaatgttttgactccgtggaaatcag cggcgttgaagaccgctttaatgcatctctgggcacctaccacgatctac tcaagatcatcaaggataaggacttcctggacaacgaagaaaatgaggat atcttggaagatattgtgctgactttaacgttgttcgaggatcgtgagat gattgaagaacgcctcaaaacgtacgcacatctgtttgacgataaggtga tgaaacagctaaagcgccgtcgttacaccggttggggtcgtctgtctaga aagctgattaacggcattcgtgacaaacaatctggcaagaccatcctgga cttcctcaaatccgacggcttcgcaaatcgtaatttcatgcaactgatcc atgatgatagcctgacctttaaagaagatattcagaaggctcaagtgtcc ggccagggtgactcgctgcatgagcatatcgcgaatctggctggctcccc tgcgataaaaaaaggtattctccaaacggtgaaagttgtggatgaactgg ttaaagtcatgggtcgtcataaaccggaaaacatcgtgattgagatggca cgtgagaaccagaccacccagaaaggtcaaaaaaacagtcgtgagcgtat gaaacgtatcgaagaggggattaaggagttaggcagccagattctgaagg agcacccggttgagaacacccagctgcaaaacgagaagctctacctgtat tacctgcaaaacggccgtgacatgtatgttgaccaggagctggacatcaa tcgtctcagcgactacgacgtggatgctatcgtgccgcagagctttctaa aagatgattccatcgacaataaagtgctcacccgtagcgacaagaaccgt ggtaaaagcgacaacgtgccgagcgaggaagtagttaagaaaatgaaaaa ctactggcgtcagctattgaacgccaagcttatcacccagcgtaagtttg acaacttgacgaaggcagagcgtggcggcctgagcgagctagacaaggcg ggttttattaaacgccagctggtggaaactcgccagattaccaaacacgt tgcgcaaatcttggactcacgcatgaatacgaagtacgacgaaaacgata aattgatccgcgaggtgaaggtcataaccctgaaatctaaactggttagc gatttccggaaggactttcaattttataaagtccgggagattaacaacta tcaccatgcacacgacgcttacttaaatgcggttgttggcacggccctga tcaagaagtacccgaaactggaaagcgagtttgtttatggtgactacaag gtgtatgacgttcgcaagatgattgcaaaatccgaacaagagattggtaa ggcgacggctaagtattttttctacagcaatatcatgaacttcttcaaga ctgaaatcaccctggcgaacggtgaaattcgtaaacgtccgttgatcgaa accaacggtgaaaccggtgaaatcgtttgggataaaggtagggattttgc gaccgttcgtaaggtcctgagcatgccgcaggttaacatcgtgaaaaaga ccgaagtgcagaccggcggtttctccaaggagagtatcttaccgaagcgc aacagtgacaagctgatcgcgcgtaaaaaagactgggatccgaaaaaata cggcggctttgactccccgaccgtcgcgtacagcgtactggtcgtggcta aagtggagaaaggcaaatcgaaaaagctgaaatccgttaaagagttgctg ggtattacgattatggaacgttcgagcttcgagaaaaatccgatcgactt cctggaggccaaaggctacaaggaagttaaaaaagacctgatcattaaac tgccgaagtacagcctgttcgagctcgagaacggtcgcaaacgcatgctg gcgagcgcgggtgagctccaaaaaggcaacgaattggctctgccgagcaa gtacgtgaacttcctgtatctggcctcccattatgaaaaactgaagggta gcccggaagataacgaacaaaagcagctgttcgtggaacaacataaacac tatctggacgagattattgagcaaatcagcgagttcagcaaacgcgtgat tctggcggatgctaatctggacaaggttctttcagcctataataaacacc gtgataagccgatccgtgaacaggcagaaaatattattcacctgttcacc ctgacgaacctgggtgcgccagcagcgtttaaatacttcgacacaacgat cgaccggaagcgttataccagcaccaaagaggttcttgacgccaccttga ttcaccaaagcatcacgggtctgtatgaaacccgtattgacttgagccag ttgggcggagattcagggggaagtggcggaagcggtgggtctacgaacct gagcgacattattgaaaaagaaactggtaaacagttggtgatccaagaat ccattctgatgttaccggaggaagtggaagaggtgatcggcaacaagccg gagtccgacatcctggttcacaccgcgtatgatgagtcgaccgatgagaa tgttatgctgctgaccagcgacgccccagagtacaaaccgtgggcgctcg tcatccaggatagcaatggcgaaaacaagatcaagatgttgtctggcggt agcatggctccgaaaaagaagcgtaaagtaggtattcatggtgttccggc atcaggttaa 35 Base editor minStart-dCasPhi-2 atgggcagccaccaccaccaccaccacagcggcgagaacctgtacttcca gtccatggctccaaagaagaagagaaaggttggaatccacggagttccag cttctggaatgccaaaacccgctgtagagtcagaattttcaaaagttttg aaaaagcactttccgggagaacgtttccgctcgagctatatgaaaagagg cggtaagatcctggctgcccaaggcgaagaggcagttgttgcgtatctac agggcaagtccgaggaggagcctccgaacttccagccaccggcgaagtgc cacgtggtgaccaaatcccgtgacttcgcggaatggccgatcatgaaggc gtcggaagcgattcaacgttatatctatgcactgtcgaccaccgaacgcg cggcctgtaaaccgggcaaaagtagtgagagccatgcagcgtggttcgcc gctaccggtgtcagcaaccacggctacagccacgttcagggtctgaacct gatttttgatcataccttgggccgttacgatggtgttctgaaaaaggtcc aactgcgcaacgaaaaggcgagagcgcgtttagagagcattaacgcgtct agagcagatgaaggtttaccggagattaaagccgaggaggaagaagtggc tacgaacgaaaccggccacctgttgcaaccgccgggtatcaatccgagct tttacgtgtatcagaccattagcccgcaggcataccgtccgcgtgacgag atcgtgctgccgccggagtacgcaggttacgtacgtgacccgaatgctcc gattccgctgggtgtggtgcgtaaccgttgcgatatccaaaaagggtgcc cgggctacatcccggaatggcagcgtgaagcaggtaccgcgatcagcccg aaaacaggcaaggccgtaactgtgccgggcctgtctccgaagaaaaacaa acgtatgcgtaggtactggcgctctgagaaggagaaagctcaagatgcgc tgttggttaccgtacgcattggtaccgattgggttgtcatcgacgtgcgc ggtctgttgcgcaacgcccgttggcgcaccatcgctcccaaggacatcag cctgaatgcgctcctcgatttgtttaccggtgatccggtgatcgatgtgc gtcgcaatattgttacctttacgtacaccctcgacgcctgtggtacctac gcccgtaaatggaccttgaaaggcaaacagacgaaagcgaccctggacaa actgacggccactcagacggttgcgttggttgcgattgcgcttggtcaga ccaacccgatttccgctggcattagccgtgttacacaagaaaatggtgca ctgcaatgcgaaccgctggaccggttcaccctgccggatgacctgttgaa ggacatcagcgcatatcgcattgcttgggacagaaacgaagaggaactac gcgctcgcagcgtcgaggccctgccggaggcgcaacaagcggaggtccgt gcgctggacggggtgtccaaagaaaccgcgcgtacccaactgtgcgcaga tttcggcctggacccgaaacgtctgccgtgggataaaatgagctccaata ctacctttatcagcgaagccttgctgtctaacagcgtgagccgtgatcag gtttttttcactccggctccgaagaagggtgctaagaaaaaagcgcctgt tgaagttatgcgtaaagaccgcacttgggcacgtgcgtacaagccgcgtc tgagcgtcgaagctcagaaactgaagaacgaagccctgtgggcacttaag cgcacctccccggagtatttgaagctgagccgtcgcaaagaggagctgtg tcgtcgtagcatcaactatgttatcgaaaagacccgtcgccgtacgcaat gtcagattgtgatcccggtgatcgaggatctgaatgttcgcttctttcat ggttctggtaagagactgcccggttgggataatttcttcaccgctaaaaa agagaaccgttggttcatccagggcctgcacaaagcgtttagcgatctgc gtacgcaccgttccttctatgtttttgaagttcgtccggagcgcacctct attacctgtccaaagtgcggtcattgcgaggtgggtaatcgtgacggtga ggcgtttcagtgcctgagctgcggcaagacgtgcaacgcagatcttgacg tcgcgacccataatctgacccaagtggcgttgaccggtaagaccatgccg aagcgcgaggagccgcgtgacgctcagggtacagcgccagcgcgcaagac taagaaggcgagcaaatcaaaggcgccaccggcggagcgcgaagaccaga ccccggcgcaagagccaagccagaccagttctggaggtagcgggggtagc ggtggtagcactaacttaagtgatattatcgagaaagaaaccgggaaaca gctggtgatccaagaaagcattctgatgctgcccgaagaagttgaagaag tgattggtaacaagcctgagtcggacatcttagtgcacaccgcgtacgat gaaagcacggatgagaatgtgatgctgctcacctctgatgcccccgaata caagccgtgggctctggtgatccaggactctaacggagaaaacaaaatta agatgctctctggcggctccatggcgcctaaaaaaaaacgcaaagtgggg attcacggggttccggcgtaa 36 Base editor minStart-dLbCas12a atgggcagccaccaccaccaccaccacagcggcgagaacctgtacttcca gtccatggctccaaagaagaagagaaaggttggaatccacggagttccag cttctggaatgtcaaaactagaaaagtttacaaattgttactccctgtcg aaaaccctgagattcaaagcgatcccggtgggtaaaactcaagagaacat tgataacaaacgtctgctggttgaggacgaaaagcgcgcggaggattaca aaggcgttaaaaagctgttggaccgttattacctgtcctttattaatgat gttctgcacagcattaaattaaagaacctaaacaattacatctccctctt ccgtaaaaagacccgcaccgaaaaggaaaataaagaactggagaaccttg agattaatctgcgtaaagaaatcgctaaagcgtttaaaggcaacgagggt tataaatccttatttaaaaaagacatcatcgaaacgattctcccagaatt cctggacgacaaagacgagatcgcgctggttaattccttcaacggcttta ccaccgcattcaccggcttttttgataaccgcgaaaacatgttctctgaa gaggccaaaagcacctcaattgcgtttcgctgcattaacgaaaatctgac gcgttatatctctaacatggatatcttcgagaaggttgacgctatctttg ataaacatgaagtccaggagatcaaggagaagatcctgaacagcgactac gacgtggaggatttcttcgagggtgagttcttcaattttgttttgaccca agaaggcatcgatgtctacaatgcgataattggtggttttgttaccgaga gcggggagaaaattaagggtctgaacgaatatatcaacttgtacaaccag aaaaccaaacaaaaactgccgaagtttaagccgctgtacaagcaagtctt gtcggatcgtgaatcgctgagcttttacggcgaaggctacaccagcgatg aggaggtgttggaggtgttccgcaatacgttgaataagaactctgaaatt ttttccagcattaagaagctggaaaaactattcaagaacttcgacgagta tagcagcgcaggtatctttgtgaaaaacggtccggctattagcaccatct cgaaagacattttcggcgaatggaatgttattcgtgataagtggaatgcc gaatacgacgacattcatctgaagaaaaaggcggttgtaactgaaaagta cgaggacgatcgtcgtaagtcgttcaaaaagatcggctccttctctctgg agcaactgcaagagtacgccgatgccgatttgtcagtcgtggagaagctg aaagagatcatcattcaaaaagttgacgaaatctataaggtctatggtag cagtgaaaaactgtttgacgcggacttcgtgctggagaaaagcctgaaga aaaatgacgccgtggtggcaatcatgaaagatcttctggatagcgtcaag tctttcgaaaactacatcaaagcgtttttcggtgaaggcaaggaaacgaa tcgtgacgagagcttctatggtgatttcgtcctagcctatgatatcctgc ttaaggtggatcacatctatgatgccatccgcaactatgttacccagaaa ccgtactcaaaggacaagttcaagttatacttccagaatccgcagtttat gggtggctgggataaagataaggaaaccgactatcgcgccaccattttac gttacggtagtaagtactatctggcaatcatggataaaaaatatgcgaaa tgcctgcaaaagatcgacaaggacgatgttaacggcaattatgagaagat caactacaaactgctgccgggcccaaataagatgctgccgaaggtgtttt tcagcaaaaaatggatggcgtattacaatccgagcgaggacatccaaaag atctacaaaaacggtacgtttaagaagggtgatatgttcaacctcaacga ttgtcataaacttattgacttcttcaaggatagcatatctcgttatccga agtggagcaacgcgtatgactttaactttagcgaaaccgagaaatacaaa gatatcgcgggtttctatcgtgaagttgaagaacagggttacaaagtgtc cttcgagtccgcgagcaagaaggaggtagacaagctggtcgaggagggta agttgtacatgtttcagatttacaataaggacttttccgacaagtcccat ggtacaccgaatttgcacaccatgtatttcaagcttctgttcgacgagaa caaccacggccagatccgtctgagcggtggtgcagagctgttcatgcgta gagctagcctgaagaaagaagagttggtcgttcatccggctaattcgccg atcgcgaacaaaaatccagataaccctaaaaagactacgaccctgagcta tgatgtgtataaagacaaacgctttagcgaagaccagtatgagttacaca ttccgatcgctatcaacaagtgcccgaagaatattttcaagatcaacacc gaagtgcgtgttcttttgaagcacgatgacaacccgtatgtgattggtat tgctcgtggtgaacgtaatctgctgtacattgtggttgtggacggcaaag gaaacatcgtggaacagtacagcctgaacgaaatcattaacaatttcaac ggcattcgcattaagacggattaccattctttgctggacaaaaaggagaa agagcgtttcgaggcccgtcagaactggacctccatcgagaacattaagg agctgaaggcgggttacatcagccaggtggtgcacaaaatctgcgaactg gtggagaagtacgacgcggtgattgctttggcggatttgaactccggttt taagaacagccgcgttaaagtggaaaagcaggtttatcagaaattcgaaa aaatgctgattgataaattgaattacatggttgacaaaaagtctaacccg tgtgcaaccggcggtgcgctgaagggctaccaaatcaccaataagtttga aagctttaagagcatgagcacgcaaaatggcttcattttttacattccgg cgtggctgaccagcaagatcgatccgtcaaccggctttgttaatttactg aagacgaagtatacctctattgccgactctaaaaaatttattagttcctt cgatagaatcatgtatgttccggaagaggacctgttcgaatttgcactgg actacaagaactttagccgtaccgatgctgattatataaagaaatggaaa ctctacagctatggcaaccgcatccgtatctttcgcaacccgaaaaaaaa caacgtgttcgactgggaagaggtatgtctgacttcagcgtacaaggagc ttttcaataaatatggtatcaactaccagcagggtgatatccgtgcactg ctttgcgagcaaagcgataaagcgttctattcaagcttcatggcgctgat gagcctgatgctgcaaatgcgcaacagcatcaccggtcgtaccgatgttg catttctgatttctccagtaaaaaacagcgatggtatcttttacgacagc cgtaattacgaggcccaagaaaatgcgattttgccgaagaacgctgacgc gaatggtgcatacaacattgcaaggaaagttctgtgggcaatcggccaat ttaaaaaagcggaagatgagaagctggacaaagtgaaaattgcgattagc aacaaggagtggctggagtatgcgcagacctccgttaaatcagggggaag tggcggaagcggtgggtctacgaacctgagcgacattattgaaaaagaaa ctggtaaacagttggtgatccaagaatccattctgatgttaccggaggaa gtggaagaggtgatcggcaacaagccggagtccgacatcctggttcacac cgcgtatgatgagtcgaccgatgagaatgttatgctgctgaccagcgacg ccccagagtacaaaccgtgggcgctcgtcatccaggatagcaatggcgaa aacaagatcaagatgttgtctggcggtagcatggctccgaaaaagaagcg taaagtaggtattcatggtgttccggcatcaggttaa 37 Base editor mTadA8e-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgagcggattagtaatgcaaaattataggctaatagacgctacgttgtat gtgacctttgaaccgtgcgttatgtgcgctggtgcaatgattcattctcg tatcggccgtgtcgtgttcggcgtgagaaacagcaagcgcggtgcggcgg gtagcctgatgaatgttctgaactacccgggtatgaaccaccgtgttgaa attaccgagggtatcttggcagacgagtgcgccgccctgctgtgtgattt ctaccgcatgccgcgtcaggtttttaacgcgcagaaaaaggcgcaaagca gcatcaatagcggcggtagctctggcggctcctccggttcggagtctgga agtgagacacccgggacttcagaatccgcgaccccggagtctggaatgga taaaaagtattcaataggactagctattggcaccaacagcgttggttggg cagttatcaccgatgaatataaggtcccgagcaagaagtttaaggtcctg ggcaacaccgatcgccacagcataaaaaagaaccttattggtgcgctgct gttcgattctggtgagactgccgaagcgacccgtctgaagagaaccgcgc gtcgtagatacacccggcgcaagaaccgtatctgctatctgcaagaaatt ttcagcaacgagatggctaaggtcgacgactccttctttcatcgcctgga ggaaagctttctggttgaggaagacaaaaagcacgagcgtcatccgattt tcggtaacattgttgatgaagttgcctaccacgaaaaataccccacaatt tatcatctgcgtaaaaaactggtagactccaccgataaggcggatttacg ccttatctatttggcgctggcgcatatgattaagttccgcggtcattttt tgatcgagggcgacctgaatccggataacagcgacgttgacaaactgttt atccagctggtgcagacctataaccagttgttcgaagagaacccgattaa tgcgtctggcgtggacgcgaaggcgatcctgagcgctcgtctgtccaagt cacgccgcctggagaacttgatcgcgcaactgccgggtgagaagaaaaac ggcttgttcggcaatctgattgctctgtccctaggtttgaccccgaattt caaatctaattttgatctggcggaagatgcgaaattacagttgagcaagg acacttacgatgacgatctggacaacctgctcgctcagatcggcgatcag tatgccgatcttttcctggccgcgaagaacctgagcgatgccatcttgct atcggacatcttacgtgttaacaccgaaatcaccaaagctccgctaagcg cgtccatgattaaacgttacgatgaacaccaccaggatctgacgctgctg aaagcgttggtgcgccagcaactgccggaaaaatacaaggaaattttctt cgaccaaagcaagaacggttatgcaggctatatcgacggtggtgcgtcgc aagaagaattttataaattcatcaaaccgattttggagaagatggatggt accgaggagctgctggtaaaattgaatcgggaagacctcttgcgaaagca gcgtactttcgataatggtagcatcccgcaccagattcatctgggcgaac ttcacgcaatcctacgtcgtcaagaggatttctacccgtttctgaaggat aaccgtgaaaagatcgagaagattctgacctttcgtattccgtattatgt gggtccgctggcgagaggcaacagccgttttgcgtggatgacccgcaagt cggaagagactatcacgccgtggaatttcgaggaggtcgtggacaagggt gcatcagcgcaatcttttattgaacgtatgaccaattttgataaaaacct tccaaatgaaaaagtgttgccgaagcacagcttgctgtacgagtatttca ccgtttacaatgaactgacgaaagtcaagtacgttaccgaaggtatgcgt aagccagcctttctgtctggggagcaaaaaaaagccattgtggatctgct gttcaagaccaatcgcaaggttaccgtcaagcaactgaaagaggattact tcaaaaaaatcgaatgttttgactccgtggaaatcagcggcgttgaagac cgctttaatgcatctctgggcacctaccacgatctactcaagatcatcaa ggataaggacttcctggacaacgaagaaaatgaggatatcttggaagata ttgtgctgactttaacgttgttcgaggatcgtgagatgattgaagaacgc ctcaaaacgtacgcacatctgtttgacgataaggtgatgaaacagctaaa gcgccgtcgttacaccggttggggtcgtctgtctagaaagctgattaacg gcattcgtgacaaacaatctggcaagaccatcctggacttcctcaaatcc gacggcttcgcaaatcgtaatttcatgcaactgatccatgatgatagcct gacctttaaagaagatattcagaaggctcaagtgtccggccagggtgact cgctgcatgagcatatcgcgaatctggctggctcccctgcgataaaaaaa ggtattctccaaacggtgaaagttgtggatgaactggttaaagtcatggg tcgtcataaaccggaaaacatcgtgattgagatggcacgtgagaaccaga ccacccagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgtatcgaa gaggggattaaggagttaggcagccagattctgaaggagcacccggttga gaacacccagctgcaaaacgagaagctctacctgtattacctgcaaaacg gccgtgacatgtatgttgaccaggagctggacatcaatcgtctcagcgac tacgacgtggatgctatcgtgccgcagagctttctaaaagatgattccat cgacaataaagtgctcacccgtagcgacaagaaccgtggtaaaagcgaca acgtgccgagcgaggaagtagttaagaaaatgaaaaactactggcgtcag ctattgaacgccaagcttatcacccagcgtaagtttgacaacttgacgaa ggcagagcgtggcggcctgagcgagctagacaaggcgggttttattaaac gccagctggtggaaactcgccagattaccaaacacgttgcgcaaatcttg gactcacgcatgaatacgaagtacgacgaaaacgataaattgatccgcga ggtgaaggtcataaccctgaaatctaaactggttagcgatttccggaagg actttcaattttataaagtccgggagattaacaactatcaccatgcacac gacgcttacttaaatgcggttgttggcacggccctgatcaagaagtaccc gaaactggaaagcgagtttgtttatggtgactacaaggtgtatgacgttc gcaagatgattgcaaaatccgaacaagagattggtaaggcgacggctaag tattttttctacagcaatatcatgaacttcttcaagactgaaatcaccct ggcgaacggtgaaattcgtaaacgtccgttgatcgaaaccaacggtgaaa ccggtgaaatcgtttgggataaaggtagggattttgcgaccgttcgtaag gtcctgagcatgccgcaggttaacatcgtgaaaaagaccgaagtgcagac cggcggtttctccaaggagagtatcttaccgaagcgcaacagtgacaagc tgatcgcgcgtaaaaaagactgggatccgaaaaaatacggcggctttgac tccccgaccgtcgcgtacagcgtactggtcgtggctaaagtggagaaagg caaatcgaaaaagctgaaatccgttaaagagttgctgggtattacgatta tggaacgttcgagcttcgagaaaaatccgatcgacttcctggaggccaaa ggctacaaggaagttaaaaaagacctgatcattaaactgccgaagtacag cctgttcgagctcgagaacggtcgcaaacgcatgctggcgagcgcgggtg agctccaaaaaggcaacgaattggctctgccgagcaagtacgtgaacttc ctgtatctggcctcccattatgaaaaactgaagggtagcccggaagataa cgaacaaaagcagctgttcgtggaacaacataaacactatctggacgaga ttattgagcaaatcagcgagttcagcaaacgcgtgattctggcggatgct aatctggacaaggttctttcagcctataataaacaccgtgataagccgat ccgtgaacaggcagaaaatattattcacctgttcaccctgacgaacctgg gtgcgccagcagcgtttaaatacttcgacacaacgatcgaccggaagcgt tataccagcaccaaagaggttcttgacgccaccttgattcaccaaagcat cacgggtctgtatgaaacccgtattgacttgagccagttgggcggagatt cagggggaagtggcggaagcggtgggtctacgaacctgagcgacattatt gaaaaagaaactggtaaacagttggtgatccaagaatccattctgatgtt accggaggaagtggaagaggtgatcggcaacaagccggagtccgacatcc tggttcacaccgcgtatgatgagtcgaccgatgagaatgttatgctgctg accagcgacgccccagagtacaaaccgtgggcgctcgtcatccaggatag caatggcgaaaacaagatcaagatgttgtctggcggtagcatggctccga aaaagaagcgtaaagtaggtattcatggtgttccggcatcaggttaa 38 Base editor mTadA8e-dCasPhi-2 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgagcggattagtaatgcaaaattataggctaatagacgctacgttgtat gtgacctttgaaccgtgcgttatgtgcgctggtgcaatgattcattctcg tatcggccgtgtcgtgttcggcgtgagaaacagcaagcgcggtgcggcgg gtagcctgatgaatgttctgaactacccgggtatgaaccaccgtgttgaa attaccgagggtatcttggcagacgagtgcgccgccctgctgtgtgattt ctaccgcatgccgcgtcaggtttttaacgcgcagaaaaaggcgcaaagca gcatcaatagcggcggtagctctggcggctcctccggttcggagtctgga agtgagacacccgggacttcagaatccgcgaccccggagtctggaatgcc aaaacccgctgtagagtcagaattttcaaaagttttgaaaaagcactttc cgggagaacgtttccgctcgagctatatgaaaagaggcggtaagatcctg gctgcccaaggcgaagaggcagttgttgcgtatctacagggcaagtccga ggaggagcctccgaacttccagccaccggcgaagtgccacgtggtgacca aatcccgtgacttcgcggaatggccgatcatgaaggcgtcggaagcgatt caacgttatatctatgcactgtcgaccaccgaacgcgcggcctgtaaacc gggcaaaagtagtgagagccatgcagcgtggttcgccgctaccggtgtca gcaaccacggctacagccacgttcagggtctgaacctgatttttgatcat accttgggccgttacgatggtgttctgaaaaaggtccaactgcgcaacga aaaggcgagagcgcgtttagagagcattaacgcgtctagagcagatgaag gtttaccggagattaaagccgaggaggaagaagtggctacgaacgaaacc ggccacctgttgcaaccgccgggtatcaatccgagcttttacgtgtatca gaccattagcccgcaggcataccgtccgcgtgacgagatcgtgctgccgc cggagtacgcaggttacgtacgtgacccgaatgctccgattccgctgggt gtggtgcgtaaccgttgcgatatccaaaaagggtgcccgggctacatccc ggaatggcagcgtgaagcaggtaccgcgatcagcccgaaaacaggcaagg ccgtaactgtgccgggcctgtctccgaagaaaaacaaacgtatgcgtagg tactggcgctctgagaaggagaaagctcaagatgcgctgttggttaccgt acgcattggtaccgattgggttgtcatcgacgtgcgcggtctgttgcgca acgcccgttggcgcaccatcgctcccaaggacatcagcctgaatgcgctc ctcgatttgtttaccggtgatccggtgatcgatgtgcgtcgcaatattgt tacctttacgtacaccctcgacgcctgtggtacctacgcccgtaaatgga ccttgaaaggcaaacagacgaaagcgaccctggacaaactgacggccact cagacggttgcgttggttgcgattgcgcttggtcagaccaacccgatttc cgctggcattagccgtgttacacaagaaaatggtgcactgcaatgcgaac cgctggaccggttcaccctgccggatgacctgttgaaggacatcagcgca tatcgcattgcttgggacagaaacgaagaggaactacgcgctcgcagcgt cgaggccctgccggaggcgcaacaagcggaggtccgtgcgctggacgggg tgtccaaagaaaccgcgcgtacccaactgtgcgcagatttcggcctggac ccgaaacgtctgccgtgggataaaatgagctccaatactacctttatcag cgaagccttgctgtctaacagcgtgagccgtgatcaggtttttttcactc cggctccgaagaagggtgctaagaaaaaagcgcctgttgaagttatgcgt aaagaccgcacttgggcacgtgcgtacaagccgcgtctgagcgtcgaagc tcagaaactgaagaacgaagccctgtgggcacttaagcgcacctccccgg agtatttgaagctgagccgtcgcaaagaggagctgtgtcgtcgtagcatc aactatgttatcgaaaagacccgtcgccgtacgcaatgtcagattgtgat cccggtgatcgaggatctgaatgttcgcttctttcatggttctggtaaga gactgcccggttgggataatttcttcaccgctaaaaaagagaaccgttgg ttcatccagggcctgcacaaagcgtttagcgatctgcgtacgcaccgttc cttctatgtttttgaagttcgtccggagcgcacctctattacctgtccaa agtgcggtcattgcgaggtgggtaatcgtgacggtgaggcgtttcagtgc ctgagctgcggcaagacgtgcaacgcagatcttgacgtcgcgacccataa tctgacccaagtggcgttgaccggtaagaccatgccgaagcgcgaggagc cgcgtgacgctcagggtacagcgccagcgcgcaagactaagaaggcgagc aaatcaaaggcgccaccggcggagcgcgaagaccagaccccggcgcaaga gccaagccagaccagttctggaggtagcgggggtagcggtggtagcacta acttaagtgatattatcgagaaagaaaccgggaaacagctggtgatccaa gaaagcattctgatgctgcccgaagaagttgaagaagtgattggtaacaa gcctgagtcggacatcttagtgcacaccgcgtacgatgaaagcacggatg agaatgtgatgctgctcacctctgatgcccccgaatacaagccgtgggct ctggtgatccaggactctaacggagaaaacaaaattaagatgctctctgg cggctccatggcgcctaaaaaaaaacgcaaagtggggattcacggggttc cggcgtaa 39 Base editor mTadA8e-dLbCas12a atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgagcggattagtaatgcaaaattataggctaatagacgctacgttgtat gtgacctttgaaccgtgcgttatgtgcgctggtgcaatgattcattctcg tatcggccgtgtcgtgttcggcgtgagaaacagcaagcgcggtgcggcgg gtagcctgatgaatgttctgaactacccgggtatgaaccaccgtgttgaa attaccgagggtatcttggcagacgagtgcgccgccctgctgtgtgattt ctaccgcatgccgcgtcaggtttttaacgcgcagaaaaaggcgcaaagca gcatcaatagcggcggtagctctggcggctcctccggttcggagtctgga agtgagacacccgggacttcagaatccgcgaccccggagtctggaatgtc aaaactagaaaagtttacaaattgttactccctgtcgaaaaccctgagat tcaaagcgatcccggtgggtaaaactcaagagaacattgataacaaacgt ctgctggttgaggacgaaaagcgcgcggaggattacaaaggcgttaaaaa gctgttggaccgttattacctgtcctttattaatgatgttctgcacagca ttaaattaaagaacctaaacaattacatctccctcttccgtaaaaagacc cgcaccgaaaaggaaaataaagaactggagaaccttgagattaatctgcg taaagaaatcgctaaagcgtttaaaggcaacgagggttataaatccttat ttaaaaaagacatcatcgaaacgattctcccagaattcctggacgacaaa gacgagatcgcgctggttaattccttcaacggctttaccaccgcattcac cggcttttttgataaccgcgaaaacatgttctctgaagaggccaaaagca cctcaattgcgtttcgctgcattaacgaaaatctgacgcgttatatctct aacatggatatcttcgagaaggttgacgctatctttgataaacatgaagt ccaggagatcaaggagaagatcctgaacagcgactacgacgtggaggatt tcttcgagggtgagttcttcaattttgttttgacccaagaaggcatcgat gtctacaatgcgataattggtggttttgttaccgagagcggggagaaaat taagggtctgaacgaatatatcaacttgtacaaccagaaaaccaaacaaa aactgccgaagtttaagccgctgtacaagcaagtcttgtcggatcgtgaa tcgctgagcttttacggcgaaggctacaccagcgatgaggaggtgttgga ggtgttccgcaatacgttgaataagaactctgaaattttttccagcatta agaagctggaaaaactattcaagaacttcgacgagtatagcagcgcaggt atctttgtgaaaaacggtccggctattagcaccatctcgaaagacatttt cggcgaatggaatgttattcgtgataagtggaatgccgaatacgacgaca ttcatctgaagaaaaaggcggttgtaactgaaaagtacgaggacgatcgt cgtaagtcgttcaaaaagatcggctccttctctctggagcaactgcaaga gtacgccgatgccgatttgtcagtcgtggagaagctgaaagagatcatca ttcaaaaagttgacgaaatctataaggtctatggtagcagtgaaaaactg tttgacgcggacttcgtgctggagaaaagcctgaagaaaaatgacgccgt ggtggcaatcatgaaagatcttctggatagcgtcaagtctttcgaaaact acatcaaagcgtttttcggtgaaggcaaggaaacgaatcgtgacgagagc ttctatggtgatttcgtcctagcctatgatatcctgcttaaggtggatca catctatgatgccatccgcaactatgttacccagaaaccgtactcaaagg acaagttcaagttatacttccagaatccgcagtttatgggtggctgggat aaagataaggaaaccgactatcgcgccaccattttacgttacggtagtaa gtactatctggcaatcatggataaaaaatatgcgaaatgcctgcaaaaga tcgacaaggacgatgttaacggcaattatgagaagatcaactacaaactg ctgccgggcccaaataagatgctgccgaaggtgtttttcagcaaaaaatg gatggcgtattacaatccgagcgaggacatccaaaagatctacaaaaacg gtacgtttaagaagggtgatatgttcaacctcaacgattgtcataaactt attgacttcttcaaggatagcatatctcgttatccgaagtggagcaacgc gtatgactttaactttagcgaaaccgagaaatacaaagatatcgcgggtt tctatcgtgaagttgaagaacagggttacaaagtgtccttcgagtccgcg agcaagaaggaggtagacaagctggtcgaggagggtaagttgtacatgtt tcagatttacaataaggacttttccgacaagtcccatggtacaccgaatt tgcacaccatgtatttcaagcttctgttcgacgagaacaaccacggccag atccgtctgagcggtggtgcagagctgttcatgcgtagagctagcctgaa gaaagaagagttggtcgttcatccggctaattcgccgatcgcgaacaaaa atccagataaccctaaaaagactacgaccctgagctatgatgtgtataaa gacaaacgctttagcgaagaccagtatgagttacacattccgatcgctat caacaagtgcccgaagaatattttcaagatcaacaccgaagtgcgtgttc ttttgaagcacgatgacaacccgtatgtgattggtattgctcgtggtgaa cgtaatctgctgtacattgtggttgtggacggcaaaggaaacatcgtgga acagtacagcctgaacgaaatcattaacaatttcaacggcattcgcatta agacggattaccattctttgctggacaaaaaggagaaagagcgtttcgag gcccgtcagaactggacctccatcgagaacattaaggagctgaaggcggg ttacatcagccaggtggtgcacaaaatctgcgaactggtggagaagtacg acgcggtgattgctttggcggatttgaactccggttttaagaacagccgc gttaaagtggaaaagcaggtttatcagaaattcgaaaaaatgctgattga taaattgaattacatggttgacaaaaagtctaacccgtgtgcaaccggcg gtgcgctgaagggctaccaaatcaccaataagtttgaaagctttaagagc atgagcacgcaaaatggcttcattttttacattccggcgtggctgaccag caagatcgatccgtcaaccggctttgttaatttactgaagacgaagtata cctctattgccgactctaaaaaatttattagttccttcgatagaatcatg tatgttccggaagaggacctgttcgaatttgcactggactacaagaactt tagccgtaccgatgctgattatataaagaaatggaaactctacagctatg gcaaccgcatccgtatctttcgcaacccgaaaaaaaacaacgtgttcgac tgggaagaggtatgtctgacttcagcgtacaaggagcttttcaataaata tggtatcaactaccagcagggtgatatccgtgcactgctttgcgagcaaa gcgataaagcgttctattcaagcttcatggcgctgatgagcctgatgctg caaatgcgcaacagcatcaccggtcgtaccgatgttgcatttctgatttc tccagtaaaaaacagcgatggtatcttttacgacagccgtaattacgagg cccaagaaaatgcgattttgccgaagaacgctgacgcgaatggtgcatac aacattgcaaggaaagttctgtgggcaatcggccaatttaaaaaagcgga agatgagaagctggacaaagtgaaaattgcgattagcaacaaggagtggc tggagtatgcgcagacctccgttaaatcagggggaagtggcggaagcggt gggtctacgaacctgagcgacattattgaaaaagaaactggtaaacagtt ggtgatccaagaatccattctgatgttaccggaggaagtggaagaggtga tcggcaacaagccggagtccgacatcctggttcacaccgcgtatgatgag tcgaccgatgagaatgttatgctgctgaccagcgacgccccagagtacaa accgtgggcgctcgtcatccaggatagcaatggcgaaaacaagatcaaga tgttgtctggcggtagcatggctccgaaaaagaagcgtaaagtaggtatt catggtgttccggcatcaggttaa 40 Base editor pmCDA1-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgacagatgctgaatatgtaaggatacacgagaagttggacatctac acctttaaaaagcagttctttaacaacaaaaagagcgtcagccatcgttg ctatgttctgtttgagttgaagcgccgtggcgaacgtcgtgcgtgctttt ggggttatgctgtgaacaaaccgcagtctggtactgaacgcggtattcat gcagaaattttcagcattcgtaaggtggaagaatacctgcgcgataaccc aggtcagttcaccattaactggtacagcagctggtccccgtgcgcggatt gcgctgagaagatcttggagtggtacaatcaagagctgcgtggtaatggc cataccctgaaaatctgggcgtgcaaactgtattacgaaaagaacgcgcg taatcaaattggtctgtggaatctgcgtgacaacggcgtgggcctgaatg ttatggtttccgagcactatcagtgttgtcgtaaaatcttcatccaatcc tctcacaaccaattgaacgagaaccgctggctggagaagaccctgaagcg cgccgagaaaagacgtagcgaactctcgatcatgattcaggttaaaatct tacacacgaccaaaagcccggcagtgtctggaagtgagacacccgggact tcagaatccgcgaccccggagtctggaatggataaaaagtattcaatagg actagctattggcaccaacagcgttggttgggcagttatcaccgatgaat ataaggtcccgagcaagaagtttaaggtcctgggcaacaccgatcgccac agcataaaaaagaaccttattggtgcgctgctgttcgattctggtgagac tgccgaagcgacccgtctgaagagaaccgcgcgtcgtagatacacccggc gcaagaaccgtatctgctatctgcaagaaattttcagcaacgagatggct aaggtcgacgactccttctttcatcgcctggaggaaagctttctggttga ggaagacaaaaagcacgagcgtcatccgattttcggtaacattgttgatg aagttgcctaccacgaaaaataccccacaatttatcatctgcgtaaaaaa ctggtagactccaccgataaggcggatttacgccttatctatttggcgct ggcgcatatgattaagttccgcggtcattttttgatcgagggcgacctga atccggataacagcgacgttgacaaactgtttatccagctggtgcagacc tataaccagttgttcgaagagaacccgattaatgcgtctggcgtggacgc gaaggcgatcctgagcgctcgtctgtccaagtcacgccgcctggagaact tgatcgcgcaactgccgggtgagaagaaaaacggcttgttcggcaatctg attgctctgtccctaggtttgaccccgaatttcaaatctaattttgatct ggcggaagatgcgaaattacagttgagcaaggacacttacgatgacgatc tggacaacctgctcgctcagatcggcgatcagtatgccgatcttttcctg gccgcgaagaacctgagcgatgccatcttgctatcggacatcttacgtgt taacaccgaaatcaccaaagctccgctaagcgcgtccatgattaaacgtt acgatgaacaccaccaggatctgacgctgctgaaagcgttggtgcgccag caactgccggaaaaatacaaggaaattttcttcgaccaaagcaagaacgg ttatgcaggctatatcgacggtggtgcgtcgcaagaagaattttataaat tcatcaaaccgattttggagaagatggatggtaccgaggagctgctggta aaattgaatcgggaagacctcttgcgaaagcagcgtactttcgataatgg tagcatcccgcaccagattcatctgggcgaacttcacgcaatcctacgtc gtcaagaggatttctacccgtttctgaaggataaccgtgaaaagatcgag aagattctgacctttcgtattccgtattatgtgggtccgctggcgagagg caacagccgttttgcgtggatgacccgcaagtcggaagagactatcacgc cgtggaatttcgaggaggtcgtggacaagggtgcatcagcgcaatctttt attgaacgtatgaccaattttgataaaaaccttccaaatgaaaaagtgtt gccgaagcacagcttgctgtacgagtatttcaccgtttacaatgaactga cgaaagtcaagtacgttaccgaaggtatgcgtaagccagcctttctgtct ggggagcaaaaaaaagccattgtggatctgctgttcaagaccaatcgcaa ggttaccgtcaagcaactgaaagaggattacttcaaaaaaatcgaatgtt ttgactccgtggaaatcagcggcgttgaagaccgctttaatgcatctctg ggcacctaccacgatctactcaagatcatcaaggataaggacttcctgga caacgaagaaaatgaggatatcttggaagatattgtgctgactttaacgt tgttcgaggatcgtgagatgattgaagaacgcctcaaaacgtacgcacat ctgtttgacgataaggtgatgaaacagctaaagcgccgtcgttacaccgg ttggggtcgtctgtctagaaagctgattaacggcattcgtgacaaacaat ctggcaagaccatcctggacttcctcaaatccgacggcttcgcaaatcgt aatttcatgcaactgatccatgatgatagcctgacctttaaagaagatat tcagaaggctcaagtgtccggccagggtgactcgctgcatgagcatatcg cgaatctggctggctcccctgcgataaaaaaaggtattctccaaacggtg aaagttgtggatgaactggttaaagtcatgggtcgtcataaaccggaaaa catcgtgattgagatggcacgtgagaaccagaccacccagaaaggtcaaa aaaacagtcgtgagcgtatgaaacgtatcgaagaggggattaaggagtta ggcagccagattctgaaggagcacccggttgagaacacccagctgcaaaa cgagaagctctacctgtattacctgcaaaacggccgtgacatgtatgttg accaggagctggacatcaatcgtctcagcgactacgacgtggatgctatc gtgccgcagagctttctaaaagatgattccatcgacaataaagtgctcac ccgtagcgacaagaaccgtggtaaaagcgacaacgtgccgagcgaggaag tagttaagaaaatgaaaaactactggcgtcagctattgaacgccaagctt atcacccagcgtaagtttgacaacttgacgaaggcagagcgtggcggcct gagcgagctagacaaggcgggttttattaaacgccagctggtggaaactc gccagattaccaaacacgttgcgcaaatcttggactcacgcatgaatacg aagtacgacgaaaacgataaattgatccgcgaggtgaaggtcataaccct gaaatctaaactggttagcgatttccggaaggactttcaattttataaag tccgggagattaacaactatcaccatgcacacgacgcttacttaaatgcg gttgttggcacggccctgatcaagaagtacccgaaactggaaagcgagtt tgtttatggtgactacaaggtgtatgacgttcgcaagatgattgcaaaat ccgaacaagagattggtaaggcgacggctaagtattttttctacagcaat atcatgaacttcttcaagactgaaatcaccctggcgaacggtgaaattcg taaacgtccgttgatcgaaaccaacggtgaaaccggtgaaatcgtttggg ataaaggtagggattttgcgaccgttcgtaaggtcctgagcatgccgcag gttaacatcgtgaaaaagaccgaagtgcagaccggcggtttctccaagga gagtatcttaccgaagcgcaacagtgacaagctgatcgcgcgtaaaaaag actgggatccgaaaaaatacggcggctttgactccccgaccgtcgcgtac agcgtactggtcgtggctaaagtggagaaaggcaaatcgaaaaagctgaa atccgttaaagagttgctgggtattacgattatggaacgttcgagcttcg agaaaaatccgatcgacttcctggaggccaaaggctacaaggaagttaaa aaagacctgatcattaaactgccgaagtacagcctgttcgagctcgagaa cggtcgcaaacgcatgctggcgagcgcgggtgagctccaaaaaggcaacg aattggctctgccgagcaagtacgtgaacttcctgtatctggcctcccat tatgaaaaactgaagggtagcccggaagataacgaacaaaagcagctgtt cgtggaacaacataaacactatctggacgagattattgagcaaatcagcg agttcagcaaacgcgtgattctggcggatgctaatctggacaaggttctt tcagcctataataaacaccgtgataagccgatccgtgaacaggcagaaaa tattattcacctgttcaccctgacgaacctgggtgcgccagcagcgttta aatacttcgacacaacgatcgaccggaagcgttataccagcaccaaagag gttcttgacgccaccttgattcaccaaagcatcacgggtctgtatgaaac ccgtattgacttgagccagttgggcggagattcagggggaagtggcggaa gcggtgggtctacgaacctgagcgacattattgaaaaagaaactggtaaa cagttggtgatccaagaatccattctgatgttaccggaggaagtggaaga ggtgatcggcaacaagccggagtccgacatcctggttcacaccgcgtatg atgagtcgaccgatgagaatgttatgctgctgaccagcgacgccccagag tacaaaccgtgggcgctcgtcatccaggatagcaatggcgaaaacaagat caagatgttgtctggcggtagcatggctccgaaaaagaagcgtaaagtag gtattcatggtgttccggcatcaggttaa 41 Base editor pmCDA1-dCasPhi-2 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgacagatgctgaatatgtaaggatacacgagaagttggacatctac acctttaaaaagcagttctttaacaacaaaaagagcgtcagccatcgttg ctatgttctgtttgagttgaagcgccgtggcgaacgtcgtgcgtgctttt ggggttatgctgtgaacaaaccgcagtctggtactgaacgcggtattcat gcagaaattttcagcattcgtaaggtggaagaatacctgcgcgataaccc aggtcagttcaccattaactggtacagcagctggtccccgtgcgcggatt gcgctgagaagatcttggagtggtacaatcaagagctgcgtggtaatggc cataccctgaaaatctgggcgtgcaaactgtattacgaaaagaacgcgcg taatcaaattggtctgtggaatctgcgtgacaacggcgtgggcctgaatg ttatggtttccgagcactatcagtgttgtcgtaaaatcttcatccaatcc tctcacaaccaattgaacgagaaccgctggctggagaagaccctgaagcg cgccgagaaaagacgtagcgaactctcgatcatgattcaggttaaaatct tacacacgaccaaaagcccggcagtgtctggaagtgagacacccgggact tcagaatccgcgaccccggagtctggaatgccaaaacccgctgtagagtc agaattttcaaaagttttgaaaaagcactttccgggagaacgtttccgct cgagctatatgaaaagaggcggtaagatcctggctgcccaaggcgaagag gcagttgttgcgtatctacagggcaagtccgaggaggagcctccgaactt ccagccaccggcgaagtgccacgtggtgaccaaatcccgtgacttcgcgg aatggccgatcatgaaggcgtcggaagcgattcaacgttatatctatgca ctgtcgaccaccgaacgcgcggcctgtaaaccgggcaaaagtagtgagag ccatgcagcgtggttcgccgctaccggtgtcagcaaccacggctacagcc acgttcagggtctgaacctgatttttgatcataccttgggccgttacgat ggtgttctgaaaaaggtccaactgcgcaacgaaaaggcgagagcgcgttt agagagcattaacgcgtctagagcagatgaaggtttaccggagattaaag ccgaggaggaagaagtggctacgaacgaaaccggccacctgttgcaaccg ccgggtatcaatccgagcttttacgtgtatcagaccattagcccgcaggc ataccgtccgcgtgacgagatcgtgctgccgccggagtacgcaggttacg tacgtgacccgaatgctccgattccgctgggtgtggtgcgtaaccgttgc gatatccaaaaagggtgcccgggctacatcccggaatggcagcgtgaagc aggtaccgcgatcagcccgaaaacaggcaaggccgtaactgtgccgggcc tgtctccgaagaaaaacaaacgtatgcgtaggtactggcgctctgagaag gagaaagctcaagatgcgctgttggttaccgtacgcattggtaccgattg ggttgtcatcgacgtgcgcggtctgttgcgcaacgcccgttggcgcacca tcgctcccaaggacatcagcctgaatgcgctcctcgatttgtttaccggt gatccggtgatcgatgtgcgtcgcaatattgttacctttacgtacaccct cgacgcctgtggtacctacgcccgtaaatggaccttgaaaggcaaacaga cgaaagcgaccctggacaaactgacggccactcagacggttgcgttggtt gcgattgcgcttggtcagaccaacccgatttccgctggcattagccgtgt tacacaagaaaatggtgcactgcaatgcgaaccgctggaccggttcaccc tgccggatgacctgttgaaggacatcagcgcatatcgcattgcttgggac agaaacgaagaggaactacgcgctcgcagcgtcgaggccctgccggaggc gcaacaagcggaggtccgtgcgctggacggggtgtccaaagaaaccgcgc gtacccaactgtgcgcagatttcggcctggacccgaaacgtctgccgtgg gataaaatgagctccaatactacctttatcagcgaagccttgctgtctaa cagcgtgagccgtgatcaggtttttttcactccggctccgaagaagggtg ctaagaaaaaagcgcctgttgaagttatgcgtaaagaccgcacttgggca cgtgcgtacaagccgcgtctgagcgtcgaagctcagaaactgaagaacga agccctgtgggcacttaagcgcacctccccggagtatttgaagctgagcc gtcgcaaagaggagctgtgtcgtcgtagcatcaactatgttatcgaaaag acccgtcgccgtacgcaatgtcagattgtgatcccggtgatcgaggatct gaatgttcgcttctttcatggttctggtaagagactgcccggttgggata atttcttcaccgctaaaaaagagaaccgttggttcatccagggcctgcac aaagcgtttagcgatctgcgtacgcaccgttccttctatgtttttgaagt tcgtccggagcgcacctctattacctgtccaaagtgcggtcattgcgagg tgggtaatcgtgacggtgaggcgtttcagtgcctgagctgcggcaagacg tgcaacgcagatcttgacgtcgcgacccataatctgacccaagtggcgtt gaccggtaagaccatgccgaagcgcgaggagccgcgtgacgctcagggta cagcgccagcgcgcaagactaagaaggcgagcaaatcaaaggcgccaccg gcggagcgcgaagaccagaccccggcgcaagagccaagccagaccagttc tggaggtagcgggggtagcggtggtagcactaacttaagtgatattatcg agaaagaaaccgggaaacagctggtgatccaagaaagcattctgatgctg cccgaagaagttgaagaagtgattggtaacaagcctgagtcggacatctt agtgcacaccgcgtacgatgaaagcacggatgagaatgtgatgctgctca cctctgatgcccccgaatacaagccgtgggctctggtgatccaggactct aacggagaaaacaaaattaagatgctctctggcggctccatggcgcctaa aaaaaaacgcaaagtggggattcacggggttccggcgtaa 42 Base editor pmCDA1-dLbCas12a atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttccag agcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccggc gatgacagatgctgaatatgtaaggatacacgagaagttggacatctaca cctttaaaaagcagttctttaacaacaaaaagagcgtcagccatcgttgc tatgttctgtttgagttgaagcgccgtggcgaacgtcgtgcgtgcttttg gggttatgctgtgaacaaaccgcagtctggtactgaacgcggtattcatg cagaaattttcagcattcgtaaggtggaagaatacctgcgcgataaccca ggtcagttcaccattaactggtacagcagctggtccccgtgcgcggattg cgctgagaagatcttggagtggtacaatcaagagctgcgtggtaatggcc ataccctgaaaatctgggcgtgcaaactgtattacgaaaagaacgcgcgt aatcaaattggtctgtggaatctgcgtgacaacggcgtgggcctgaatgt tatggtttccgagcactatcagtgttgtcgtaaaatcttcatccaatcct ctcacaaccaattgaacgagaaccgctggctggagaagaccctgaagcgc gccgagaaaagacgtagcgaactctcgatcatgattcaggttaaaatctt acacacgaccaaaagcccggcagtgtctggaagtgagacacccgggactt cagaatccgcgaccccggagtctggaatgtcaaaactagaaaagtttaca aattgttactccctgtcgaaaaccctgagattcaaagcgatcccggtggg taaaactcaagagaacattgataacaaacgtctgctggttgaggacgaaa agcgcgcggaggattacaaaggcgttaaaaagctgttggaccgttattac ctgtcctttattaatgatgttctgcacagcattaaattaaagaacctaaa caattacatctccctcttccgtaaaaagacccgcaccgaaaaggaaaata aagaactggagaaccttgagattaatctgcgtaaagaaatcgctaaagcg tttaaaggcaacgagggttataaatccttatttaaaaaagacatcatcga aacgattctcccagaattcctggacgacaaagacgagatcgcgctggtta attccttcaacggctttaccaccgcattcaccggcttttttgataaccgc gaaaacatgttctctgaagaggccaaaagcacctcaattgcgtttcgctg cattaacgaaaatctgacgcgttatatctctaacatggatatcttcgaga aggttgacgctatctttgataaacatgaagtccaggagatcaaggagaag atcctgaacagcgactacgacgtggaggatttcttcgagggtgagttctt caattttgttttgacccaagaaggcatcgatgtctacaatgcgataattg gtggttttgttaccgagagcggggagaaaattaagggtctgaacgaatat atcaacttgtacaaccagaaaaccaaacaaaaactgccgaagtttaagcc gctgtacaagcaagtcttgtcggatcgtgaatcgctgagcttttacggcg aaggctacaccagcgatgaggaggtgttggaggtgttccgcaatacgttg aataagaactctgaaattttttccagcattaagaagctggaaaaactatt caagaacttcgacgagtatagcagcgcaggtatctttgtgaaaaacggtc cggctattagcaccatctcgaaagacattttcggcgaatggaatgttatt cgtgataagtggaatgccgaatacgacgacattcatctgaagaaaaaggc ggttgtaactgaaaagtacgaggacgatcgtcgtaagtcgttcaaaaaga tcggctccttctctctggagcaactgcaagagtacgccgatgccgatttg tcagtcgtggagaagctgaaagagatcatcattcaaaaagttgacgaaat ctataaggtctatggtagcagtgaaaaactgtttgacgcggacttcgtgc tggagaaaagcctgaagaaaaatgacgccgtggtggcaatcatgaaagat cttctggatagcgtcaagtctttcgaaaactacatcaaagcgtttttcgg tgaaggcaaggaaacgaatcgtgacgagagcttctatggtgatttcgtcc tagcctatgatatcctgcttaaggtggatcacatctatgatgccatccgc aactatgttacccagaaaccgtactcaaaggacaagttcaagttatactt ccagaatccgcagtttatgggtggctgggataaagataaggaaaccgact atcgcgccaccattttacgttacggtagtaagtactatctggcaatcatg gataaaaaatatgcgaaatgcctgcaaaagatcgacaaggacgatgttaa cggcaattatgagaagatcaactacaaactgctgccgggcccaaataaga tgctgccgaaggtgtttttcagcaaaaaatggatggcgtattacaatccg agcgaggacatccaaaagatctacaaaaacggtacgtttaagaagggtga tatgttcaacctcaacgattgtcataaacttattgacttcttcaaggata gcatatctcgttatccgaagtggagcaacgcgtatgactttaactttagc gaaaccgagaaatacaaagatatcgcgggtttctatcgtgaagttgaaga acagggttacaaagtgtccttcgagtccgcgagcaagaaggaggtagaca agctggtcgaggagggtaagttgtacatgtttcagatttacaataaggac ttttccgacaagtcccatggtacaccgaatttgcacaccatgtatttcaa gcttctgttcgacgagaacaaccacggccagatccgtctgagcggtggtg cagagctgttcatgcgtagagctagcctgaagaaagaagagttggtcgtt catccggctaattcgccgatcgcgaacaaaaatccagataaccctaaaaa gactacgaccctgagctatgatgtgtataaagacaaacgctttagcgaag accagtatgagttacacattccgatcgctatcaacaagtgcccgaagaat attttcaagatcaacaccgaagtgcgtgttcttttgaagcacgatgacaa cccgtatgtgattggtattgctcgtggtgaacgtaatctgctgtacattg tggttgtggacggcaaaggaaacatcgtggaacagtacagcctgaacgaa atcattaacaatttcaacggcattcgcattaagacggattaccattcttt gctggacaaaaaggagaaagagcgtttcgaggcccgtcagaactggacct ccatcgagaacattaaggagctgaaggcgggttacatcagccaggtggtg cacaaaatctgcgaactggtggagaagtacgacgcggtgattgctttggc ggatttgaactccggttttaagaacagccgcgttaaagtggaaaagcagg tttatcagaaattcgaaaaaatgctgattgataaattgaattacatggtt gacaaaaagtctaacccgtgtgcaaccggcggtgcgctgaagggctacca aatcaccaataagtttgaaagctttaagagcatgagcacgcaaaatggct tcattttttacattccggcgtggctgaccagcaagatcgatccgtcaacc ggctttgttaatttactgaagacgaagtatacctctattgccgactctaa aaaatttattagttccttcgatagaatcatgtatgttccggaagaggacc tgttcgaatttgcactggactacaagaactttagccgtaccgatgctgat tatataaagaaatggaaactctacagctatggcaaccgcatccgtatctt tcgcaacccgaaaaaaaacaacgtgttcgactgggaagaggtatgtctga cttcagcgtacaaggagcttttcaataaatatggtatcaactaccagcag ggtgatatccgtgcactgctttgcgagcaaagcgataaagcgttctattc aagcttcatggcgctgatgagcctgatgctgcaaatgcgcaacagcatca ccggtcgtaccgatgttgcatttctgatttctccagtaaaaaacagcgat ggtatcttttacgacagccgtaattacgaggcccaagaaaatgcgatttt gccgaagaacgctgacgcgaatggtgcatacaacattgcaaggaaagttc tgtgggcaatcggccaatttaaaaaagcggaagatgagaagctggacaaa gtgaaaattgcgattagcaacaaggagtggctggagtatgcgcagacctc cgttaaatcagggggaagtggcggaagcggtgggtctacgaacctgagcg acattattgaaaaagaaactggtaaacagttggtgatccaagaatccatt ctgatgttaccggaggaagtggaagaggtgatcggcaacaagccggagtc cgacatcctggttcacaccgcgtatgatgagtcgaccgatgagaatgtta tgctgctgaccagcgacgccccagagtacaaaccgtgggcgctcgtcatc caggatagcaatggcgaaaacaagatcaagatgttgtctggcggtagcat ggctccgaaaaagaagcgtaaagtaggtattcatggtgttccggcatcag gttaa 43 Base editor PpA1-R33A-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgacaagtgaaaaaggaccctcaactggggacccaaccctgcgtcgt cgcattgaaagctgggagttcgacgttttttatgatccgcgtgagctggc gaaagagacgtgcctgttgtacgagatcaaatggggtatgagccgtaaaa tctggagatccagcggtaaaaacaccaccaatcacgtggaagtgaatttt atcaagaagttcaccagcgaacgtcgtttccacagctccatttcttgttc tattacctggtttctgtcttggtcgccgtgttgggagtgctcccaggcaa ttcgtgaattccttagtcaacatccgggcgtgaccctggtcatctacgtc gcccgtttgttttggcatatggaccagcgcaatcgtcagggtttgcgcga tctggttaacagcggcgttacgatccaaattatgcgtgcgagcgagtatt accactgctggcgcaacttcgtgaactatccaccgggcgatgaagcacat tggccgcaatatccgccgctgtggatgatgctgtacgcgctggaactcca ctgcattatcctgtcgctgccgccttgtctgaagatcagccgacgctggc agaaccacctcgcgtttttccgcctgcacttgcaaaactgccattaccag accatcccgccgcatatcctgttagctaccggtctgattcacccgagcgt tacttggcgttctggaagtgagacacccgggacttcagaatccgcgaccc cggagtctggaatggataaaaagtattcaataggactagctattggcacc aacagcgttggttgggcagttatcaccgatgaatataaggtcccgagcaa gaagtttaaggtcctgggcaacaccgatcgccacagcataaaaaagaacc ttattggtgcgctgctgttcgattctggtgagactgccgaagcgacccgt ctgaagagaaccgcgcgtcgtagatacacccggcgcaagaaccgtatctg ctatctgcaagaaattttcagcaacgagatggctaaggtcgacgactcct tctttcatcgcctggaggaaagctttctggttgaggaagacaaaaagcac gagcgtcatccgattttcggtaacattgttgatgaagttgcctaccacga aaaataccccacaatttatcatctgcgtaaaaaactggtagactccaccg ataaggcggatttacgccttatctatttggcgctggcgcatatgattaag ttccgcggtcattttttgatcgagggcgacctgaatccggataacagcga cgttgacaaactgtttatccagctggtgcagacctataaccagttgttcg aagagaacccgattaatgcgtctggcgtggacgcgaaggcgatcctgagc gctcgtctgtccaagtcacgccgcctggagaacttgatcgcgcaactgcc gggtgagaagaaaaacggcttgttcggcaatctgattgctctgtccctag gtttgaccccgaatttcaaatctaattttgatctggcggaagatgcgaaa ttacagttgagcaaggacacttacgatgacgatctggacaacctgctcgc tcagatcggcgatcagtatgccgatcttttcctggccgcgaagaacctga gcgatgccatcttgctatcggacatcttacgtgttaacaccgaaatcacc aaagctccgctaagcgcgtccatgattaaacgttacgatgaacaccacca ggatctgacgctgctgaaagcgttggtgcgccagcaactgccggaaaaat acaaggaaattttcttcgaccaaagcaagaacggttatgcaggctatatc gacggtggtgcgtcgcaagaagaattttataaattcatcaaaccgatttt ggagaagatggatggtaccgaggagctgctggtaaaattgaatcgggaag acctcttgcgaaagcagcgtactttcgataatggtagcatcccgcaccag attcatctgggcgaacttcacgcaatcctacgtcgtcaagaggatttcta cccgtttctgaaggataaccgtgaaaagatcgagaagattctgacctttc gtattccgtattatgtgggtccgctggcgagaggcaacagccgttttgcg tggatgacccgcaagtcggaagagactatcacgccgtggaatttcgagga ggtcgtggacaagggtgcatcagcgcaatcttttattgaacgtatgacca attttgataaaaaccttccaaatgaaaaagtgttgccgaagcacagcttg ctgtacgagtatttcaccgtttacaatgaactgacgaaagtcaagtacgt taccgaaggtatgcgtaagccagcctttctgtctggggagcaaaaaaaag ccattgtggatctgctgttcaagaccaatcgcaaggttaccgtcaagcaa ctgaaagaggattacttcaaaaaaatcgaatgttttgactccgtggaaat cagcggcgttgaagaccgctttaatgcatctctgggcacctaccacgatc tactcaagatcatcaaggataaggacttcctggacaacgaagaaaatgag gatatcttggaagatattgtgctgactttaacgttgttcgaggatcgtga gatgattgaagaacgcctcaaaacgtacgcacatctgtttgacgataagg tgatgaaacagctaaagcgccgtcgttacaccggttggggtcgtctgtct agaaagctgattaacggcattcgtgacaaacaatctggcaagaccatcct ggacttcctcaaatccgacggcttcgcaaatcgtaatttcatgcaactga tccatgatgatagcctgacctttaaagaagatattcagaaggctcaagtg tccggccagggtgactcgctgcatgagcatatcgcgaatctggctggctc ccctgcgataaaaaaaggtattctccaaacggtgaaagttgtggatgaac tggttaaagtcatgggtcgtcataaaccggaaaacatcgtgattgagatg gcacgtgagaaccagaccacccagaaaggtcaaaaaaacagtcgtgagcg tatgaaacgtatcgaagaggggattaaggagttaggcagccagattctga aggagcacccggttgagaacacccagctgcaaaacgagaagctctacctg tattacctgcaaaacggccgtgacatgtatgttgaccaggagctggacat caatcgtctcagcgactacgacgtggatgctatcgtgccgcagagctttc taaaagatgattccatcgacaataaagtgctcacccgtagcgacaagaac cgtggtaaaagcgacaacgtgccgagcgaggaagtagttaagaaaatgaa aaactactggcgtcagctattgaacgccaagcttatcacccagcgtaagt ttgacaacttgacgaaggcagagcgtggcggcctgagcgagctagacaag gcgggttttattaaacgccagctggtggaaactcgccagattaccaaaca cgttgcgcaaatcttggactcacgcatgaatacgaagtacgacgaaaacg ataaattgatccgcgaggtgaaggtcataaccctgaaatctaaactggtt agcgatttccggaaggactttcaattttataaagtccgggagattaacaa ctatcaccatgcacacgacgcttacttaaatgcggttgttggcacggccc tgatcaagaagtacccgaaactggaaagcgagtttgtttatggtgactac aaggtgtatgacgttcgcaagatgattgcaaaatccgaacaagagattgg taaggcgacggctaagtattttttctacagcaatatcatgaacttcttca agactgaaatcaccctggcgaacggtgaaattcgtaaacgtccgttgatc gaaaccaacggtgaaaccggtgaaatcgtttgggataaaggtagggattt tgcgaccgttcgtaaggtcctgagcatgccgcaggttaacatcgtgaaaa agaccgaagtgcagaccggcggtttctccaaggagagtatcttaccgaag cgcaacagtgacaagctgatcgcgcgtaaaaaagactgggatccgaaaaa atacggcggctttgactccccgaccgtcgcgtacagcgtactggtcgtgg ctaaagtggagaaaggcaaatcgaaaaagctgaaatccgttaaagagttg ctgggtattacgattatggaacgttcgagcttcgagaaaaatccgatcga cttcctggaggccaaaggctacaaggaagttaaaaaagacctgatcatta aactgccgaagtacagcctgttcgagctcgagaacggtcgcaaacgcatg ctggcgagcgcgggtgagctccaaaaaggcaacgaattggctctgccgag caagtacgtgaacttcctgtatctggcctcccattatgaaaaactgaagg gtagcccggaagataacgaacaaaagcagctgttcgtggaacaacataaa cactatctggacgagattattgagcaaatcagcgagttcagcaaacgcgt gattctggcggatgctaatctggacaaggttctttcagcctataataaac accgtgataagccgatccgtgaacaggcagaaaatattattcacctgttc accctgacgaacctgggtgcgccagcagcgtttaaatacttcgacacaac gatcgaccggaagcgttataccagcaccaaagaggttcttgacgccacct tgattcaccaaagcatcacgggtctgtatgaaacccgtattgacttgagc cagttgggcggagattcagggggaagtggcggaagcggtgggtctacgaa cctgagcgacattattgaaaaagaaactggtaaacagttggtgatccaag aatccattctgatgttaccggaggaagtggaagaggtgatcggcaacaag ccggagtccgacatcctggttcacaccgcgtatgatgagtcgaccgatga gaatgttatgctgctgaccagcgacgccccagagtacaaaccgtgggcgc tcgtcatccaggatagcaatggcgaaaacaagatcaagatgttgtctggc ggtagcatggctccgaaaaagaagcgtaaagtaggtattcatggtgttcc ggcatcaggttaa 44 Base editor PpA1-R33A- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgacaagtgaaaaaggaccctcaactggggacccaaccctgcgtcgt cgcattgaaagctgggagttcgacgttttttatgatccgcgtgagctggc gaaagagacgtgcctgttgtacgagatcaaatggggtatgagccgtaaaa tctggagatccagcggtaaaaacaccaccaatcacgtggaagtgaatttt atcaagaagttcaccagcgaacgtcgtttccacagctccatttcttgttc tattacctggtttctgtcttggtcgccgtgttgggagtgctcccaggcaa ttcgtgaattccttagtcaacatccgggcgtgaccctggtcatctacgtc gcccgtttgttttggcatatggaccagcgcaatcgtcagggtttgcgcga tctggttaacagcggcgttacgatccaaattatgcgtgcgagcgagtatt accactgctggcgcaacttcgtgaactatccaccgggcgatgaagcacat tggccgcaatatccgccgctgtggatgatgctgtacgcgctggaactcca ctgcattatcctgtcgctgccgccttgtctgaagatcagccgacgctggc agaaccacctcgcgtttttccgcctgcacttgcaaaactgccattaccag accatcccgccgcatatcctgttagctaccggtctgattcacccgagcgt tacttggcgttctggaagtgagacacccgggacttcagaatccgcgaccc cggagtctggaatgccaaaacccgctgtagagtcagaattttcaaaagtt ttgaaaaagcactttccgggagaacgtttccgctcgagctatatgaaaag aggcggtaagatcctggctgcccaaggcgaagaggcagttgttgcgtatc tacagggcaagtccgaggaggagcctccgaacttccagccaccggcgaag tgccacgtggtgaccaaatcccgtgacttcgcggaatggccgatcatgaa ggcgtcggaagcgattcaacgttatatctatgcactgtcgaccaccgaac gcgcggcctgtaaaccgggcaaaagtagtgagagccatgcagcgtggttc gccgctaccggtgtcagcaaccacggctacagccacgttcagggtctgaa cctgatttttgatcataccttgggccgttacgatggtgttctgaaaaagg tccaactgcgcaacgaaaaggcgagagcgcgtttagagagcattaacgcg tctagagcagatgaaggtttaccggagattaaagccgaggaggaagaagt ggctacgaacgaaaccggccacctgttgcaaccgccgggtatcaatccga gcttttacgtgtatcagaccattagcccgcaggcataccgtccgcgtgac gagatcgtgctgccgccggagtacgcaggttacgtacgtgacccgaatgc tccgattccgctgggtgtggtgcgtaaccgttgcgatatccaaaaagggt gcccgggctacatcccggaatggcagcgtgaagcaggtaccgcgatcagc ccgaaaacaggcaaggccgtaactgtgccgggcctgtctccgaagaaaaa caaacgtatgcgtaggtactggcgctctgagaaggagaaagctcaagatg cgctgttggttaccgtacgcattggtaccgattgggttgtcatcgacgtg cgcggtctgttgcgcaacgcccgttggcgcaccatcgctcccaaggacat cagcctgaatgcgctcctcgatttgtttaccggtgatccggtgatcgatg tgcgtcgcaatattgttacctttacgtacaccctcgacgcctgtggtacc tacgcccgtaaatggaccttgaaaggcaaacagacgaaagcgaccctgga caaactgacggccactcagacggttgcgttggttgcgattgcgcttggtc agaccaacccgatttccgctggcattagccgtgttacacaagaaaatggt gcactgcaatgcgaaccgctggaccggttcaccctgccggatgacctgtt gaaggacatcagcgcatatcgcattgcttgggacagaaacgaagaggaac tacgcgctcgcagcgtcgaggccctgccggaggcgcaacaagcggaggtc cgtgcgctggacggggtgtccaaagaaaccgcgcgtacccaactgtgcgc agatttcggcctggacccgaaacgtctgccgtgggataaaatgagctcca atactacctttatcagcgaagccttgctgtctaacagcgtgagccgtgat caggtttttttcactccggctccgaagaagggtgctaagaaaaaagcgcc tgttgaagttatgcgtaaagaccgcacttgggcacgtgcgtacaagccgc gtctgagcgtcgaagctcagaaactgaagaacgaagccctgtgggcactt aagcgcacctccccggagtatttgaagctgagccgtcgcaaagaggagct gtgtcgtcgtagcatcaactatgttatcgaaaagacccgtcgccgtacgc aatgtcagattgtgatcccggtgatcgaggatctgaatgttcgcttcttt catggttctggtaagagactgcccggttgggataatttcttcaccgctaa aaaagagaaccgttggttcatccagggcctgcacaaagcgtttagcgatc tgcgtacgcaccgttccttctatgtttttgaagttcgtccggagcgcacc tctattacctgtccaaagtgcggtcattgcgaggtgggtaatcgtgacgg tgaggcgtttcagtgcctgagctgcggcaagacgtgcaacgcagatcttg acgtcgcgacccataatctgacccaagtggcgttgaccggtaagaccatg ccgaagcgcgaggagccgcgtgacgctcagggtacagcgccagcgcgcaa gactaagaaggcgagcaaatcaaaggcgccaccggcggagcgcgaagacc agaccccggcgcaagagccaagccagaccagttctggaggtagcgggggt agcggtggtagcactaacttaagtgatattatcgagaaagaaaccgggaa acagctggtgatccaagaaagcattctgatgctgcccgaagaagttgaag aagtgattggtaacaagcctgagtcggacatcttagtgcacaccgcgtac gatgaaagcacggatgagaatgtgatgctgctcacctctgatgcccccga atacaagccgtgggctctggtgatccaggactctaacggagaaaacaaaa ttaagatgctctctggcggctccatggcgcctaaaaaaaaacgcaaagtg gggattcacggggttccggcgtaa 45 Base editor PpA1-R33A- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgacaagtgaaaaaggaccctcaactggggacccaaccctgcgtcgt cgcattgaaagctgggagttcgacgttttttatgatccgcgtgagctggc gaaagagacgtgcctgttgtacgagatcaaatggggtatgagccgtaaaa tctggagatccagcggtaaaaacaccaccaatcacgtggaagtgaatttt atcaagaagttcaccagcgaacgtcgtttccacagctccatttcttgttc tattacctggtttctgtcttggtcgccgtgttgggagtgctcccaggcaa ttcgtgaattccttagtcaacatccgggcgtgaccctggtcatctacgtc gcccgtttgttttggcatatggaccagcgcaatcgtcagggtttgcgcga tctggttaacagcggcgttacgatccaaattatgcgtgcgagcgagtatt accactgctggcgcaacttcgtgaactatccaccgggcgatgaagcacat tggccgcaatatccgccgctgtggatgatgctgtacgcgctggaactcca ctgcattatcctgtcgctgccgccttgtctgaagatcagccgacgctggc agaaccacctcgcgtttttccgcctgcacttgcaaaactgccattaccag accatcccgccgcatatcctgttagctaccggtctgattcacccgagcgt tacttggcgttctggaagtgagacacccgggacttcagaatccgcgaccc cggagtctggaatgtcaaaactagaaaagtttacaaattgttactccctg tcgaaaaccctgagattcaaagcgatcccggtgggtaaaactcaagagaa cattgataacaaacgtctgctggttgaggacgaaaagcgcgcggaggatt acaaaggcgttaaaaagctgttggaccgttattacctgtcctttattaat gatgttctgcacagcattaaattaaagaacctaaacaattacatctccct cttccgtaaaaagacccgcaccgaaaaggaaaataaagaactggagaacc ttgagattaatctgcgtaaagaaatcgctaaagcgtttaaaggcaacgag ggttataaatccttatttaaaaaagacatcatcgaaacgattctcccaga attcctggacgacaaagacgagatcgcgctggttaattccttcaacggct ttaccaccgcattcaccggcttttttgataaccgcgaaaacatgttctct gaagaggccaaaagcacctcaattgcgtttcgctgcattaacgaaaatct gacgcgttatatctctaacatggatatcttcgagaaggttgacgctatct ttgataaacatgaagtccaggagatcaaggagaagatcctgaacagcgac tacgacgtggaggatttcttcgagggtgagttcttcaattttgttttgac ccaagaaggcatcgatgtctacaatgcgataattggtggttttgttaccg agagcggggagaaaattaagggtctgaacgaatatatcaacttgtacaac cagaaaaccaaacaaaaactgccgaagtttaagccgctgtacaagcaagt cttgtcggatcgtgaatcgctgagcttttacggcgaaggctacaccagcg atgaggaggtgttggaggtgttccgcaatacgttgaataagaactctgaa attttttccagcattaagaagctggaaaaactattcaagaacttcgacga gtatagcagcgcaggtatctttgtgaaaaacggtccggctattagcacca tctcgaaagacattttcggcgaatggaatgttattcgtgataagtggaat gccgaatacgacgacattcatctgaagaaaaaggcggttgtaactgaaaa gtacgaggacgatcgtcgtaagtcgttcaaaaagatcggctccttctctc tggagcaactgcaagagtacgccgatgccgatttgtcagtcgtggagaag ctgaaagagatcatcattcaaaaagttgacgaaatctataaggtctatgg tagcagtgaaaaactgtttgacgcggacttcgtgctggagaaaagcctga agaaaaatgacgccgtggtggcaatcatgaaagatcttctggatagcgtc aagtctttcgaaaactacatcaaagcgtttttcggtgaaggcaaggaaac gaatcgtgacgagagcttctatggtgatttcgtcctagcctatgatatcc tgcttaaggtggatcacatctatgatgccatccgcaactatgttacccag aaaccgtactcaaaggacaagttcaagttatacttccagaatccgcagtt tatgggtggctgggataaagataaggaaaccgactatcgcgccaccattt tacgttacggtagtaagtactatctggcaatcatggataaaaaatatgcg aaatgcctgcaaaagatcgacaaggacgatgttaacggcaattatgagaa gatcaactacaaactgctgccgggcccaaataagatgctgccgaaggtgt ttttcagcaaaaaatggatggcgtattacaatccgagcgaggacatccaa aagatctacaaaaacggtacgtttaagaagggtgatatgttcaacctcaa cgattgtcataaacttattgacttcttcaaggatagcatatctcgttatc cgaagtggagcaacgcgtatgactttaactttagcgaaaccgagaaatac aaagatatcgcgggtttctatcgtgaagttgaagaacagggttacaaagt gtccttcgagtccgcgagcaagaaggaggtagacaagctggtcgaggagg gtaagttgtacatgtttcagatttacaataaggacttttccgacaagtcc catggtacaccgaatttgcacaccatgtatttcaagcttctgttcgacga gaacaaccacggccagatccgtctgagcggtggtgcagagctgttcatgc gtagagctagcctgaagaaagaagagttggtcgttcatccggctaattcg ccgatcgcgaacaaaaatccagataaccctaaaaagactacgaccctgag ctatgatgtgtataaagacaaacgctttagcgaagaccagtatgagttac acattccgatcgctatcaacaagtgcccgaagaatattttcaagatcaac accgaagtgcgtgttcttttgaagcacgatgacaacccgtatgtgattgg tattgctcgtggtgaacgtaatctgctgtacattgtggttgtggacggca aaggaaacatcgtggaacagtacagcctgaacgaaatcattaacaatttc aacggcattcgcattaagacggattaccattctttgctggacaaaaagga gaaagagcgtttcgaggcccgtcagaactggacctccatcgagaacatta aggagctgaaggcgggttacatcagccaggtggtgcacaaaatctgcgaa ctggtggagaagtacgacgcggtgattgctttggcggatttgaactccgg ttttaagaacagccgcgttaaagtggaaaagcaggtttatcagaaattcg aaaaaatgctgattgataaattgaattacatggttgacaaaaagtctaac ccgtgtgcaaccggcggtgcgctgaagggctaccaaatcaccaataagtt tgaaagctttaagagcatgagcacgcaaaatggcttcattttttacattc cggcgtggctgaccagcaagatcgatccgtcaaccggctttgttaattta ctgaagacgaagtatacctctattgccgactctaaaaaatttattagttc cttcgatagaatcatgtatgttccggaagaggacctgttcgaatttgcac tggactacaagaactttagccgtaccgatgctgattatataaagaaatgg aaactctacagctatggcaaccgcatccgtatctttcgcaacccgaaaaa aaacaacgtgttcgactgggaagaggtatgtctgacttcagcgtacaagg agcttttcaataaatatggtatcaactaccagcagggtgatatccgtgca ctgctttgcgagcaaagcgataaagcgttctattcaagcttcatggcgct gatgagcctgatgctgcaaatgcgcaacagcatcaccggtcgtaccgatg ttgcatttctgatttctccagtaaaaaacagcgatggtatcttttacgac agccgtaattacgaggcccaagaaaatgcgattttgccgaagaacgctga cgcgaatggtgcatacaacattgcaaggaaagttctgtgggcaatcggcc aatttaaaaaagcggaagatgagaagctggacaaagtgaaaattgcgatt agcaacaaggagtggctggagtatgcgcagacctccgttaaatcaggggg aagtggcggaagcggtgggtctacgaacctgagcgacattattgaaaaag aaactggtaaacagttggtgatccaagaatccattctgatgttaccggag gaagtggaagaggtgatcggcaacaagccggagtccgacatcctggttca caccgcgtatgatgagtcgaccgatgagaatgttatgctgctgaccagcg acgccccagagtacaaaccgtgggcgctcgtcatccaggatagcaatggc gaaaacaagatcaagatgttgtctggcggtagcatggctccgaaaaagaa gcgtaaagtaggtattcatggtgttccggcatcaggttaa 46 Base editor rA1-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgaccctgcgtcgc cgcattgagccgcacgagttcgaagtcttttttgatccgcgtgaactgcg caaagaaacctgtctgctgtatgaaattaactggggtggccgtcacagca tttggcgtcacactagtcaaaacaccaataaacacgtggaagttaacttc atcgagaaatttaccaccgagcgctacttctgcccgaatactcgttgttc tattacgtggtttctctcttggtcgccgtgcggcgagtgcagccgtgcga ttaccgagttcctgagccgttacccgcacgttaccctgtttatctatatc gcgcgtctgtaccatcatgcggacccgcgtaaccgtcaaggtctgcgtga tctgatcagcagcggtgttacgatccagattatgacggagcaggagtccg gctattgctggcgcaacttcgtgaactatagcccatccaatgaagctcat tggccgcgctacccgcacctgtgggtacgtttgtacgtgctggaactcta ctgcatcatccttggcctgccaccgtgcttgaatattttgagacgcaagc agccgcaactgaccttcttcaccatcgccctgcaaagctgtcattatcag cgtttgccgcctcacatcttatgggcaaccggtttgaagtctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatggataaaa agtattcaataggactagctattggcaccaacagcgttggttgggcagtt atcaccgatgaatataaggtcccgagcaagaagtttaaggtcctgggcaa caccgatcgccacagcataaaaaagaaccttattggtgcgctgctgttcg attctggtgagactgccgaagcgacccgtctgaagagaaccgcgcgtcgt agatacacccggcgcaagaaccgtatctgctatctgcaagaaattttcag caacgagatggctaaggtcgacgactccttctttcatcgcctggaggaaa gctttctggttgaggaagacaaaaagcacgagcgtcatccgattttcggt aacattgttgatgaagttgcctaccacgaaaaataccccacaatttatca tctgcgtaaaaaactggtagactccaccgataaggcggatttacgcctta tctatttggcgctggcgcatatgattaagttccgcggtcattttttgatc gagggcgacctgaatccggataacagcgacgttgacaaactgtttatcca gctggtgcagacctataaccagttgttcgaagagaacccgattaatgcgt ctggcgtggacgcgaaggcgatcctgagcgctcgtctgtccaagtcacgc cgcctggagaacttgatcgcgcaactgccgggtgagaagaaaaacggctt gttcggcaatctgattgctctgtccctaggtttgaccccgaatttcaaat ctaattttgatctggcggaagatgcgaaattacagttgagcaaggacact tacgatgacgatctggacaacctgctcgctcagatcggcgatcagtatgc cgatcttttcctggccgcgaagaacctgagcgatgccatcttgctatcgg acatcttacgtgttaacaccgaaatcaccaaagctccgctaagcgcgtcc atgattaaacgttacgatgaacaccaccaggatctgacgctgctgaaagc gttggtgcgccagcaactgccggaaaaatacaaggaaattttcttcgacc aaagcaagaacggttatgcaggctatatcgacggtggtgcgtcgcaagaa gaattttataaattcatcaaaccgattttggagaagatggatggtaccga ggagctgctggtaaaattgaatcgggaagacctcttgcgaaagcagcgta ctttcgataatggtagcatcccgcaccagattcatctgggcgaacttcac gcaatcctacgtcgtcaagaggatttctacccgtttctgaaggataaccg tgaaaagatcgagaagattctgacctttcgtattccgtattatgtgggtc cgctggcgagaggcaacagccgttttgcgtggatgacccgcaagtcggaa gagactatcacgccgtggaatttcgaggaggtcgtggacaagggtgcatc agcgcaatcttttattgaacgtatgaccaattttgataaaaaccttccaa atgaaaaagtgttgccgaagcacagcttgctgtacgagtatttcaccgtt tacaatgaactgacgaaagtcaagtacgttaccgaaggtatgcgtaagcc agcctttctgtctggggagcaaaaaaaagccattgtggatctgctgttca agaccaatcgcaaggttaccgtcaagcaactgaaagaggattacttcaaa aaaatcgaatgttttgactccgtggaaatcagcggcgttgaagaccgctt taatgcatctctgggcacctaccacgatctactcaagatcatcaaggata aggacttcctggacaacgaagaaaatgaggatatcttggaagatattgtg ctgactttaacgttgttcgaggatcgtgagatgattgaagaacgcctcaa aacgtacgcacatctgtttgacgataaggtgatgaaacagctaaagcgcc gtcgttacaccggttggggtcgtctgtctagaaagctgattaacggcatt cgtgacaaacaatctggcaagaccatcctggacttcctcaaatccgacgg cttcgcaaatcgtaatttcatgcaactgatccatgatgatagcctgacct ttaaagaagatattcagaaggctcaagtgtccggccagggtgactcgctg catgagcatatcgcgaatctggctggctcccctgcgataaaaaaaggtat tctccaaacggtgaaagttgtggatgaactggttaaagtcatgggtcgtc ataaaccggaaaacatcgtgattgagatggcacgtgagaaccagaccacc cagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgtatcgaagaggg gattaaggagttaggcagccagattctgaaggagcacccggttgagaaca cccagctgcaaaacgagaagctctacctgtattacctgcaaaacggccgt gacatgtatgttgaccaggagctggacatcaatcgtctcagcgactacga cgtggatgctatcgtgccgcagagctttctaaaagatgattccatcgaca ataaagtgctcacccgtagcgacaagaaccgtggtaaaagcgacaacgtg ccgagcgaggaagtagttaagaaaatgaaaaactactggcgtcagctatt gaacgccaagcttatcacccagcgtaagtttgacaacttgacgaaggcag agcgtggcggcctgagcgagctagacaaggcgggttttattaaacgccag ctggtggaaactcgccagattaccaaacacgttgcgcaaatcttggactc acgcatgaatacgaagtacgacgaaaacgataaattgatccgcgaggtga aggtcataaccctgaaatctaaactggttagcgatttccggaaggacttt caattttataaagtccgggagattaacaactatcaccatgcacacgacgc ttacttaaatgcggttgttggcacggccctgatcaagaagtacccgaaac tggaaagcgagtttgtttatggtgactacaaggtgtatgacgttcgcaag atgattgcaaaatccgaacaagagattggtaaggcgacggctaagtattt tttctacagcaatatcatgaacttcttcaagactgaaatcaccctggcga acggtgaaattcgtaaacgtccgttgatcgaaaccaacggtgaaaccggt gaaatcgtttgggataaaggtagggattttgcgaccgttcgtaaggtcct gagcatgccgcaggttaacatcgtgaaaaagaccgaagtgcagaccggcg gtttctccaaggagagtatcttaccgaagcgcaacagtgacaagctgatc gcgcgtaaaaaagactgggatccgaaaaaatacggcggctttgactcccc gaccgtcgcgtacagcgtactggtcgtggctaaagtggagaaaggcaaat cgaaaaagctgaaatccgttaaagagttgctgggtattacgattatggaa cgttcgagcttcgagaaaaatccgatcgacttcctggaggccaaaggcta caaggaagttaaaaaagacctgatcattaaactgccgaagtacagcctgt tcgagctcgagaacggtcgcaaacgcatgctggcgagcgcgggtgagctc caaaaaggcaacgaattggctctgccgagcaagtacgtgaacttcctgta tctggcctcccattatgaaaaactgaagggtagcccggaagataacgaac aaaagcagctgttcgtggaacaacataaacactatctggacgagattatt gagcaaatcagcgagttcagcaaacgcgtgattctggcggatgctaatct ggacaaggttctttcagcctataataaacaccgtgataagccgatccgtg aacaggcagaaaatattattcacctgttcaccctgacgaacctgggtgcg ccagcagcgtttaaatacttcgacacaacgatcgaccggaagcgttatac cagcaccaaagaggttcttgacgccaccttgattcaccaaagcatcacgg gtctgtatgaaacccgtattgacttgagccagttgggcggagattcaggg ggaagtggcggaagcggtgggtctacgaacctgagcgacattattgaaaa agaaactggtaaacagttggtgatccaagaatccattctgatgttaccgg aggaagtggaagaggtgatcggcaacaagccggagtccgacatcctggtt cacaccgcgtatgatgagtcgaccgatgagaatgttatgctgctgaccag cgacgccccagagtacaaaccgtgggcgctcgtcatccaggatagcaatg gcgaaaacaagatcaagatgttgtctggcggtagcatggctccgaaaaag aagcgtaaagtaggtattcatggtgttccggcatcaggttaa 47 Base editor rA1-dCasPhi-2 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgaccctgcgtcgc cgcattgagccgcacgagttcgaagtcttttttgatccgcgtgaactgcg caaagaaacctgtctgctgtatgaaattaactggggtggccgtcacagca tttggcgtcacactagtcaaaacaccaataaacacgtggaagttaacttc atcgagaaatttaccaccgagcgctacttctgcccgaatactcgttgttc tattacgtggtttctctcttggtcgccgtgcggcgagtgcagccgtgcga ttaccgagttcctgagccgttacccgcacgttaccctgtttatctatatc gcgcgtctgtaccatcatgcggacccgcgtaaccgtcaaggtctgcgtga tctgatcagcagcggtgttacgatccagattatgacggagcaggagtccg gctattgctggcgcaacttcgtgaactatagcccatccaatgaagctcat tggccgcgctacccgcacctgtgggtacgtttgtacgtgctggaactcta ctgcatcatccttggcctgccaccgtgcttgaatattttgagacgcaagc agccgcaactgaccttcttcaccatcgccctgcaaagctgtcattatcag cgtttgccgcctcacatcttatgggcaaccggtttgaagtctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatgccaaaac ccgctgtagagtcagaattttcaaaagttttgaaaaagcactttccggga gaacgtttccgctcgagctatatgaaaagaggcggtaagatcctggctgc ccaaggcgaagaggcagttgttgcgtatctacagggcaagtccgaggagg agcctccgaacttccagccaccggcgaagtgccacgtggtgaccaaatcc cgtgacttcgcggaatggccgatcatgaaggcgtcggaagcgattcaacg ttatatctatgcactgtcgaccaccgaacgcgcggcctgtaaaccgggca aaagtagtgagagccatgcagcgtggttcgccgctaccggtgtcagcaac cacggctacagccacgttcagggtctgaacctgatttttgatcatacctt gggccgttacgatggtgttctgaaaaaggtccaactgcgcaacgaaaagg cgagagcgcgtttagagagcattaacgcgtctagagcagatgaaggttta ccggagattaaagccgaggaggaagaagtggctacgaacgaaaccggcca cctgttgcaaccgccgggtatcaatccgagcttttacgtgtatcagacca ttagcccgcaggcataccgtccgcgtgacgagatcgtgctgccgccggag tacgcaggttacgtacgtgacccgaatgctccgattccgctgggtgtggt gcgtaaccgttgcgatatccaaaaagggtgcccgggctacatcccggaat ggcagcgtgaagcaggtaccgcgatcagcccgaaaacaggcaaggccgta actgtgccgggcctgtctccgaagaaaaacaaacgtatgcgtaggtactg gcgctctgagaaggagaaagctcaagatgcgctgttggttaccgtacgca ttggtaccgattgggttgtcatcgacgtgcgcggtctgttgcgcaacgcc cgttggcgcaccatcgctcccaaggacatcagcctgaatgcgctcctcga tttgtttaccggtgatccggtgatcgatgtgcgtcgcaatattgttacct ttacgtacaccctcgacgcctgtggtacctacgcccgtaaatggaccttg aaaggcaaacagacgaaagcgaccctggacaaactgacggccactcagac ggttgcgttggttgcgattgcgcttggtcagaccaacccgatttccgctg gcattagccgtgttacacaagaaaatggtgcactgcaatgcgaaccgctg gaccggttcaccctgccggatgacctgttgaaggacatcagcgcatatcg cattgcttgggacagaaacgaagaggaactacgcgctcgcagcgtcgagg ccctgccggaggcgcaacaagcggaggtccgtgcgctggacggggtgtcc aaagaaaccgcgcgtacccaactgtgcgcagatttcggcctggacccgaa acgtctgccgtgggataaaatgagctccaatactacctttatcagcgaag ccttgctgtctaacagcgtgagccgtgatcaggtttttttcactccggct ccgaagaagggtgctaagaaaaaagcgcctgttgaagttatgcgtaaaga ccgcacttgggcacgtgcgtacaagccgcgtctgagcgtcgaagctcaga aactgaagaacgaagccctgtgggcacttaagcgcacctccccggagtat ttgaagctgagccgtcgcaaagaggagctgtgtcgtcgtagcatcaacta tgttatcgaaaagacccgtcgccgtacgcaatgtcagattgtgatcccgg tgatcgaggatctgaatgttcgcttctttcatggttctggtaagagactg cccggttgggataatttcttcaccgctaaaaaagagaaccgttggttcat ccagggcctgcacaaagcgtttagcgatctgcgtacgcaccgttccttct atgtttttgaagttcgtccggagcgcacctctattacctgtccaaagtgc ggtcattgcgaggtgggtaatcgtgacggtgaggcgtttcagtgcctgag ctgcggcaagacgtgcaacgcagatcttgacgtcgcgacccataatctga cccaagtggcgttgaccggtaagaccatgccgaagcgcgaggagccgcgt gacgctcagggtacagcgccagcgcgcaagactaagaaggcgagcaaatc aaaggcgccaccggcggagcgcgaagaccagaccccggcgcaagagccaa gccagaccagttctggaggtagcgggggtagcggtggtagcactaactta agtgatattatcgagaaagaaaccgggaaacagctggtgatccaagaaag cattctgatgctgcccgaagaagttgaagaagtgattggtaacaagcctg agtcggacatcttagtgcacaccgcgtacgatgaaagcacggatgagaat gtgatgctgctcacctctgatgcccccgaatacaagccgtgggctctggt gatccaggactctaacggagaaaacaaaattaagatgctctctggcggct ccatggcgcctaaaaaaaaacgcaaagtggggattcacggggttccggcg taa 48 Base editor rA1-dLbCas12a atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgaccctgcgtcgc cgcattgagccgcacgagttcgaagtcttttttgatccgcgtgaactgcg caaagaaacctgtctgctgtatgaaattaactggggtggccgtcacagca tttggcgtcacactagtcaaaacaccaataaacacgtggaagttaacttc atcgagaaatttaccaccgagcgctacttctgcccgaatactcgttgttc tattacgtggtttctctcttggtcgccgtgcggcgagtgcagccgtgcga ttaccgagttcctgagccgttacccgcacgttaccctgtttatctatatc gcgcgtctgtaccatcatgcggacccgcgtaaccgtcaaggtctgcgtga tctgatcagcagcggtgttacgatccagattatgacggagcaggagtccg gctattgctggcgcaacttcgtgaactatagcccatccaatgaagctcat tggccgcgctacccgcacctgtgggtacgtttgtacgtgctggaactcta ctgcatcatccttggcctgccaccgtgcttgaatattttgagacgcaagc agccgcaactgaccttcttcaccatcgccctgcaaagctgtcattatcag cgtttgccgcctcacatcttatgggcaaccggtttgaagtctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatgtcaaaac tagaaaagtttacaaattgttactccctgtcgaaaaccctgagattcaaa gcgatcccggtgggtaaaactcaagagaacattgataacaaacgtctgct ggttgaggacgaaaagcgcgcggaggattacaaaggcgttaaaaagctgt tggaccgttattacctgtcctttattaatgatgttctgcacagcattaaa ttaaagaacctaaacaattacatctccctcttccgtaaaaagacccgcac cgaaaaggaaaataaagaactggagaaccttgagattaatctgcgtaaag aaatcgctaaagcgtttaaaggcaacgagggttataaatccttatttaaa aaagacatcatcgaaacgattctcccagaattcctggacgacaaagacga gatcgcgctggttaattccttcaacggctttaccaccgcattcaccggct tttttgataaccgcgaaaacatgttctctgaagaggccaaaagcacctca attgcgtttcgctgcattaacgaaaatctgacgcgttatatctctaacat ggatatcttcgagaaggttgacgctatctttgataaacatgaagtccagg agatcaaggagaagatcctgaacagcgactacgacgtggaggatttcttc gagggtgagttcttcaattttgttttgacccaagaaggcatcgatgtcta caatgcgataattggtggttttgttaccgagagcggggagaaaattaagg gtctgaacgaatatatcaacttgtacaaccagaaaaccaaacaaaaactg ccgaagtttaagccgctgtacaagcaagtcttgtcggatcgtgaatcgct gagcttttacggcgaaggctacaccagcgatgaggaggtgttggaggtgt tccgcaatacgttgaataagaactctgaaattttttccagcattaagaag ctggaaaaactattcaagaacttcgacgagtatagcagcgcaggtatctt tgtgaaaaacggtccggctattagcaccatctcgaaagacattttcggcg aatggaatgttattcgtgataagtggaatgccgaatacgacgacattcat ctgaagaaaaaggcggttgtaactgaaaagtacgaggacgatcgtcgtaa gtcgttcaaaaagatcggctccttctctctggagcaactgcaagagtacg ccgatgccgatttgtcagtcgtggagaagctgaaagagatcatcattcaa aaagttgacgaaatctataaggtctatggtagcagtgaaaaactgtttga cgcggacttcgtgctggagaaaagcctgaagaaaaatgacgccgtggtgg caatcatgaaagatcttctggatagcgtcaagtctttcgaaaactacatc aaagcgtttttcggtgaaggcaaggaaacgaatcgtgacgagagcttcta tggtgatttcgtcctagcctatgatatcctgcttaaggtggatcacatct atgatgccatccgcaactatgttacccagaaaccgtactcaaaggacaag ttcaagttatacttccagaatccgcagtttatgggtggctgggataaaga taaggaaaccgactatcgcgccaccattttacgttacggtagtaagtact atctggcaatcatggataaaaaatatgcgaaatgcctgcaaaagatcgac aaggacgatgttaacggcaattatgagaagatcaactacaaactgctgcc gggcccaaataagatgctgccgaaggtgtttttcagcaaaaaatggatgg cgtattacaatccgagcgaggacatccaaaagatctacaaaaacggtacg tttaagaagggtgatatgttcaacctcaacgattgtcataaacttattga cttcttcaaggatagcatatctcgttatccgaagtggagcaacgcgtatg actttaactttagcgaaaccgagaaatacaaagatatcgcgggtttctat cgtgaagttgaagaacagggttacaaagtgtccttcgagtccgcgagcaa gaaggaggtagacaagctggtcgaggagggtaagttgtacatgtttcaga tttacaataaggacttttccgacaagtcccatggtacaccgaatttgcac accatgtatttcaagcttctgttcgacgagaacaaccacggccagatccg tctgagcggtggtgcagagctgttcatgcgtagagctagcctgaagaaag aagagttggtcgttcatccggctaattcgccgatcgcgaacaaaaatcca gataaccctaaaaagactacgaccctgagctatgatgtgtataaagacaa acgctttagcgaagaccagtatgagttacacattccgatcgctatcaaca agtgcccgaagaatattttcaagatcaacaccgaagtgcgtgttcttttg aagcacgatgacaacccgtatgtgattggtattgctcgtggtgaacgtaa tctgctgtacattgtggttgtggacggcaaaggaaacatcgtggaacagt acagcctgaacgaaatcattaacaatttcaacggcattcgcattaagacg gattaccattctttgctggacaaaaaggagaaagagcgtttcgaggcccg tcagaactggacctccatcgagaacattaaggagctgaaggcgggttaca tcagccaggtggtgcacaaaatctgcgaactggtggagaagtacgacgcg gtgattgctttggcggatttgaactccggttttaagaacagccgcgttaa agtggaaaagcaggtttatcagaaattcgaaaaaatgctgattgataaat tgaattacatggttgacaaaaagtctaacccgtgtgcaaccggcggtgcg ctgaagggctaccaaatcaccaataagtttgaaagctttaagagcatgag cacgcaaaatggcttcattttttacattccggcgtggctgaccagcaaga tcgatccgtcaaccggctttgttaatttactgaagacgaagtatacctct attgccgactctaaaaaatttattagttccttcgatagaatcatgtatgt tccggaagaggacctgttcgaatttgcactggactacaagaactttagcc gtaccgatgctgattatataaagaaatggaaactctacagctatggcaac cgcatccgtatctttcgcaacccgaaaaaaaacaacgtgttcgactggga agaggtatgtctgacttcagcgtacaaggagcttttcaataaatatggta tcaactaccagcagggtgatatccgtgcactgctttgcgagcaaagcgat aaagcgttctattcaagcttcatggcgctgatgagcctgatgctgcaaat gcgcaacagcatcaccggtcgtaccgatgttgcatttctgatttctccag taaaaaacagcgatggtatcttttacgacagccgtaattacgaggcccaa gaaaatgcgattttgccgaagaacgctgacgcgaatggtgcatacaacat tgcaaggaaagttctgtgggcaatcggccaatttaaaaaagcggaagatg agaagctggacaaagtgaaaattgcgattagcaacaaggagtggctggag tatgcgcagacctccgttaaatcagggggaagtggcggaagcggtgggtc tacgaacctgagcgacattattgaaaaagaaactggtaaacagttggtga tccaagaatccattctgatgttaccggaggaagtggaagaggtgatcggc aacaagccggagtccgacatcctggttcacaccgcgtatgatgagtcgac cgatgagaatgttatgctgctgaccagcgacgccccagagtacaaaccgt gggcgctcgtcatccaggatagcaatggcgaaaacaagatcaagatgttg tctggcggtagcatggctccgaaaaagaagcgtaaagtaggtattcatgg tgttccggcatcaggttaa 49 Base editor rA1-YE1-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgaccttgcgcaga cgtattgagccgcacgaattcgaggtgtttttcgacccgagagaattgcg caaagaaacctgtctgctgtacgagatcaactggggtggtcgtcatagca tctggcgtcacacctctcagaatacgaacaaacacgtggaagtcaatttc atcgagaagttcacgaccgagcgctacttctgtccgaacacccgttgttc gatcacgtggtttctgagctattctccgtgcggcgaatgcagccgtgcaa ttaccgagttcctgtcacgttacccgcacgtaactctgtttatctacatt gcgcgtctctaccatcatgctgatccggaaaaccgtcaaggtttacgcga tctgattagctccggcgtgaccatccagattatgactgagcaggagagcg gctattgctggcgcaactttgttaactattccccgtccaatgaggcgcat tggcctcgttatccgcacctgtgggttcgtctatacgttctggaattgta ctgcattatcctgggcctgccaccatgcttgaatattctgcgtcgcaagc agccgcaattgacctttttcaccatcgccctgcaaagctgccattatcag cgccttccgccgcacatcctgtgggcgaccggtctgaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatggataaaa agtattcaataggactagctattggcaccaacagcgttggttgggcagtt atcaccgatgaatataaggtcccgagcaagaagtttaaggtcctgggcaa caccgatcgccacagcataaaaaagaaccttattggtgcgctgctgttcg attctggtgagactgccgaagcgacccgtctgaagagaaccgcgcgtcgt agatacacccggcgcaagaaccgtatctgctatctgcaagaaattttcag caacgagatggctaaggtcgacgactccttctttcatcgcctggaggaaa gctttctggttgaggaagacaaaaagcacgagcgtcatccgattttcggt aacattgttgatgaagttgcctaccacgaaaaataccccacaatttatca tctgcgtaaaaaactggtagactccaccgataaggcggatttacgcctta tctatttggcgctggcgcatatgattaagttccgcggtcattttttgatc gagggcgacctgaatccggataacagcgacgttgacaaactgtttatcca gctggtgcagacctataaccagttgttcgaagagaacccgattaatgcgt ctggcgtggacgcgaaggcgatcctgagcgctcgtctgtccaagtcacgc cgcctggagaacttgatcgcgcaactgccgggtgagaagaaaaacggctt gttcggcaatctgattgctctgtccctaggtttgaccccgaatttcaaat ctaattttgatctggcggaagatgcgaaattacagttgagcaaggacact tacgatgacgatctggacaacctgctcgctcagatcggcgatcagtatgc cgatcttttcctggccgcgaagaacctgagcgatgccatcttgctatcgg acatcttacgtgttaacaccgaaatcaccaaagctccgctaagcgcgtcc atgattaaacgttacgatgaacaccaccaggatctgacgctgctgaaagc gttggtgcgccagcaactgccggaaaaatacaaggaaattttcttcgacc aaagcaagaacggttatgcaggctatatcgacggtggtgcgtcgcaagaa gaattttataaattcatcaaaccgattttggagaagatggatggtaccga ggagctgctggtaaaattgaatcgggaagacctcttgcgaaagcagcgta ctttcgataatggtagcatcccgcaccagattcatctgggcgaacttcac gcaatcctacgtcgtcaagaggatttctacccgtttctgaaggataaccg tgaaaagatcgagaagattctgacctttcgtattccgtattatgtgggtc cgctggcgagaggcaacagccgttttgcgtggatgacccgcaagtcggaa gagactatcacgccgtggaatttcgaggaggtcgtggacaagggtgcatc agcgcaatcttttattgaacgtatgaccaattttgataaaaaccttccaa atgaaaaagtgttgccgaagcacagcttgctgtacgagtatttcaccgtt tacaatgaactgacgaaagtcaagtacgttaccgaaggtatgcgtaagcc agcctttctgtctggggagcaaaaaaaagccattgtggatctgctgttca agaccaatcgcaaggttaccgtcaagcaactgaaagaggattacttcaaa aaaatcgaatgttttgactccgtggaaatcagcggcgttgaagaccgctt taatgcatctctgggcacctaccacgatctactcaagatcatcaaggata aggacttcctggacaacgaagaaaatgaggatatcttggaagatattgtg ctgactttaacgttgttcgaggatcgtgagatgattgaagaacgcctcaa aacgtacgcacatctgtttgacgataaggtgatgaaacagctaaagcgcc gtcgttacaccggttggggtcgtctgtctagaaagctgattaacggcatt cgtgacaaacaatctggcaagaccatcctggacttcctcaaatccgacgg cttcgcaaatcgtaatttcatgcaactgatccatgatgatagcctgacct ttaaagaagatattcagaaggctcaagtgtccggccagggtgactcgctg catgagcatatcgcgaatctggctggctcccctgcgataaaaaaaggtat tctccaaacggtgaaagttgtggatgaactggttaaagtcatgggtcgtc ataaaccggaaaacatcgtgattgagatggcacgtgagaaccagaccacc cagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgtatcgaagaggg gattaaggagttaggcagccagattctgaaggagcacccggttgagaaca cccagctgcaaaacgagaagctctacctgtattacctgcaaaacggccgt gacatgtatgttgaccaggagctggacatcaatcgtctcagcgactacga cgtggatgctatcgtgccgcagagctttctaaaagatgattccatcgaca ataaagtgctcacccgtagcgacaagaaccgtggtaaaagcgacaacgtg ccgagcgaggaagtagttaagaaaatgaaaaactactggcgtcagctatt gaacgccaagcttatcacccagcgtaagtttgacaacttgacgaaggcag agcgtggcggcctgagcgagctagacaaggcgggttttattaaacgccag ctggtggaaactcgccagattaccaaacacgttgcgcaaatcttggactc acgcatgaatacgaagtacgacgaaaacgataaattgatccgcgaggtga aggtcataaccctgaaatctaaactggttagcgatttccggaaggacttt caattttataaagtccgggagattaacaactatcaccatgcacacgacgc ttacttaaatgcggttgttggcacggccctgatcaagaagtacccgaaac tggaaagcgagtttgtttatggtgactacaaggtgtatgacgttcgcaag atgattgcaaaatccgaacaagagattggtaaggcgacggctaagtattt tttctacagcaatatcatgaacttcttcaagactgaaatcaccctggcga acggtgaaattcgtaaacgtccgttgatcgaaaccaacggtgaaaccggt gaaatcgtttgggataaaggtagggattttgcgaccgttcgtaaggtcct gagcatgccgcaggttaacatcgtgaaaaagaccgaagtgcagaccggcg gtttctccaaggagagtatcttaccgaagcgcaacagtgacaagctgatc gcgcgtaaaaaagactgggatccgaaaaaatacggcggctttgactcccc gaccgtcgcgtacagcgtactggtcgtggctaaagtggagaaaggcaaat cgaaaaagctgaaatccgttaaagagttgctgggtattacgattatggaa cgttcgagcttcgagaaaaatccgatcgacttcctggaggccaaaggcta caaggaagttaaaaaagacctgatcattaaactgccgaagtacagcctgt tcgagctcgagaacggtcgcaaacgcatgctggcgagcgcgggtgagctc caaaaaggcaacgaattggctctgccgagcaagtacgtgaacttcctgta tctggcctcccattatgaaaaactgaagggtagcccggaagataacgaac aaaagcagctgttcgtggaacaacataaacactatctggacgagattatt gagcaaatcagcgagttcagcaaacgcgtgattctggcggatgctaatct ggacaaggttctttcagcctataataaacaccgtgataagccgatccgtg aacaggcagaaaatattattcacctgttcaccctgacgaacctgggtgcg ccagcagcgtttaaatacttcgacacaacgatcgaccggaagcgttatac cagcaccaaagaggttcttgacgccaccttgattcaccaaagcatcacgg gtctgtatgaaacccgtattgacttgagccagttgggcggagattcaggg ggaagtggcggaagcggtgggtctacgaacctgagcgacattattgaaaa agaaactggtaaacagttggtgatccaagaatccattctgatgttaccgg aggaagtggaagaggtgatcggcaacaagccggagtccgacatcctggtt cacaccgcgtatgatgagtcgaccgatgagaatgttatgctgctgaccag cgacgccccagagtacaaaccgtgggcgctcgtcatccaggatagcaatg gcgaaaacaagatcaagatgttgtctggcggtagcatggctccgaaaaag aagcgtaaagtaggtattcatggtgttccggcatcaggttaa 50 Base editor rA1-YE1- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgaccttgcgcaga cgtattgagccgcacgaattcgaggtgtttttcgacccgagagaattgcg caaagaaacctgtctgctgtacgagatcaactggggtggtcgtcatagca tctggcgtcacacctctcagaatacgaacaaacacgtggaagtcaatttc atcgagaagttcacgaccgagcgctacttctgtccgaacacccgttgttc gatcacgtggtttctgagctattctccgtgcggcgaatgcagccgtgcaa ttaccgagttcctgtcacgttacccgcacgtaactctgtttatctacatt gcgcgtctctaccatcatgctgatccggaaaaccgtcaaggtttacgcga tctgattagctccggcgtgaccatccagattatgactgagcaggagagcg gctattgctggcgcaactttgttaactattccccgtccaatgaggcgcat tggcctcgttatccgcacctgtgggttcgtctatacgttctggaattgta ctgcattatcctgggcctgccaccatgcttgaatattctgcgtcgcaagc agccgcaattgacctttttcaccatcgccctgcaaagctgccattatcag cgccttccgccgcacatcctgtgggcgaccggtctgaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatgccaaaac ccgctgtagagtcagaattttcaaaagttttgaaaaagcactttccggga gaacgtttccgctcgagctatatgaaaagaggcggtaagatcctggctgc ccaaggcgaagaggcagttgttgcgtatctacagggcaagtccgaggagg agcctccgaacttccagccaccggcgaagtgccacgtggtgaccaaatcc cgtgacttcgcggaatggccgatcatgaaggcgtcggaagcgattcaacg ttatatctatgcactgtcgaccaccgaacgcgcggcctgtaaaccgggca aaagtagtgagagccatgcagcgtggttcgccgctaccggtgtcagcaac cacggctacagccacgttcagggtctgaacctgatttttgatcatacctt gggccgttacgatggtgttctgaaaaaggtccaactgcgcaacgaaaagg cgagagcgcgtttagagagcattaacgcgtctagagcagatgaaggttta ccggagattaaagccgaggaggaagaagtggctacgaacgaaaccggcca cctgttgcaaccgccgggtatcaatccgagcttttacgtgtatcagacca ttagcccgcaggcataccgtccgcgtgacgagatcgtgctgccgccggag tacgcaggttacgtacgtgacccgaatgctccgattccgctgggtgtggt gcgtaaccgttgcgatatccaaaaagggtgcccgggctacatcccggaat ggcagcgtgaagcaggtaccgcgatcagcccgaaaacaggcaaggccgta actgtgccgggcctgtctccgaagaaaaacaaacgtatgcgtaggtactg gcgctctgagaaggagaaagctcaagatgcgctgttggttaccgtacgca ttggtaccgattgggttgtcatcgacgtgcgcggtctgttgcgcaacgcc cgttggcgcaccatcgctcccaaggacatcagcctgaatgcgctcctcga tttgtttaccggtgatccggtgatcgatgtgcgtcgcaatattgttacct ttacgtacaccctcgacgcctgtggtacctacgcccgtaaatggaccttg aaaggcaaacagacgaaagcgaccctggacaaactgacggccactcagac ggttgcgttggttgcgattgcgcttggtcagaccaacccgatttccgctg gcattagccgtgttacacaagaaaatggtgcactgcaatgcgaaccgctg gaccggttcaccctgccggatgacctgttgaaggacatcagcgcatatcg cattgcttgggacagaaacgaagaggaactacgcgctcgcagcgtcgagg ccctgccggaggcgcaacaagcggaggtccgtgcgctggacggggtgtcc aaagaaaccgcgcgtacccaactgtgcgcagatttcggcctggacccgaa acgtctgccgtgggataaaatgagctccaatactacctttatcagcgaag ccttgctgtctaacagcgtgagccgtgatcaggtttttttcactccggct ccgaagaagggtgctaagaaaaaagcgcctgttgaagttatgcgtaaaga ccgcacttgggcacgtgcgtacaagccgcgtctgagcgtcgaagctcaga aactgaagaacgaagccctgtgggcacttaagcgcacctccccggagtat ttgaagctgagccgtcgcaaagaggagctgtgtcgtcgtagcatcaacta tgttatcgaaaagacccgtcgccgtacgcaatgtcagattgtgatcccgg tgatcgaggatctgaatgttcgcttctttcatggttctggtaagagactg cccggttgggataatttcttcaccgctaaaaaagagaaccgttggttcat ccagggcctgcacaaagcgtttagcgatctgcgtacgcaccgttccttct atgtttttgaagttcgtccggagcgcacctctattacctgtccaaagtgc ggtcattgcgaggtgggtaatcgtgacggtgaggcgtttcagtgcctgag ctgcggcaagacgtgcaacgcagatcttgacgtcgcgacccataatctga cccaagtggcgttgaccggtaagaccatgccgaagcgcgaggagccgcgt gacgctcagggtacagcgccagcgcgcaagactaagaaggcgagcaaatc aaaggcgccaccggcggagcgcgaagaccagaccccggcgcaagagccaa gccagaccagttctggaggtagcgggggtagcggtggtagcactaactta agtgatattatcgagaaagaaaccgggaaacagctggtgatccaagaaag cattctgatgctgcccgaagaagttgaagaagtgattggtaacaagcctg agtcggacatcttagtgcacaccgcgtacgatgaaagcacggatgagaat gtgatgctgctcacctctgatgcccccgaatacaagccgtgggctctggt gatccaggactctaacggagaaaacaaaattaagatgctctctggcggct ccatggcgcctaaaaaaaaacgcaaagtggggattcacggggttccggcg taa 51 Base editor rA1-YE1- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgaccttgcgcaga cgtattgagccgcacgaattcgaggtgtttttcgacccgagagaattgcg caaagaaacctgtctgctgtacgagatcaactggggtggtcgtcatagca tctggcgtcacacctctcagaatacgaacaaacacgtggaagtcaatttc atcgagaagttcacgaccgagcgctacttctgtccgaacacccgttgttc gatcacgtggtttctgagctattctccgtgcggcgaatgcagccgtgcaa ttaccgagttcctgtcacgttacccgcacgtaactctgtttatctacatt gcgcgtctctaccatcatgctgatccggaaaaccgtcaaggtttacgcga tctgattagctccggcgtgaccatccagattatgactgagcaggagagcg gctattgctggcgcaactttgttaactattccccgtccaatgaggcgcat tggcctcgttatccgcacctgtgggttcgtctatacgttctggaattgta ctgcattatcctgggcctgccaccatgcttgaatattctgcgtcgcaagc agccgcaattgacctttttcaccatcgccctgcaaagctgccattatcag cgccttccgccgcacatcctgtgggcgaccggtctgaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatgtcaaaac tagaaaagtttacaaattgttactccctgtcgaaaaccctgagattcaaa gcgatcccggtgggtaaaactcaagagaacattgataacaaacgtctgct ggttgaggacgaaaagcgcgcggaggattacaaaggcgttaaaaagctgt tggaccgttattacctgtcctttattaatgatgttctgcacagcattaaa ttaaagaacctaaacaattacatctccctcttccgtaaaaagacccgcac cgaaaaggaaaataaagaactggagaaccttgagattaatctgcgtaaag aaatcgctaaagcgtttaaaggcaacgagggttataaatccttatttaaa aaagacatcatcgaaacgattctcccagaattcctggacgacaaagacga gatcgcgctggttaattccttcaacggctttaccaccgcattcaccggct tttttgataaccgcgaaaacatgttctctgaagaggccaaaagcacctca attgcgtttcgctgcattaacgaaaatctgacgcgttatatctctaacat ggatatcttcgagaaggttgacgctatctttgataaacatgaagtccagg agatcaaggagaagatcctgaacagcgactacgacgtggaggatttcttc gagggtgagttcttcaattttgttttgacccaagaaggcatcgatgtcta caatgcgataattggtggttttgttaccgagagcggggagaaaattaagg gtctgaacgaatatatcaacttgtacaaccagaaaaccaaacaaaaactg ccgaagtttaagccgctgtacaagcaagtcttgtcggatcgtgaatcgct gagcttttacggcgaaggctacaccagcgatgaggaggtgttggaggtgt tccgcaatacgttgaataagaactctgaaattttttccagcattaagaag ctggaaaaactattcaagaacttcgacgagtatagcagcgcaggtatctt tgtgaaaaacggtccggctattagcaccatctcgaaagacattttcggcg aatggaatgttattcgtgataagtggaatgccgaatacgacgacattcat ctgaagaaaaaggcggttgtaactgaaaagtacgaggacgatcgtcgtaa gtcgttcaaaaagatcggctccttctctctggagcaactgcaagagtacg ccgatgccgatttgtcagtcgtggagaagctgaaagagatcatcattcaa aaagttgacgaaatctataaggtctatggtagcagtgaaaaactgtttga cgcggacttcgtgctggagaaaagcctgaagaaaaatgacgccgtggtgg caatcatgaaagatcttctggatagcgtcaagtctttcgaaaactacatc aaagcgtttttcggtgaaggcaaggaaacgaatcgtgacgagagcttcta tggtgatttcgtcctagcctatgatatcctgcttaaggtggatcacatct atgatgccatccgcaactatgttacccagaaaccgtactcaaaggacaag ttcaagttatacttccagaatccgcagtttatgggtggctgggataaaga taaggaaaccgactatcgcgccaccattttacgttacggtagtaagtact atctggcaatcatggataaaaaatatgcgaaatgcctgcaaaagatcgac aaggacgatgttaacggcaattatgagaagatcaactacaaactgctgcc gggcccaaataagatgctgccgaaggtgtttttcagcaaaaaatggatgg cgtattacaatccgagcgaggacatccaaaagatctacaaaaacggtacg tttaagaagggtgatatgttcaacctcaacgattgtcataaacttattga cttcttcaaggatagcatatctcgttatccgaagtggagcaacgcgtatg actttaactttagcgaaaccgagaaatacaaagatatcgcgggtttctat cgtgaagttgaagaacagggttacaaagtgtccttcgagtccgcgagcaa gaaggaggtagacaagctggtcgaggagggtaagttgtacatgtttcaga tttacaataaggacttttccgacaagtcccatggtacaccgaatttgcac accatgtatttcaagcttctgttcgacgagaacaaccacggccagatccg tctgagcggtggtgcagagctgttcatgcgtagagctagcctgaagaaag aagagttggtcgttcatccggctaattcgccgatcgcgaacaaaaatcca gataaccctaaaaagactacgaccctgagctatgatgtgtataaagacaa acgctttagcgaagaccagtatgagttacacattccgatcgctatcaaca agtgcccgaagaatattttcaagatcaacaccgaagtgcgtgttcttttg aagcacgatgacaacccgtatgtgattggtattgctcgtggtgaacgtaa tctgctgtacattgtggttgtggacggcaaaggaaacatcgtggaacagt acagcctgaacgaaatcattaacaatttcaacggcattcgcattaagacg gattaccattctttgctggacaaaaaggagaaagagcgtttcgaggcccg tcagaactggacctccatcgagaacattaaggagctgaaggcgggttaca tcagccaggtggtgcacaaaatctgcgaactggtggagaagtacgacgcg gtgattgctttggcggatttgaactccggttttaagaacagccgcgttaa agtggaaaagcaggtttatcagaaattcgaaaaaatgctgattgataaat tgaattacatggttgacaaaaagtctaacccgtgtgcaaccggcggtgcg ctgaagggctaccaaatcaccaataagtttgaaagctttaagagcatgag cacgcaaaatggcttcattttttacattccggcgtggctgaccagcaaga tcgatccgtcaaccggctttgttaatttactgaagacgaagtatacctct attgccgactctaaaaaatttattagttccttcgatagaatcatgtatgt tccggaagaggacctgttcgaatttgcactggactacaagaactttagcc gtaccgatgctgattatataaagaaatggaaactctacagctatggcaac cgcatccgtatctttcgcaacccgaaaaaaaacaacgtgttcgactggga agaggtatgtctgacttcagcgtacaaggagcttttcaataaatatggta tcaactaccagcagggtgatatccgtgcactgctttgcgagcaaagcgat aaagcgttctattcaagcttcatggcgctgatgagcctgatgctgcaaat gcgcaacagcatcaccggtcgtaccgatgttgcatttctgatttctccag taaaaaacagcgatggtatcttttacgacagccgtaattacgaggcccaa gaaaatgcgattttgccgaagaacgctgacgcgaatggtgcatacaacat tgcaaggaaagttctgtgggcaatcggccaatttaaaaaagcggaagatg agaagctggacaaagtgaaaattgcgattagcaacaaggagtggctggag tatgcgcagacctccgttaaatcagggggaagtggcggaagcggtgggtc tacgaacctgagcgacattattgaaaaagaaactggtaaacagttggtga tccaagaatccattctgatgttaccggaggaagtggaagaggtgatcggc aacaagccggagtccgacatcctggttcacaccgcgtatgatgagtcgac cgatgagaatgttatgctgctgaccagcgacgccccagagtacaaaccgt gggcgctcgtcatccaggatagcaatggcgaaaacaagatcaagatgttg tctggcggtagcatggctccgaaaaagaagcgtaaagtaggtattcatgg tgttccggcatcaggttaa 52 Base editor rA1-YEE-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaagtgaaacaggacccgttgctgtagacccgaccttgagacgc cgcattgagccgcacgaatttgaagttttcttcgacccgcgtgaattgcg taaagagacgtgcttgctgtacgagattaactggggtggccgtcacagca tttggcgccacaccagccaaaacaccaacaaacatgtggaagtcaacttc atcgagaagttcactaccgagcgttacttttgtccgaatacgcgttgttc gatcacctggtttctgtcctattccccgtgcggtgaatgctcacgcgcaa tcactgagttcctgtctcgttacccgcacgtaaccctgtttatctatatc gcgcgtttgtaccatcatgcggatccggagaaccgccagggtctggaaga tttaattagcagcggcgttacgatccagattatgaccgagcaggagagcg gctattgctggcgtaatttcgtgaactattccccgtctaatgaagcgcat tggccgcgttacccacacctgtgggttcgtctctacgtgctggaattgta ctgcattatcctgggtttaccgccttgcctgaatattctacgtcgcaagc aaccgcagctgacctttttcaccatcgccctgcaaagctgtcattatcag cgtctgccgccacacatcctgtgggctaccggccttaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatggataaaa agtattcaataggactagctattggcaccaacagcgttggttgggcagtt atcaccgatgaatataaggtcccgagcaagaagtttaaggtcctgggcaa caccgatcgccacagcataaaaaagaaccttattggtgcgctgctgttcg attctggtgagactgccgaagcgacccgtctgaagagaaccgcgcgtcgt agatacacccggcgcaagaaccgtatctgctatctgcaagaaattttcag caacgagatggctaaggtcgacgactccttctttcatcgcctggaggaaa gctttctggttgaggaagacaaaaagcacgagcgtcatccgattttcggt aacattgttgatgaagttgcctaccacgaaaaataccccacaatttatca tctgcgtaaaaaactggtagactccaccgataaggcggatttacgcctta tctatttggcgctggcgcatatgattaagttccgcggtcattttttgatc gagggcgacctgaatccggataacagcgacgttgacaaactgtttatcca gctggtgcagacctataaccagttgttcgaagagaacccgattaatgcgt ctggcgtggacgcgaaggcgatcctgagcgctcgtctgtccaagtcacgc cgcctggagaacttgatcgcgcaactgccgggtgagaagaaaaacggctt gttcggcaatctgattgctctgtccctaggtttgaccccgaatttcaaat ctaattttgatctggcggaagatgcgaaattacagttgagcaaggacact tacgatgacgatctggacaacctgctcgctcagatcggcgatcagtatgc cgatcttttcctggccgcgaagaacctgagcgatgccatcttgctatcgg acatcttacgtgttaacaccgaaatcaccaaagctccgctaagcgcgtcc atgattaaacgttacgatgaacaccaccaggatctgacgctgctgaaagc gttggtgcgccagcaactgccggaaaaatacaaggaaattttcttcgacc aaagcaagaacggttatgcaggctatatcgacggtggtgcgtcgcaagaa gaattttataaattcatcaaaccgattttggagaagatggatggtaccga ggagctgctggtaaaattgaatcgggaagacctcttgcgaaagcagcgta ctttcgataatggtagcatcccgcaccagattcatctgggcgaacttcac gcaatcctacgtcgtcaagaggatttctacccgtttctgaaggataaccg tgaaaagatcgagaagattctgacctttcgtattccgtattatgtgggtc cgctggcgagaggcaacagccgttttgcgtggatgacccgcaagtcggaa gagactatcacgccgtggaatttcgaggaggtcgtggacaagggtgcatc agcgcaatcttttattgaacgtatgaccaattttgataaaaaccttccaa atgaaaaagtgttgccgaagcacagcttgctgtacgagtatttcaccgtt tacaatgaactgacgaaagtcaagtacgttaccgaaggtatgcgtaagcc agcctttctgtctggggagcaaaaaaaagccattgtggatctgctgttca agaccaatcgcaaggttaccgtcaagcaactgaaagaggattacttcaaa aaaatcgaatgttttgactccgtggaaatcagcggcgttgaagaccgctt taatgcatctctgggcacctaccacgatctactcaagatcatcaaggata aggacttcctggacaacgaagaaaatgaggatatcttggaagatattgtg ctgactttaacgttgttcgaggatcgtgagatgattgaagaacgcctcaa aacgtacgcacatctgtttgacgataaggtgatgaaacagctaaagcgcc gtcgttacaccggttggggtcgtctgtctagaaagctgattaacggcatt cgtgacaaacaatctggcaagaccatcctggacttcctcaaatccgacgg cttcgcaaatcgtaatttcatgcaactgatccatgatgatagcctgacct ttaaagaagatattcagaaggctcaagtgtccggccagggtgactcgctg catgagcatatcgcgaatctggctggctcccctgcgataaaaaaaggtat tctccaaacggtgaaagttgtggatgaactggttaaagtcatgggtcgtc ataaaccggaaaacatcgtgattgagatggcacgtgagaaccagaccacc cagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgtatcgaagaggg gattaaggagttaggcagccagattctgaaggagcacccggttgagaaca cccagctgcaaaacgagaagctctacctgtattacctgcaaaacggccgt gacatgtatgttgaccaggagctggacatcaatcgtctcagcgactacga cgtggatgctatcgtgccgcagagctttctaaaagatgattccatcgaca ataaagtgctcacccgtagcgacaagaaccgtggtaaaagcgacaacgtg ccgagcgaggaagtagttaagaaaatgaaaaactactggcgtcagctatt gaacgccaagcttatcacccagcgtaagtttgacaacttgacgaaggcag agcgtggcggcctgagcgagctagacaaggcgggttttattaaacgccag ctggtggaaactcgccagattaccaaacacgttgcgcaaatcttggactc acgcatgaatacgaagtacgacgaaaacgataaattgatccgcgaggtga aggtcataaccctgaaatctaaactggttagcgatttccggaaggacttt caattttataaagtccgggagattaacaactatcaccatgcacacgacgc ttacttaaatgcggttgttggcacggccctgatcaagaagtacccgaaac tggaaagcgagtttgtttatggtgactacaaggtgtatgacgttcgcaag atgattgcaaaatccgaacaagagattggtaaggcgacggctaagtattt tttctacagcaatatcatgaacttcttcaagactgaaatcaccctggcga acggtgaaattcgtaaacgtccgttgatcgaaaccaacggtgaaaccggt gaaatcgtttgggataaaggtagggattttgcgaccgttcgtaaggtcct gagcatgccgcaggttaacatcgtgaaaaagaccgaagtgcagaccggcg gtttctccaaggagagtatcttaccgaagcgcaacagtgacaagctgatc gcgcgtaaaaaagactgggatccgaaaaaatacggcggctttgactcccc gaccgtcgcgtacagcgtactggtcgtggctaaagtggagaaaggcaaat cgaaaaagctgaaatccgttaaagagttgctgggtattacgattatggaa cgttcgagcttcgagaaaaatccgatcgacttcctggaggccaaaggcta caaggaagttaaaaaagacctgatcattaaactgccgaagtacagcctgt tcgagctcgagaacggtcgcaaacgcatgctggcgagcgcgggtgagctc caaaaaggcaacgaattggctctgccgagcaagtacgtgaacttcctgta tctggcctcccattatgaaaaactgaagggtagcccggaagataacgaac aaaagcagctgttcgtggaacaacataaacactatctggacgagattatt gagcaaatcagcgagttcagcaaacgcgtgattctggcggatgctaatct ggacaaggttctttcagcctataataaacaccgtgataagccgatccgtg aacaggcagaaaatattattcacctgttcaccctgacgaacctgggtgcg ccagcagcgtttaaatacttcgacacaacgatcgaccggaagcgttatac cagcaccaaagaggttcttgacgccaccttgattcaccaaagcatcacgg gtctgtatgaaacccgtattgacttgagccagttgggcggagattcaggg ggaagtggcggaagcggtgggtctacgaacctgagcgacattattgaaaa agaaactggtaaacagttggtgatccaagaatccattctgatgttaccgg aggaagtggaagaggtgatcggcaacaagccggagtccgacatcctggtt cacaccgcgtatgatgagtcgaccgatgagaatgttatgctgctgaccag cgacgccccagagtacaaaccgtgggcgctcgtcatccaggatagcaatg gcgaaaacaagatcaagatgttgtctggcggtagcatggctccgaaaaag aagcgtaaagtaggtattcatggtgttccggcatcaggttaa 53 Base editor rA1-YEE- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaagtgaaacaggacccgttgctgtagacccgaccttgagacgc cgcattgagccgcacgaatttgaagttttcttcgacccgcgtgaattgcg taaagagacgtgcttgctgtacgagattaactggggtggccgtcacagca tttggcgccacaccagccaaaacaccaacaaacatgtggaagtcaacttc atcgagaagttcactaccgagcgttacttttgtccgaatacgcgttgttc gatcacctggtttctgtcctattccccgtgcggtgaatgctcacgcgcaa tcactgagttcctgtctcgttacccgcacgtaaccctgtttatctatatc gcgcgtttgtaccatcatgcggatccggagaaccgccagggtctggaaga tttaattagcagcggcgttacgatccagattatgaccgagcaggagagcg gctattgctggcgtaatttcgtgaactattccccgtctaatgaagcgcat tggccgcgttacccacacctgtgggttcgtctctacgtgctggaattgta ctgcattatcctgggtttaccgccttgcctgaatattctacgtcgcaagc aaccgcagctgacctttttcaccatcgccctgcaaagctgtcattatcag cgtctgccgccacacatcctgtgggctaccggccttaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatgccaaaac ccgctgtagagtcagaattttcaaaagttttgaaaaagcactttccggga gaacgtttccgctcgagctatatgaaaagaggcggtaagatcctggctgc ccaaggcgaagaggcagttgttgcgtatctacagggcaagtccgaggagg agcctccgaacttccagccaccggcgaagtgccacgtggtgaccaaatcc cgtgacttcgcggaatggccgatcatgaaggcgtcggaagcgattcaacg ttatatctatgcactgtcgaccaccgaacgcgcggcctgtaaaccgggca aaagtagtgagagccatgcagcgtggttcgccgctaccggtgtcagcaac cacggctacagccacgttcagggtctgaacctgatttttgatcatacctt gggccgttacgatggtgttctgaaaaaggtccaactgcgcaacgaaaagg cgagagcgcgtttagagagcattaacgcgtctagagcagatgaaggttta ccggagattaaagccgaggaggaagaagtggctacgaacgaaaccggcca cctgttgcaaccgccgggtatcaatccgagcttttacgtgtatcagacca ttagcccgcaggcataccgtccgcgtgacgagatcgtgctgccgccggag tacgcaggttacgtacgtgacccgaatgctccgattccgctgggtgtggt gcgtaaccgttgcgatatccaaaaagggtgcccgggctacatcccggaat ggcagcgtgaagcaggtaccgcgatcagcccgaaaacaggcaaggccgta actgtgccgggcctgtctccgaagaaaaacaaacgtatgcgtaggtactg gcgctctgagaaggagaaagctcaagatgcgctgttggttaccgtacgca ttggtaccgattgggttgtcatcgacgtgcgcggtctgttgcgcaacgcc cgttggcgcaccatcgctcccaaggacatcagcctgaatgcgctcctcga tttgtttaccggtgatccggtgatcgatgtgcgtcgcaatattgttacct ttacgtacaccctcgacgcctgtggtacctacgcccgtaaatggaccttg aaaggcaaacagacgaaagcgaccctggacaaactgacggccactcagac ggttgcgttggttgcgattgcgcttggtcagaccaacccgatttccgctg gcattagccgtgttacacaagaaaatggtgcactgcaatgcgaaccgctg gaccggttcaccctgccggatgacctgttgaaggacatcagcgcatatcg cattgcttgggacagaaacgaagaggaactacgcgctcgcagcgtcgagg ccctgccggaggcgcaacaagcggaggtccgtgcgctggacggggtgtcc aaagaaaccgcgcgtacccaactgtgcgcagatttcggcctggacccgaa acgtctgccgtgggataaaatgagctccaatactacctttatcagcgaag ccttgctgtctaacagcgtgagccgtgatcaggtttttttcactccggct ccgaagaagggtgctaagaaaaaagcgcctgttgaagttatgcgtaaaga ccgcacttgggcacgtgcgtacaagccgcgtctgagcgtcgaagctcaga aactgaagaacgaagccctgtgggcacttaagcgcacctccccggagtat ttgaagctgagccgtcgcaaagaggagctgtgtcgtcgtagcatcaacta tgttatcgaaaagacccgtcgccgtacgcaatgtcagattgtgatcccgg tgatcgaggatctgaatgttcgcttctttcatggttctggtaagagactg cccggttgggataatttcttcaccgctaaaaaagagaaccgttggttcat ccagggcctgcacaaagcgtttagcgatctgcgtacgcaccgttccttct atgtttttgaagttcgtccggagcgcacctctattacctgtccaaagtgc ggtcattgcgaggtgggtaatcgtgacggtgaggcgtttcagtgcctgag ctgcggcaagacgtgcaacgcagatcttgacgtcgcgacccataatctga cccaagtggcgttgaccggtaagaccatgccgaagcgcgaggagccgcgt gacgctcagggtacagcgccagcgcgcaagactaagaaggcgagcaaatc aaaggcgccaccggcggagcgcgaagaccagaccccggcgcaagagccaa gccagaccagttctggaggtagcgggggtagcggtggtagcactaactta agtgatattatcgagaaagaaaccgggaaacagctggtgatccaagaaag cattctgatgctgcccgaagaagttgaagaagtgattggtaacaagcctg agtcggacatcttagtgcacaccgcgtacgatgaaagcacggatgagaat gtgatgctgctcacctctgatgcccccgaatacaagccgtgggctctggt gatccaggactctaacggagaaaacaaaattaagatgctctctggcggct ccatggcgcctaaaaaaaaacgcaaagtggggattcacggggttccggcg taa 54 Base editor rA1-YEE- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaagtgaaacaggacccgttgctgtagacccgaccttgagacgc cgcattgagccgcacgaatttgaagttttcttcgacccgcgtgaattgcg taaagagacgtgcttgctgtacgagattaactggggtggccgtcacagca tttggcgccacaccagccaaaacaccaacaaacatgtggaagtcaacttc atcgagaagttcactaccgagcgttacttttgtccgaatacgcgttgttc gatcacctggtttctgtcctattccccgtgcggtgaatgctcacgcgcaa tcactgagttcctgtctcgttacccgcacgtaaccctgtttatctatatc gcgcgtttgtaccatcatgcggatccggagaaccgccagggtctggaaga tttaattagcagcggcgttacgatccagattatgaccgagcaggagagcg gctattgctggcgtaatttcgtgaactattccccgtctaatgaagcgcat tggccgcgttacccacacctgtgggttcgtctctacgtgctggaattgta ctgcattatcctgggtttaccgccttgcctgaatattctacgtcgcaagc aaccgcagctgacctttttcaccatcgccctgcaaagctgtcattatcag cgtctgccgccacacatcctgtgggctaccggccttaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctggaatgtcaaaac tagaaaagtttacaaattgttactccctgtcgaaaaccctgagattcaaa gcgatcccggtgggtaaaactcaagagaacattgataacaaacgtctgct ggttgaggacgaaaagcgcgcggaggattacaaaggcgttaaaaagctgt tggaccgttattacctgtcctttattaatgatgttctgcacagcattaaa ttaaagaacctaaacaattacatctccctcttccgtaaaaagacccgcac cgaaaaggaaaataaagaactggagaaccttgagattaatctgcgtaaag aaatcgctaaagcgtttaaaggcaacgagggttataaatccttatttaaa aaagacatcatcgaaacgattctcccagaattcctggacgacaaagacga gatcgcgctggttaattccttcaacggctttaccaccgcattcaccggct tttttgataaccgcgaaaacatgttctctgaagaggccaaaagcacctca attgcgtttcgctgcattaacgaaaatctgacgcgttatatctctaacat ggatatcttcgagaaggttgacgctatctttgataaacatgaagtccagg agatcaaggagaagatcctgaacagcgactacgacgtggaggatttcttc gagggtgagttcttcaattttgttttgacccaagaaggcatcgatgtcta caatgcgataattggtggttttgttaccgagagcggggagaaaattaagg gtctgaacgaatatatcaacttgtacaaccagaaaaccaaacaaaaactg ccgaagtttaagccgctgtacaagcaagtcttgtcggatcgtgaatcgct gagcttttacggcgaaggctacaccagcgatgaggaggtgttggaggtgt tccgcaatacgttgaataagaactctgaaattttttccagcattaagaag ctggaaaaactattcaagaacttcgacgagtatagcagcgcaggtatctt tgtgaaaaacggtccggctattagcaccatctcgaaagacattttcggcg aatggaatgttattcgtgataagtggaatgccgaatacgacgacattcat ctgaagaaaaaggcggttgtaactgaaaagtacgaggacgatcgtcgtaa gtcgttcaaaaagatcggctccttctctctggagcaactgcaagagtacg ccgatgccgatttgtcagtcgtggagaagctgaaagagatcatcattcaa aaagttgacgaaatctataaggtctatggtagcagtgaaaaactgtttga cgcggacttcgtgctggagaaaagcctgaagaaaaatgacgccgtggtgg caatcatgaaagatcttctggatagcgtcaagtctttcgaaaactacatc aaagcgtttttcggtgaaggcaaggaaacgaatcgtgacgagagcttcta tggtgatttcgtcctagcctatgatatcctgcttaaggtggatcacatct atgatgccatccgcaactatgttacccagaaaccgtactcaaaggacaag ttcaagttatacttccagaatccgcagtttatgggtggctgggataaaga taaggaaaccgactatcgcgccaccattttacgttacggtagtaagtact atctggcaatcatggataaaaaatatgcgaaatgcctgcaaaagatcgac aaggacgatgttaacggcaattatgagaagatcaactacaaactgctgcc gggcccaaataagatgctgccgaaggtgtttttcagcaaaaaatggatgg cgtattacaatccgagcgaggacatccaaaagatctacaaaaacggtacg tttaagaagggtgatatgttcaacctcaacgattgtcataaacttattga cttcttcaaggatagcatatctcgttatccgaagtggagcaacgcgtatg actttaactttagcgaaaccgagaaatacaaagatatcgcgggtttctat cgtgaagttgaagaacagggttacaaagtgtccttcgagtccgcgagcaa gaaggaggtagacaagctggtcgaggagggtaagttgtacatgtttcaga tttacaataaggacttttccgacaagtcccatggtacaccgaatttgcac accatgtatttcaagcttctgttcgacgagaacaaccacggccagatccg tctgagcggtggtgcagagctgttcatgcgtagagctagcctgaagaaag aagagttggtcgttcatccggctaattcgccgatcgcgaacaaaaatcca gataaccctaaaaagactacgaccctgagctatgatgtgtataaagacaa acgctttagcgaagaccagtatgagttacacattccgatcgctatcaaca agtgcccgaagaatattttcaagatcaacaccgaagtgcgtgttcttttg aagcacgatgacaacccgtatgtgattggtattgctcgtggtgaacgtaa tctgctgtacattgtggttgtggacggcaaaggaaacatcgtggaacagt acagcctgaacgaaatcattaacaatttcaacggcattcgcattaagacg gattaccattctttgctggacaaaaaggagaaagagcgtttcgaggcccg tcagaactggacctccatcgagaacattaaggagctgaaggcgggttaca tcagccaggtggtgcacaaaatctgcgaactggtggagaagtacgacgcg gtgattgctttggcggatttgaactccggttttaagaacagccgcgttaa agtggaaaagcaggtttatcagaaattcgaaaaaatgctgattgataaat tgaattacatggttgacaaaaagtctaacccgtgtgcaaccggcggtgcg ctgaagggctaccaaatcaccaataagtttgaaagctttaagagcatgag cacgcaaaatggcttcattttttacattccggcgtggctgaccagcaaga tcgatccgtcaaccggctttgttaatttactgaagacgaagtatacctct attgccgactctaaaaaatttattagttccttcgatagaatcatgtatgt tccggaagaggacctgttcgaatttgcactggactacaagaactttagcc gtaccgatgctgattatataaagaaatggaaactctacagctatggcaac cgcatccgtatctttcgcaacccgaaaaaaaacaacgtgttcgactggga agaggtatgtctgacttcagcgtacaaggagcttttcaataaatatggta tcaactaccagcagggtgatatccgtgcactgctttgcgagcaaagcgat aaagcgttctattcaagcttcatggcgctgatgagcctgatgctgcaaat gcgcaacagcatcaccggtcgtaccgatgttgcatttctgatttctccag taaaaaacagcgatggtatcttttacgacagccgtaattacgaggcccaa gaaaatgcgattttgccgaagaacgctgacgcgaatggtgcatacaacat tgcaaggaaagttctgtgggcaatcggccaatttaaaaaagcggaagatg agaagctggacaaagtgaaaattgcgattagcaacaaggagtggctggag tatgcgcagacctccgttaaatcagggggaagtggcggaagcggtgggtc tacgaacctgagcgacattattgaaaaagaaactggtaaacagttggtga tccaagaatccattctgatgttaccggaggaagtggaagaggtgatcggc aacaagccggagtccgacatcctggttcacaccgcgtatgatgagtcgac cgatgagaatgttatgctgctgaccagcgacgccccagagtacaaaccgt gggcgctcgtcatccaggatagcaatggcgaaaacaagatcaagatgttg tctggcggtagcatggctccgaaaaagaagcgtaaagtaggtattcatgg tgttccggcatcaggttaa 55 Base editor RrA3F-F1301-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgaaacctcagattcgcgatcatcgtccgaatcctatggaggcgatg tatccgcatattttctactttcattttgaaaacttagaaaaagcctatgg ccgtaacgaaacttggctgtgctttaccgtagagattatcaaacaatatt taccggtaccctggaaaaaaggtgttttccgtaatcaggttgatccggag acacattgtcatgcagagaagtgcttcctgtcctggttctgcaataacac ccttagcccgaaaaagaattaccaagttacttggtacacgagctggtcgc catgtccagagtgcgcaggagaagtagcagaattcttagctgaacattcg aacgtaaaattgacaatctacaccgcccgtctctactacctgtgggacac cgactatcaggaaggcctgcgctcattgtctgaggagggcgcatcggtcg aaatcatggattatgaagattttcagtattgttgggaaaatttcgtatac gacgatggtgagccttttaaacgttggaaaggcctgaagtacaactttca gtctttgacccgtcgcttgcgcgaaattctgcaatctggaagtgagacac ccgggacttcagaatccgcgaccccggagtctggaatggataaaaagtat tcaataggactagctattggcaccaacagcgttggttgggcagttatcac cgatgaatataaggtcccgagcaagaagtttaaggtcctgggcaacaccg atcgccacagcataaaaaagaaccttattggtgcgctgctgttcgattct ggtgagactgccgaagcgacccgtctgaagagaaccgcgcgtcgtagata cacccggcgcaagaaccgtatctgctatctgcaagaaattttcagcaacg agatggctaaggtcgacgactccttctttcatcgcctggaggaaagcttt ctggttgaggaagacaaaaagcacgagcgtcatccgattttcggtaacat tgttgatgaagttgcctaccacgaaaaataccccacaatttatcatctgc gtaaaaaactggtagactccaccgataaggcggatttacgccttatctat ttggcgctggcgcatatgattaagttccgcggtcattttttgatcgaggg cgacctgaatccggataacagcgacgttgacaaactgtttatccagctgg tgcagacctataaccagttgttcgaagagaacccgattaatgcgtctggc gtggacgcgaaggcgatcctgagcgctcgtctgtccaagtcacgccgcct ggagaacttgatcgcgcaactgccgggtgagaagaaaaacggcttgttcg gcaatctgattgctctgtccctaggtttgaccccgaatttcaaatctaat tttgatctggcggaagatgcgaaattacagttgagcaaggacacttacga tgacgatctggacaacctgctcgctcagatcggcgatcagtatgccgatc ttttcctggccgcgaagaacctgagcgatgccatcttgctatcggacatc ttacgtgttaacaccgaaatcaccaaagctccgctaagcgcgtccatgat taaacgttacgatgaacaccaccaggatctgacgctgctgaaagcgttgg tgcgccagcaactgccggaaaaatacaaggaaattttcttcgaccaaagc aagaacggttatgcaggctatatcgacggtggtgcgtcgcaagaagaatt ttataaattcatcaaaccgattttggagaagatggatggtaccgaggagc tgctggtaaaattgaatcgggaagacctcttgcgaaagcagcgtactttc gataatggtagcatcccgcaccagattcatctgggcgaacttcacgcaat cctacgtcgtcaagaggatttctacccgtttctgaaggataaccgtgaaa agatcgagaagattctgacctttcgtattccgtattatgtgggtccgctg gcgagaggcaacagccgttttgcgtggatgacccgcaagtcggaagagac tatcacgccgtggaatttcgaggaggtcgtggacaagggtgcatcagcgc aatcttttattgaacgtatgaccaattttgataaaaaccttccaaatgaa aaagtgttgccgaagcacagcttgctgtacgagtatttcaccgtttacaa tgaactgacgaaagtcaagtacgttaccgaaggtatgcgtaagccagcct ttctgtctggggagcaaaaaaaagccattgtggatctgctgttcaagacc aatcgcaaggttaccgtcaagcaactgaaagaggattacttcaaaaaaat cgaatgttttgactccgtggaaatcagcggcgttgaagaccgctttaatg catctctgggcacctaccacgatctactcaagatcatcaaggataaggac ttcctggacaacgaagaaaatgaggatatcttggaagatattgtgctgac tttaacgttgttcgaggatcgtgagatgattgaagaacgcctcaaaacgt acgcacatctgtttgacgataaggtgatgaaacagctaaagcgccgtcgt tacaccggttggggtcgtctgtctagaaagctgattaacggcattcgtga caaacaatctggcaagaccatcctggacttcctcaaatccgacggcttcg caaatcgtaatttcatgcaactgatccatgatgatagcctgacctttaaa gaagatattcagaaggctcaagtgtccggccagggtgactcgctgcatga gcatatcgcgaatctggctggctcccctgcgataaaaaaaggtattctcc aaacggtgaaagttgtggatgaactggttaaagtcatgggtcgtcataaa ccggaaaacatcgtgattgagatggcacgtgagaaccagaccacccagaa aggtcaaaaaaacagtcgtgagcgtatgaaacgtatcgaagaggggatta aggagttaggcagccagattctgaaggagcacccggttgagaacacccag ctgcaaaacgagaagctctacctgtattacctgcaaaacggccgtgacat gtatgttgaccaggagctggacatcaatcgtctcagcgactacgacgtgg atgctatcgtgccgcagagctttctaaaagatgattccatcgacaataaa gtgctcacccgtagcgacaagaaccgtggtaaaagcgacaacgtgccgag cgaggaagtagttaagaaaatgaaaaactactggcgtcagctattgaacg ccaagcttatcacccagcgtaagtttgacaacttgacgaaggcagagcgt ggcggcctgagcgagctagacaaggcgggttttattaaacgccagctggt ggaaactcgccagattaccaaacacgttgcgcaaatcttggactcacgca tgaatacgaagtacgacgaaaacgataaattgatccgcgaggtgaaggtc ataaccctgaaatctaaactggttagcgatttccggaaggactttcaatt ttataaagtccgggagattaacaactatcaccatgcacacgacgcttact taaatgcggttgttggcacggccctgatcaagaagtacccgaaactggaa agcgagtttgtttatggtgactacaaggtgtatgacgttcgcaagatgat tgcaaaatccgaacaagagattggtaaggcgacggctaagtattttttct acagcaatatcatgaacttcttcaagactgaaatcaccctggcgaacggt gaaattcgtaaacgtccgttgatcgaaaccaacggtgaaaccggtgaaat cgtttgggataaaggtagggattttgcgaccgttcgtaaggtcctgagca tgccgcaggttaacatcgtgaaaaagaccgaagtgcagaccggcggtttc tccaaggagagtatcttaccgaagcgcaacagtgacaagctgatcgcgcg taaaaaagactgggatccgaaaaaatacggcggctttgactccccgaccg tcgcgtacagcgtactggtcgtggctaaagtggagaaaggcaaatcgaaa aagctgaaatccgttaaagagttgctgggtattacgattatggaacgttc gagcttcgagaaaaatccgatcgacttcctggaggccaaaggctacaagg aagttaaaaaagacctgatcattaaactgccgaagtacagcctgttcgag ctcgagaacggtcgcaaacgcatgctggcgagcgcgggtgagctccaaaa aggcaacgaattggctctgccgagcaagtacgtgaacttcctgtatctgg cctcccattatgaaaaactgaagggtagcccggaagataacgaacaaaag cagctgttcgtggaacaacataaacactatctggacgagattattgagca aatcagcgagttcagcaaacgcgtgattctggcggatgctaatctggaca aggttctttcagcctataataaacaccgtgataagccgatccgtgaacag gcagaaaatattattcacctgttcaccctgacgaacctgggtgcgccagc agcgtttaaatacttcgacacaacgatcgaccggaagcgttataccagca ccaaagaggttcttgacgccaccttgattcaccaaagcatcacgggtctg tatgaaacccgtattgacttgagccagttgggcggagattcagggggaag tggcggaagcggtgggtctacgaacctgagcgacattattgaaaaagaaa ctggtaaacagttggtgatccaagaatccattctgatgttaccggaggaa gtggaagaggtgatcggcaacaagccggagtccgacatcctggttcacac cgcgtatgatgagtcgaccgatgagaatgttatgctgctgaccagcgacg ccccagagtacaaaccgtgggcgctcgtcatccaggatagcaatggcgaa aacaagatcaagatgttgtctggcggtagcatggctccgaaaaagaagcg taaagtaggtattcatggtgttccggcatcaggttaa 56 Base editor RrA3F-F1301- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgaaacctcagattcgcgatcatcgtccgaatcctatggaggcgatg tatccgcatattttctactttcattttgaaaacttagaaaaagcctatgg ccgtaacgaaacttggctgtgctttaccgtagagattatcaaacaatatt taccggtaccctggaaaaaaggtgttttccgtaatcaggttgatccggag acacattgtcatgcagagaagtgcttcctgtcctggttctgcaataacac ccttagcccgaaaaagaattaccaagttacttggtacacgagctggtcgc catgtccagagtgcgcaggagaagtagcagaattcttagctgaacattcg aacgtaaaattgacaatctacaccgcccgtctctactacctgtgggacac cgactatcaggaaggcctgcgctcattgtctgaggagggcgcatcggtcg aaatcatggattatgaagattttcagtattgttgggaaaatttcgtatac gacgatggtgagccttttaaacgttggaaaggcctgaagtacaactttca gtctttgacccgtcgcttgcgcgaaattctgcaatctggaagtgagacac ccgggacttcagaatccgcgaccccggagtctggaatgccaaaacccgct gtagagtcagaattttcaaaagttttgaaaaagcactttccgggagaacg tttccgctcgagctatatgaaaagaggcggtaagatcctggctgcccaag gcgaagaggcagttgttgcgtatctacagggcaagtccgaggaggagcct ccgaacttccagccaccggcgaagtgccacgtggtgaccaaatcccgtga cttcgcggaatggccgatcatgaaggcgtcggaagcgattcaacgttata tctatgcactgtcgaccaccgaacgcgcggcctgtaaaccgggcaaaagt agtgagagccatgcagcgtggttcgccgctaccggtgtcagcaaccacgg ctacagccacgttcagggtctgaacctgatttttgatcataccttgggcc gttacgatggtgttctgaaaaaggtccaactgcgcaacgaaaaggcgaga gcgcgtttagagagcattaacgcgtctagagcagatgaaggtttaccgga gattaaagccgaggaggaagaagtggctacgaacgaaaccggccacctgt tgcaaccgccgggtatcaatccgagcttttacgtgtatcagaccattagc ccgcaggcataccgtccgcgtgacgagatcgtgctgccgccggagtacgc aggttacgtacgtgacccgaatgctccgattccgctgggtgtggtgcgta accgttgcgatatccaaaaagggtgcccgggctacatcccggaatggcag cgtgaagcaggtaccgcgatcagcccgaaaacaggcaaggccgtaactgt gccgggcctgtctccgaagaaaaacaaacgtatgcgtaggtactggcgct ctgagaaggagaaagctcaagatgcgctgttggttaccgtacgcattggt accgattgggttgtcatcgacgtgcgcggtctgttgcgcaacgcccgttg gcgcaccatcgctcccaaggacatcagcctgaatgcgctcctcgatttgt ttaccggtgatccggtgatcgatgtgcgtcgcaatattgttacctttacg tacaccctcgacgcctgtggtacctacgcccgtaaatggaccttgaaagg caaacagacgaaagcgaccctggacaaactgacggccactcagacggttg cgttggttgcgattgcgcttggtcagaccaacccgatttccgctggcatt agccgtgttacacaagaaaatggtgcactgcaatgcgaaccgctggaccg gttcaccctgccggatgacctgttgaaggacatcagcgcatatcgcattg cttgggacagaaacgaagaggaactacgcgctcgcagcgtcgaggccctg ccggaggcgcaacaagcggaggtccgtgcgctggacggggtgtccaaaga aaccgcgcgtacccaactgtgcgcagatttcggcctggacccgaaacgtc tgccgtgggataaaatgagctccaatactacctttatcagcgaagccttg ctgtctaacagcgtgagccgtgatcaggtttttttcactccggctccgaa gaagggtgctaagaaaaaagcgcctgttgaagttatgcgtaaagaccgca cttgggcacgtgcgtacaagccgcgtctgagcgtcgaagctcagaaactg aagaacgaagccctgtgggcacttaagcgcacctccccggagtatttgaa gctgagccgtcgcaaagaggagctgtgtcgtcgtagcatcaactatgtta tcgaaaagacccgtcgccgtacgcaatgtcagattgtgatcccggtgatc gaggatctgaatgttcgcttctttcatggttctggtaagagactgcccgg ttgggataatttcttcaccgctaaaaaagagaaccgttggttcatccagg gcctgcacaaagcgtttagcgatctgcgtacgcaccgttccttctatgtt tttgaagttcgtccggagcgcacctctattacctgtccaaagtgcggtca ttgcgaggtgggtaatcgtgacggtgaggcgtttcagtgcctgagctgcg gcaagacgtgcaacgcagatcttgacgtcgcgacccataatctgacccaa gtggcgttgaccggtaagaccatgccgaagcgcgaggagccgcgtgacgc tcagggtacagcgccagcgcgcaagactaagaaggcgagcaaatcaaagg cgccaccggcggagcgcgaagaccagaccccggcgcaagagccaagccag accagttctggaggtagcgggggtagcggtggtagcactaacttaagtga tattatcgagaaagaaaccgggaaacagctggtgatccaagaaagcattc tgatgctgcccgaagaagttgaagaagtgattggtaacaagcctgagtcg gacatcttagtgcacaccgcgtacgatgaaagcacggatgagaatgtgat gctgctcacctctgatgcccccgaatacaagccgtgggctctggtgatcc aggactctaacggagaaaacaaaattaagatgctctctggcggctccatg gcgcctaaaaaaaaacgcaaagtggggattcacggggttccggcgtaa 57 Base editor RrA3F-F1301- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgaaacctcagattcgcgatcatcgtccgaatcctatggaggcgatg tatccgcatattttctactttcattttgaaaacttagaaaaagcctatgg ccgtaacgaaacttggctgtgctttaccgtagagattatcaaacaatatt taccggtaccctggaaaaaaggtgttttccgtaatcaggttgatccggag acacattgtcatgcagagaagtgcttcctgtcctggttctgcaataacac ccttagcccgaaaaagaattaccaagttacttggtacacgagctggtcgc catgtccagagtgcgcaggagaagtagcagaattcttagctgaacattcg aacgtaaaattgacaatctacaccgcccgtctctactacctgtgggacac cgactatcaggaaggcctgcgctcattgtctgaggagggcgcatcggtcg aaatcatggattatgaagattttcagtattgttgggaaaatttcgtatac gacgatggtgagccttttaaacgttggaaaggcctgaagtacaactttca gtctttgacccgtcgcttgcgcgaaattctgcaatctggaagtgagacac ccgggacttcagaatccgcgaccccggagtctggaatgtcaaaactagaa aagtttacaaattgttactccctgtcgaaaaccctgagattcaaagcgat cccggtgggtaaaactcaagagaacattgataacaaacgtctgctggttg aggacgaaaagcgcgcggaggattacaaaggcgttaaaaagctgttggac cgttattacctgtcctttattaatgatgttctgcacagcattaaattaaa gaacctaaacaattacatctccctcttccgtaaaaagacccgcaccgaaa aggaaaataaagaactggagaaccttgagattaatctgcgtaaagaaatc gctaaagcgtttaaaggcaacgagggttataaatccttatttaaaaaaga catcatcgaaacgattctcccagaattcctggacgacaaagacgagatcg cgctggttaattccttcaacggctttaccaccgcattcaccggctttttt gataaccgcgaaaacatgttctctgaagaggccaaaagcacctcaattgc gtttcgctgcattaacgaaaatctgacgcgttatatctctaacatggata tcttcgagaaggttgacgctatctttgataaacatgaagtccaggagatc aaggagaagatcctgaacagcgactacgacgtggaggatttcttcgaggg tgagttcttcaattttgttttgacccaagaaggcatcgatgtctacaatg cgataattggtggttttgttaccgagagcggggagaaaattaagggtctg aacgaatatatcaacttgtacaaccagaaaaccaaacaaaaactgccgaa gtttaagccgctgtacaagcaagtcttgtcggatcgtgaatcgctgagct tttacggcgaaggctacaccagcgatgaggaggtgttggaggtgttccgc aatacgttgaataagaactctgaaattttttccagcattaagaagctgga aaaactattcaagaacttcgacgagtatagcagcgcaggtatctttgtga aaaacggtccggctattagcaccatctcgaaagacattttcggcgaatgg aatgttattcgtgataagtggaatgccgaatacgacgacattcatctgaa gaaaaaggcggttgtaactgaaaagtacgaggacgatcgtcgtaagtcgt tcaaaaagatcggctccttctctctggagcaactgcaagagtacgccgat gccgatttgtcagtcgtggagaagctgaaagagatcatcattcaaaaagt tgacgaaatctataaggtctatggtagcagtgaaaaactgtttgacgcgg acttcgtgctggagaaaagcctgaagaaaaatgacgccgtggtggcaatc atgaaagatcttctggatagcgtcaagtctttcgaaaactacatcaaagc gtttttcggtgaaggcaaggaaacgaatcgtgacgagagcttctatggtg atttcgtcctagcctatgatatcctgcttaaggtggatcacatctatgat gccatccgcaactatgttacccagaaaccgtactcaaaggacaagttcaa gttatacttccagaatccgcagtttatgggtggctgggataaagataagg aaaccgactatcgcgccaccattttacgttacggtagtaagtactatctg gcaatcatggataaaaaatatgcgaaatgcctgcaaaagatcgacaagga cgatgttaacggcaattatgagaagatcaactacaaactgctgccgggcc caaataagatgctgccgaaggtgtttttcagcaaaaaatggatggcgtat tacaatccgagcgaggacatccaaaagatctacaaaaacggtacgtttaa gaagggtgatatgttcaacctcaacgattgtcataaacttattgacttct tcaaggatagcatatctcgttatccgaagtggagcaacgcgtatgacttt aactttagcgaaaccgagaaatacaaagatatcgcgggtttctatcgtga agttgaagaacagggttacaaagtgtccttcgagtccgcgagcaagaagg aggtagacaagctggtcgaggagggtaagttgtacatgtttcagatttac aataaggacttttccgacaagtcccatggtacaccgaatttgcacaccat gtatttcaagcttctgttcgacgagaacaaccacggccagatccgtctga gcggtggtgcagagctgttcatgcgtagagctagcctgaagaaagaagag ttggtcgttcatccggctaattcgccgatcgcgaacaaaaatccagataa ccctaaaaagactacgaccctgagctatgatgtgtataaagacaaacgct ttagcgaagaccagtatgagttacacattccgatcgctatcaacaagtgc ccgaagaatattttcaagatcaacaccgaagtgcgtgttcttttgaagca cgatgacaacccgtatgtgattggtattgctcgtggtgaacgtaatctgc tgtacattgtggttgtggacggcaaaggaaacatcgtggaacagtacagc ctgaacgaaatcattaacaatttcaacggcattcgcattaagacggatta ccattctttgctggacaaaaaggagaaagagcgtttcgaggcccgtcaga actggacctccatcgagaacattaaggagctgaaggcgggttacatcagc caggtggtgcacaaaatctgcgaactggtggagaagtacgacgcggtgat tgctttggcggatttgaactccggttttaagaacagccgcgttaaagtgg aaaagcaggtttatcagaaattcgaaaaaatgctgattgataaattgaat tacatggttgacaaaaagtctaacccgtgtgcaaccggcggtgcgctgaa gggctaccaaatcaccaataagtttgaaagctttaagagcatgagcacgc aaaatggcttcattttttacattccggcgtggctgaccagcaagatcgat ccgtcaaccggctttgttaatttactgaagacgaagtatacctctattgc cgactctaaaaaatttattagttccttcgatagaatcatgtatgttccgg aagaggacctgttcgaatttgcactggactacaagaactttagccgtacc gatgctgattatataaagaaatggaaactctacagctatggcaaccgcat ccgtatctttcgcaacccgaaaaaaaacaacgtgttcgactgggaagagg tatgtctgacttcagcgtacaaggagcttttcaataaatatggtatcaac taccagcagggtgatatccgtgcactgctttgcgagcaaagcgataaagc gttctattcaagcttcatggcgctgatgagcctgatgctgcaaatgcgca acagcatcaccggtcgtaccgatgttgcatttctgatttctccagtaaaa aacagcgatggtatcttttacgacagccgtaattacgaggcccaagaaaa tgcgattttgccgaagaacgctgacgcgaatggtgcatacaacattgcaa ggaaagttctgtgggcaatcggccaatttaaaaaagcggaagatgagaag ctggacaaagtgaaaattgcgattagcaacaaggagtggctggagtatgc gcagacctccgttaaatcagggggaagtggcggaagcggtgggtctacga acctgagcgacattattgaaaaagaaactggtaaacagttggtgatccaa gaatccattctgatgttaccggaggaagtggaagaggtgatcggcaacaa gccggagtccgacatcctggttcacaccgcgtatgatgagtcgaccgatg agaatgttatgctgctgaccagcgacgccccagagtacaaaccgtgggcg ctcgtcatccaggatagcaatggcgaaaacaagatcaagatgttgtctgg cggtagcatggctccgaaaaagaagcgtaaagtaggtattcatggtgttc cggcatcaggttaa 58 Base editor SsA3B-R54Q-dCas9 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggatccacagaggctaagacaatggcccggtccgggtccggcgagc cgcggtggctacggccagcgtccgcgtatccgcaatccggaagagtggtt ccacgaactgagtccgagaacctttagcttccactttcgtaacctgcgtt ttgctagcggtcagaatcgcagctatatctgctgccaggtggaaggcaag aactgcttcttccaaggtatttttcaaaaccaggttccgccggacccacc ttgtcatgctgaactttgctttttgtcctggttccaaagctggggtttgt cgccggacgagcactattacgtgacctggttcatctcctggtccccgtgc tgtgaatgtgcggcgaaagtcgcccaatttctggaagagaaccgcaacgt gagcttgtctttgtctgcggcgcgtctgtactacttctggaaaagcgagt cccgtgagggcctgcgccgtctgtccgatctgggtgcacaggttggtatt atgtcgttccaagattttcagcattgttggaataactttgttcataatct gggcatgccgttccagccgtggaagaaattgcacaaaaactaccaacgtc tggtgaccgaattaaaacagattctccgcgaggagccggctacctatggc tctccacaggcgcaaggtaaggtgcgcatcggcagcaccgcggcgggtct gcgtcacagccatagccacacccgtagcgaggcgcatctgcgtcccaacc actcatctcgtcagcaccgtatcctgaatccgccgcgcgaggcccgtgcg cgtacgtgcgttctggtagacgcatcctggatttgctatcgttctggaag tgagacacccgggacttcagaatccgcgaccccggagtctggaatggata aaaagtattcaataggactagctattggcaccaacagcgttggttgggca gttatcaccgatgaatataaggtcccgagcaagaagtttaaggtcctggg caacaccgatcgccacagcataaaaaagaaccttattggtgcgctgctgt tcgattctggtgagactgccgaagcgacccgtctgaagagaaccgcgcgt cgtagatacacccggcgcaagaaccgtatctgctatctgcaagaaatttt cagcaacgagatggctaaggtcgacgactccttctttcatcgcctggagg aaagctttctggttgaggaagacaaaaagcacgagcgtcatccgattttc ggtaacattgttgatgaagttgcctaccacgaaaaataccccacaattta tcatctgcgtaaaaaactggtagactccaccgataaggcggatttacgcc ttatctatttggcgctggcgcatatgattaagttccgcggtcattttttg atcgagggcgacctgaatccggataacagcgacgttgacaaactgtttat ccagctggtgcagacctataaccagttgttcgaagagaacccgattaatg cgtctggcgtggacgcgaaggcgatcctgagcgctcgtctgtccaagtca cgccgcctggagaacttgatcgcgcaactgccgggtgagaagaaaaacgg cttgttcggcaatctgattgctctgtccctaggtttgaccccgaatttca aatctaattttgatctggcggaagatgcgaaattacagttgagcaaggac acttacgatgacgatctggacaacctgctcgctcagatcggcgatcagta tgccgatcttttcctggccgcgaagaacctgagcgatgccatcttgctat cggacatcttacgtgttaacaccgaaatcaccaaagctccgctaagcgcg tccatgattaaacgttacgatgaacaccaccaggatctgacgctgctgaa agcgttggtgcgccagcaactgccggaaaaatacaaggaaattttcttcg accaaagcaagaacggttatgcaggctatatcgacggtggtgcgtcgcaa gaagaattttataaattcatcaaaccgattttggagaagatggatggtac cgaggagctgctggtaaaattgaatcgggaagacctcttgcgaaagcagc gtactttcgataatggtagcatcccgcaccagattcatctgggcgaactt cacgcaatcctacgtcgtcaagaggatttctacccgtttctgaaggataa ccgtgaaaagatcgagaagattctgacctttcgtattccgtattatgtgg gtccgctggcgagaggcaacagccgttttgcgtggatgacccgcaagtcg gaagagactatcacgccgtggaatttcgaggaggtcgtggacaagggtgc atcagcgcaatcttttattgaacgtatgaccaattttgataaaaaccttc caaatgaaaaagtgttgccgaagcacagcttgctgtacgagtatttcacc gtttacaatgaactgacgaaagtcaagtacgttaccgaaggtatgcgtaa gccagcctttctgtctggggagcaaaaaaaagccattgtggatctgctgt tcaagaccaatcgcaaggttaccgtcaagcaactgaaagaggattacttc aaaaaaatcgaatgttttgactccgtggaaatcagcggcgttgaagaccg ctttaatgcatctctgggcacctaccacgatctactcaagatcatcaagg ataaggacttcctggacaacgaagaaaatgaggatatcttggaagatatt gtgctgactttaacgttgttcgaggatcgtgagatgattgaagaacgcct caaaacgtacgcacatctgtttgacgataaggtgatgaaacagctaaagc gccgtcgttacaccggttggggtcgtctgtctagaaagctgattaacggc attcgtgacaaacaatctggcaagaccatcctggacttcctcaaatccga cggcttcgcaaatcgtaatttcatgcaactgatccatgatgatagcctga cctttaaagaagatattcagaaggctcaagtgtccggccagggtgactcg ctgcatgagcatatcgcgaatctggctggctcccctgcgataaaaaaagg tattctccaaacggtgaaagttgtggatgaactggttaaagtcatgggtc gtcataaaccggaaaacatcgtgattgagatggcacgtgagaaccagacc acccagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgtatcgaaga ggggattaaggagttaggcagccagattctgaaggagcacccggttgaga acacccagctgcaaaacgagaagctctacctgtattacctgcaaaacggc cgtgacatgtatgttgaccaggagctggacatcaatcgtctcagcgacta cgacgtggatgctatcgtgccgcagagctttctaaaagatgattccatcg acaataaagtgctcacccgtagcgacaagaaccgtggtaaaagcgacaac gtgccgagcgaggaagtagttaagaaaatgaaaaactactggcgtcagct attgaacgccaagcttatcacccagcgtaagtttgacaacttgacgaagg cagagcgtggcggcctgagcgagctagacaaggcgggttttattaaacgc cagctggtggaaactcgccagattaccaaacacgttgcgcaaatcttgga ctcacgcatgaatacgaagtacgacgaaaacgataaattgatccgcgagg tgaaggtcataaccctgaaatctaaactggttagcgatttccggaaggac tttcaattttataaagtccgggagattaacaactatcaccatgcacacga cgcttacttaaatgcggttgttggcacggccctgatcaagaagtacccga aactggaaagcgagtttgtttatggtgactacaaggtgtatgacgttcgc aagatgattgcaaaatccgaacaagagattggtaaggcgacggctaagta ttttttctacagcaatatcatgaacttcttcaagactgaaatcaccctgg cgaacggtgaaattcgtaaacgtccgttgatcgaaaccaacggtgaaacc ggtgaaatcgtttgggataaaggtagggattttgcgaccgttcgtaaggt cctgagcatgccgcaggttaacatcgtgaaaaagaccgaagtgcagaccg gcggtttctccaaggagagtatcttaccgaagcgcaacagtgacaagctg atcgcgcgtaaaaaagactgggatccgaaaaaatacggcggctttgactc cccgaccgtcgcgtacagcgtactggtcgtggctaaagtggagaaaggca aatcgaaaaagctgaaatccgttaaagagttgctgggtattacgattatg gaacgttcgagcttcgagaaaaatccgatcgacttcctggaggccaaagg ctacaaggaagttaaaaaagacctgatcattaaactgccgaagtacagcc tgttcgagctcgagaacggtcgcaaacgcatgctggcgagcgcgggtgag ctccaaaaaggcaacgaattggctctgccgagcaagtacgtgaacttcct gtatctggcctcccattatgaaaaactgaagggtagcccggaagataacg aacaaaagcagctgttcgtggaacaacataaacactatctggacgagatt attgagcaaatcagcgagttcagcaaacgcgtgattctggcggatgctaa tctggacaaggttctttcagcctataataaacaccgtgataagccgatcc gtgaacaggcagaaaatattattcacctgttcaccctgacgaacctgggt gcgccagcagcgtttaaatacttcgacacaacgatcgaccggaagcgtta taccagcaccaaagaggttcttgacgccaccttgattcaccaaagcatca cgggtctgtatgaaacccgtattgacttgagccagttgggcggagattca gggggaagtggcggaagcggtgggtctacgaacctgagcgacattattga aaaagaaactggtaaacagttggtgatccaagaatccattctgatgttac cggaggaagtggaagaggtgatcggcaacaagccggagtccgacatcctg gttcacaccgcgtatgatgagtcgaccgatgagaatgttatgctgctgac cagcgacgccccagagtacaaaccgtgggcgctcgtcatccaggatagca atggcgaaaacaagatcaagatgttgtctggcggtagcatggctccgaaa aagaagcgtaaagtaggtattcatggtgttccggcatcaggttaa 59 Base editor SsA3B-R54Q- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dCasPhi-2 gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggatccacagaggctaagacaatggcccggtccgggtccggcgagc cgcggtggctacggccagcgtccgcgtatccgcaatccggaagagtggtt ccacgaactgagtccgagaacctttagcttccactttcgtaacctgcgtt ttgctagcggtcagaatcgcagctatatctgctgccaggtggaaggcaag aactgcttcttccaaggtatttttcaaaaccaggttccgccggacccacc ttgtcatgctgaactttgctttttgtcctggttccaaagctggggtttgt cgccggacgagcactattacgtgacctggttcatctcctggtccccgtgc tgtgaatgtgcggcgaaagtcgcccaatttctggaagagaaccgcaacgt gagcttgtctttgtctgcggcgcgtctgtactacttctggaaaagcgagt cccgtgagggcctgcgccgtctgtccgatctgggtgcacaggttggtatt atgtcgttccaagattttcagcattgttggaataactttgttcataatct gggcatgccgttccagccgtggaagaaattgcacaaaaactaccaacgtc tggtgaccgaattaaaacagattctccgcgaggagccggctacctatggc tctccacaggcgcaaggtaaggtgcgcatcggcagcaccgcggcgggtct gcgtcacagccatagccacacccgtagcgaggcgcatctgcgtcccaacc actcatctcgtcagcaccgtatcctgaatccgccgcgcgaggcccgtgcg cgtacgtgcgttctggtagacgcatcctggatttgctatcgttctggaag tgagacacccgggacttcagaatccgcgaccccggagtctggaatgccaa aacccgctgtagagtcagaattttcaaaagttttgaaaaagcactttccg ggagaacgtttccgctcgagctatatgaaaagaggcggtaagatcctggc tgcccaaggcgaagaggcagttgttgcgtatctacagggcaagtccgagg aggagcctccgaacttccagccaccggcgaagtgccacgtggtgaccaaa tcccgtgacttcgcggaatggccgatcatgaaggcgtcggaagcgattca acgttatatctatgcactgtcgaccaccgaacgcgcggcctgtaaaccgg gcaaaagtagtgagagccatgcagcgtggttcgccgctaccggtgtcagc aaccacggctacagccacgttcagggtctgaacctgatttttgatcatac cttgggccgttacgatggtgttctgaaaaaggtccaactgcgcaacgaaa aggcgagagcgcgtttagagagcattaacgcgtctagagcagatgaaggt ttaccggagattaaagccgaggaggaagaagtggctacgaacgaaaccgg ccacctgttgcaaccgccgggtatcaatccgagcttttacgtgtatcaga ccattagcccgcaggcataccgtccgcgtgacgagatcgtgctgccgccg gagtacgcaggttacgtacgtgacccgaatgctccgattccgctgggtgt ggtgcgtaaccgttgcgatatccaaaaagggtgcccgggctacatcccgg aatggcagcgtgaagcaggtaccgcgatcagcccgaaaacaggcaaggcc gtaactgtgccgggcctgtctccgaagaaaaacaaacgtatgcgtaggta ctggcgctctgagaaggagaaagctcaagatgcgctgttggttaccgtac gcattggtaccgattgggttgtcatcgacgtgcgcggtctgttgcgcaac gcccgttggcgcaccatcgctcccaaggacatcagcctgaatgcgctcct cgatttgtttaccggtgatccggtgatcgatgtgcgtcgcaatattgtta cctttacgtacaccctcgacgcctgtggtacctacgcccgtaaatggacc ttgaaaggcaaacagacgaaagcgaccctggacaaactgacggccactca gacggttgcgttggttgcgattgcgcttggtcagaccaacccgatttccg ctggcattagccgtgttacacaagaaaatggtgcactgcaatgcgaaccg ctggaccggttcaccctgccggatgacctgttgaaggacatcagcgcata tcgcattgcttgggacagaaacgaagaggaactacgcgctcgcagcgtcg aggccctgccggaggcgcaacaagcggaggtccgtgcgctggacggggtg tccaaagaaaccgcgcgtacccaactgtgcgcagatttcggcctggaccc gaaacgtctgccgtgggataaaatgagctccaatactacctttatcagcg aagccttgctgtctaacagcgtgagccgtgatcaggtttttttcactccg gctccgaagaagggtgctaagaaaaaagcgcctgttgaagttatgcgtaa agaccgcacttgggcacgtgcgtacaagccgcgtctgagcgtcgaagctc agaaactgaagaacgaagccctgtgggcacttaagcgcacctccccggag tatttgaagctgagccgtcgcaaagaggagctgtgtcgtcgtagcatcaa ctatgttatcgaaaagacccgtcgccgtacgcaatgtcagattgtgatcc cggtgatcgaggatctgaatgttcgcttctttcatggttctggtaagaga ctgcccggttgggataatttcttcaccgctaaaaaagagaaccgttggtt catccagggcctgcacaaagcgtttagcgatctgcgtacgcaccgttcct tctatgtttttgaagttcgtccggagcgcacctctattacctgtccaaag tgcggtcattgcgaggtgggtaatcgtgacggtgaggcgtttcagtgcct gagctgcggcaagacgtgcaacgcagatcttgacgtcgcgacccataatc tgacccaagtggcgttgaccggtaagaccatgccgaagcgcgaggagccg cgtgacgctcagggtacagcgccagcgcgcaagactaagaaggcgagcaa atcaaaggcgccaccggcggagcgcgaagaccagaccccggcgcaagagc caagccagaccagttctggaggtagcgggggtagcggtggtagcactaac ttaagtgatattatcgagaaagaaaccgggaaacagctggtgatccaaga aagcattctgatgctgcccgaagaagttgaagaagtgattggtaacaagc ctgagtcggacatcttagtgcacaccgcgtacgatgaaagcacggatgag aatgtgatgctgctcacctctgatgcccccgaatacaagccgtgggctct ggtgatccaggactctaacggagaaaacaaaattaagatgctctctggcg gctccatggcgcctaaaaaaaaacgcaaagtggggattcacggggttccg gcgtaa 60 Base editor SsA3B-R54Q- atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca dLbCas12a gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggatccacagaggctaagacaatggcccggtccgggtccggcgagc cgcggtggctacggccagcgtccgcgtatccgcaatccggaagagtggtt ccacgaactgagtccgagaacctttagcttccactttcgtaacctgcgtt ttgctagcggtcagaatcgcagctatatctgctgccaggtggaaggcaag aactgcttcttccaaggtatttttcaaaaccaggttccgccggacccacc ttgtcatgctgaactttgctttttgtcctggttccaaagctggggtttgt cgccggacgagcactattacgtgacctggttcatctcctggtccccgtgc tgtgaatgtgcggcgaaagtcgcccaatttctggaagagaaccgcaacgt gagcttgtctttgtctgcggcgcgtctgtactacttctggaaaagcgagt cccgtgagggcctgcgccgtctgtccgatctgggtgcacaggttggtatt atgtcgttccaagattttcagcattgttggaataactttgttcataatct gggcatgccgttccagccgtggaagaaattgcacaaaaactaccaacgtc tggtgaccgaattaaaacagattctccgcgaggagccggctacctatggc tctccacaggcgcaaggtaaggtgcgcatcggcagcaccgcggcgggtct gcgtcacagccatagccacacccgtagcgaggcgcatctgcgtcccaacc actcatctcgtcagcaccgtatcctgaatccgccgcgcgaggcccgtgcg cgtacgtgcgttctggtagacgcatcctggatttgctatcgttctggaag tgagacacccgggacttcagaatccgcgaccccggagtctggaatgtcaa aactagaaaagtttacaaattgttactccctgtcgaaaaccctgagattc aaagcgatcccggtgggtaaaactcaagagaacattgataacaaacgtct gctggttgaggacgaaaagcgcgcggaggattacaaaggcgttaaaaagc tgttggaccgttattacctgtcctttattaatgatgttctgcacagcatt aaattaaagaacctaaacaattacatctccctcttccgtaaaaagacccg caccgaaaaggaaaataaagaactggagaaccttgagattaatctgcgta aagaaatcgctaaagcgtttaaaggcaacgagggttataaatccttattt aaaaaagacatcatcgaaacgattctcccagaattcctggacgacaaaga cgagatcgcgctggttaattccttcaacggctttaccaccgcattcaccg gcttttttgataaccgcgaaaacatgttctctgaagaggccaaaagcacc tcaattgcgtttcgctgcattaacgaaaatctgacgcgttatatctctaa catggatatcttcgagaaggttgacgctatctttgataaacatgaagtcc aggagatcaaggagaagatcctgaacagcgactacgacgtggaggatttc ttcgagggtgagttcttcaattttgttttgacccaagaaggcatcgatgt ctacaatgcgataattggtggttttgttaccgagagcggggagaaaatta agggtctgaacgaatatatcaacttgtacaaccagaaaaccaaacaaaaa ctgccgaagtttaagccgctgtacaagcaagtcttgtcggatcgtgaatc gctgagcttttacggcgaaggctacaccagcgatgaggaggtgttggagg tgttccgcaatacgttgaataagaactctgaaattttttccagcattaag aagctggaaaaactattcaagaacttcgacgagtatagcagcgcaggtat ctttgtgaaaaacggtccggctattagcaccatctcgaaagacattttcg gcgaatggaatgttattcgtgataagtggaatgccgaatacgacgacatt catctgaagaaaaaggcggttgtaactgaaaagtacgaggacgatcgtcg taagtcgttcaaaaagatcggctccttctctctggagcaactgcaagagt acgccgatgccgatttgtcagtcgtggagaagctgaaagagatcatcatt caaaaagttgacgaaatctataaggtctatggtagcagtgaaaaactgtt tgacgcggacttcgtgctggagaaaagcctgaagaaaaatgacgccgtgg tggcaatcatgaaagatcttctggatagcgtcaagtctttcgaaaactac atcaaagcgtttttcggtgaaggcaaggaaacgaatcgtgacgagagctt ctatggtgatttcgtcctagcctatgatatcctgcttaaggtggatcaca tctatgatgccatccgcaactatgttacccagaaaccgtactcaaaggac aagttcaagttatacttccagaatccgcagtttatgggtggctgggataa agataaggaaaccgactatcgcgccaccattttacgttacggtagtaagt actatctggcaatcatggataaaaaatatgcgaaatgcctgcaaaagatc gacaaggacgatgttaacggcaattatgagaagatcaactacaaactgct gccgggcccaaataagatgctgccgaaggtgtttttcagcaaaaaatgga tggcgtattacaatccgagcgaggacatccaaaagatctacaaaaacggt acgtttaagaagggtgatatgttcaacctcaacgattgtcataaacttat tgacttcttcaaggatagcatatctcgttatccgaagtggagcaacgcgt atgactttaactttagcgaaaccgagaaatacaaagatatcgcgggtttc tatcgtgaagttgaagaacagggttacaaagtgtccttcgagtccgcgag caagaaggaggtagacaagctggtcgaggagggtaagttgtacatgtttc agatttacaataaggacttttccgacaagtcccatggtacaccgaatttg cacaccatgtatttcaagcttctgttcgacgagaacaaccacggccagat ccgtctgagcggtggtgcagagctgttcatgcgtagagctagcctgaaga aagaagagttggtcgttcatccggctaattcgccgatcgcgaacaaaaat ccagataaccctaaaaagactacgaccctgagctatgatgtgtataaaga caaacgctttagcgaagaccagtatgagttacacattccgatcgctatca acaagtgcccgaagaatattttcaagatcaacaccgaagtgcgtgttctt ttgaagcacgatgacaacccgtatgtgattggtattgctcgtggtgaacg taatctgctgtacattgtggttgtggacggcaaaggaaacatcgtggaac agtacagcctgaacgaaatcattaacaatttcaacggcattcgcattaag acggattaccattctttgctggacaaaaaggagaaagagcgtttcgaggc ccgtcagaactggacctccatcgagaacattaaggagctgaaggcgggtt acatcagccaggtggtgcacaaaatctgcgaactggtggagaagtacgac gcggtgattgctttggcggatttgaactccggttttaagaacagccgcgt taaagtggaaaagcaggtttatcagaaattcgaaaaaatgctgattgata aattgaattacatggttgacaaaaagtctaacccgtgtgcaaccggcggt gcgctgaagggctaccaaatcaccaataagtttgaaagctttaagagcat gagcacgcaaaatggcttcattttttacattccggcgtggctgaccagca agatcgatccgtcaaccggctttgttaatttactgaagacgaagtatacc tctattgccgactctaaaaaatttattagttccttcgatagaatcatgta tgttccggaagaggacctgttcgaatttgcactggactacaagaacttta gccgtaccgatgctgattatataaagaaatggaaactctacagctatggc aaccgcatccgtatctttcgcaacccgaaaaaaaacaacgtgttcgactg ggaagaggtatgtctgacttcagcgtacaaggagcttttcaataaatatg gtatcaactaccagcagggtgatatccgtgcactgctttgcgagcaaagc gataaagcgttctattcaagcttcatggcgctgatgagcctgatgctgca aatgcgcaacagcatcaccggtcgtaccgatgttgcatttctgatttctc cagtaaaaaacagcgatggtatcttttacgacagccgtaattacgaggcc caagaaaatgcgattttgccgaagaacgctgacgcgaatggtgcatacaa cattgcaaggaaagttctgtgggcaatcggccaatttaaaaaagcggaag atgagaagctggacaaagtgaaaattgcgattagcaacaaggagtggctg gagtatgcgcagacctccgttaaatcagggggaagtggcggaagcggtgg gtctacgaacctgagcgacattattgaaaaagaaactggtaaacagttgg tgatccaagaatccattctgatgttaccggaggaagtggaagaggtgatc ggcaacaagccggagtccgacatcctggttcacaccgcgtatgatgagtc gaccgatgagaatgttatgctgctgaccagcgacgccccagagtacaaac cgtgggcgctcgtcatccaggatagcaatggcgaaaacaagatcaagatg ttgtctggcggtagcatggctccgaaaaagaagcgtaaagtaggtattca tggtgttccggcatcaggttaa 61 Purification HisX6 atgggaagtcatcaccaccaccaccattcaggt tag 62 Nuclear Nucleoplasmin tctggcggtagcatggctccgaaaaagaagcgtaaagtag localization -NLS gtattcatggtgttccggca  sequence 63 Linker SGGSx2 tcagggggaagtggcggaagcggtgggtct sequence 64 Nuclear SV40-NLS atggctccgaaaaagaaacgtaaggtgggtatccacggcgttccggcg localization sequence 65 Protease TEV-RS gagaacctgtacttccagagc cleavage site 66 Accessory UGI acgaacctgagcgacattattgaaaaagaaactggtaaacagttggtg component atccaagaatccattctgatgttaccggaggaagtggaagaggtgatc ggcaacaagccggagtccgacatcctggttcacaccgcgtatgatgag tcgaccgatgagaatgttatgctgctgaccagcgacgccccagagtac aaaccgtgggcgctcgtcatccaggatagcaatggcgaaaacaagatc aagatgttg 67 Linker XTEN-linker tctggaagtgagacacccgggacttcagaatccgcgaccccggag sequence 68 Deaminase A3A atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaagcaagtccagcttcaggacccaggcacctgatggacccgcat attttcacctctaattttaacaacggtattggccgtcacaagacgtacct gtgttatgaagtggaacgtcttgacaacggcacctccgtgaaaatggacc agcatcgtggtttcttgcataatcaagctaaaaacctgctgtgcggtttc tacggccgtcacgcggaactgcgttttttggacctggttccgagcctgca actggacccggcacagatttatcgtgttacttggttcatcagctggtcgc cgtgttttagctggggttgcgccggcgaggtacgcgcgtttttgcaagag aacacccacgtgcgtttgcgcatcttcgccgctcgtatctacgattatga cccactgtataaagaagcgctccagatgctgcgcgatgcaggcgcgcagg tttccatcatgacctacgacgagttcaagcactgctgggatacctttgtc gatcatcagggctgcccgttccagccgtgggatggtctggatgagcacag ccaggcgttaagcggtcgcctcagagcgattctgcaaaaccaaggtaatt ctggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga 69 Deaminase A3A-Y130F atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaagcatcaccagctagtggacccaggcacctgatggatccgcac atcttcacctccaattttaataacggcatcggccgtcataagacgtacct gtgctatgaggttgaacgtttggacaacggtactagcgtcaagatggacc agcatcgtggtttccttcacaaccaagcgaaaaatctgctgtgcggtttt tatggtcgtcacgccgaactgagattcttggatctggttccgtctctgca actggacccggcgcagatttatcgtgtgacctggttcatcagctggtcgc cgtgctttagctggggttgcgccggtgaagtgcgcgcatttctccaggag aacacccatgttcgtttgcgcatcttcgcggcacgtatcttcgattacga cccgctgtacaaggaggcgctgcaaatgttgcgtgatgctggcgctcaag ttagcattatgacctacgacgaatttaaacactgttgggataccttcgtg gatcatcagggctgtccgtttcagccatgggacggcctggacgagcacag ccaggcgttatccggtcgcctgcgcgcgattctgcaaaaccagggaaact ctggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga 70 Deaminase A3B atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaaatactaaggtatttaatggatcccgacactttcaccttcaat ttcaacaacgatccattggtcttgcgccgtcgtcagacctacttgtgcta tgaggttgaacgtctggataacggtacgtgggttttaatggatcagcata tgggtttcctgtgtaatgaagcgaagaacctgctgtgcggtttttacggc cgtcatgcggaactgcgttttcttgacctggttccgagcctgcaactgga cccggctcagatttaccgtgttacctggtttatctcgtggagcccgtgtt ttagctggggctgcgcgggtgaagtgcgcgcgtttttgcaagagaacacc cacgtgcgtctccgcatcttcgccgcacgtatttacgattatgacccgct gtataaagaggccctgcaaatgctgagagatgctggcgcacaagtgagca ttatgacctacgacgagttcgagtactgctgggatacgttcgtgtatcgc caaggttgcccgtttcagccgtgggacggcctggaggagcacagccaggc gctctccggtcgtttgcgcgcgatcctgcaatctggaagtgagacacccg ggacttcagaatccgcgaccccggagtctgga 71 Deaminase AID atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggattcactattaatgaataggagaaaattcctgtatcagtttaag aacgtccgttgggctaaaggtcgtcgtgagacgtatttatgctacgtggt gaaacgtcgcgacagcgcaacctccttcagcctggacttcggctatctgc gtaacaaaaacggctgccacgtggagctgctgtttttgcgctacattagc gactgggatttggacccaggtcgctgctatcgtgttacctggtttacgag ctggtcgccgtgttacgactgtgcgcgtcatgtcgcggattttctgcgcg gtaatccgaatctgtccctgcgtatttttaccgcacgtctctacttctgc gaagatcgtaaggcggaaccggaaggcttgcgtcgcctgcatagagcggg tgttcagatcgctatcatgaccttcaaagattatttctactgctggaata ccttcgtggagaaccacgagcgtactttcaaggcctgggaaggccttcac gaaaacagcgttcgcttgtctcgtcaactgcgccgcatcctgctgccgct gtacgaggttgatgatctcagagacgcgtttcgtaccctgggtttgtctg gaagtgagacacccgggacttcagaatccgcgaccccggagtctgga 72 Deaminase AmA1 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggctgattcaagtgaaaaaatgaggggacaatatatcagccgtgac acctttgagaaaaactacaaaccgattgacggcacgaaagaggcgcatct gctgtgcgaaattaaatggggtaagtacggcaagccgtggctgcattggt gtcaaaaccaacgtatgaatatccatgctgaagactacttcatgaacaac atcttcaaagccaaaaagcatccggtgcactgctacgtgacctggtattt gtcctggtcaccgtgcgcggattgtgcgagcaagatcgttaagttcctgg aggagcgtccttatctgaaactgaccatttatgttgcacagctgtattat cacactgaagaggagaaccgtaaaggtctgcgtttgctgcgttcgaagaa ggtgattatccgcgtgatggatatctctgattacaactactgctggaaag tctttgttagcaatcagaacggtaatgaagactactggccgctgcaattc gatccgtgggttaaggagaactacagccgcctcttggacattttctggga aagcaagtgccgttccccaaatccgtggtctggaagtgagacacccggga cttcagaatccgcgaccccggagtctgga 73 Deaminase Anc-rA1 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgacgctgcgccgt cgtattgagccgcacgagttcgaggttttttttgatccgcgtgaactccg caaggagacatgcttgctgtacgagatcaaatggggcacttcacacaaaa tctggcgccacagcagcaagaacaccaccaagcacgtggaagtgaacttc atcgagaaattcacgtctgaacgtcacttttgtccgtccaccagctgtag cattacctggtttctatcctggagcccgtgcggtgaatgttccaaggcga ttaccgaattcttgtcgcaacatccgaacgtgactcttgttatttatgtg gcccgtttgtaccatcacatggatcagcagaatcgtcaaggcttgcgcga cctggttaacagcggtgttaccatccagatcatgaccgcaccggaatacg actactgctggcgtaatttcgtcaactatccgccgggcaaggaggcgcat tggccgcgttatccgccgctgtggatgaaactgtacgctctggaactgca tgcgggtattttaggcctgccaccgtgcttgaatattctgagacgcaagc agcctcagctgacctttttcacgatcgcgctgcaaagctgtcattatcaa cgtctgccgccacacatcctgtgggctaccggtctgaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctgga 74 Deaminase eA3A atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggaagcaagtcccgcttcaggaccaaggcacctgatggacccacat attttcaccagtaattttaacaacggcatcggccgtcacaagacctacct gtgttatgaggtcgaacgtctggataatggcacttccgtgaaaatggatc agcatcgtggtttcctgcatggtcaggctaagaatctgctttgcggtttc tatggtcgccacgccgaactgcgttttttggacctggttccgtccctcca actggacccggcgcaaatctatcgtgttacctggtttatcagctggtcgc cgtgtttcagctggggttgcgcaggcgaagtacgtgcgttcttacaagag aacacccatgtgcgcttgcgcatcttcgccgcacgtatttacgactacga cccgctgtataaagaggcgttgcaaatgctgcgcgatgctggcgcacagg ttagcattatgacgtacgacgaatttaagcactgctgggataccttcgtg gatcaccagggctgcccgtttcagccgtgggatggtttggacgagcactc tcaggcgctgagcggtcgtctcagagcgattctgcaaaaccagggaaact ctggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga 75 Deaminase evo APOBEC 1 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaagtaaaacaggacccgttgctgtagatccgacgctgagacgt cgcatcgagccgcacgaattcgaggtgttttttgatccgcgtgaactgcg caaggagacgtgcctgctgtatgagatcaactggggtggccgtcacagca tttggcgtcacacctcccaaaacacgaacaaacacgtggaagtcaatttc atcgaaaaattcaccaccgaacgttacttctgcccgaacacccgttgttc catcacctggttcctgtcttggagcccgtgtggtgagtgcagccgcgcaa ttactgagttcctgagccgttacccgaatgttaccctgtttatctatatc gcccgtttgtaccatctggcgaacccgcgcaaccgtcagggtttacgcga cttaattagctctggcgttaccattcagattatgaccgagcaagagagcg gttattgctggcataactttgtaaactatagcccgagcaatgaaagccat tggcctcgctacccgcacctgtgggttcgtttgtacgtgctggaactgta ctgcatcatccttggtttgccaccgtgcttgaatattttgagacgtaagc agtcgcaactgaccagttttacgatcgcgctacagagctgtcattatcag cgtctcccgccacacattctgtgggctaccggcctgaaaagcggcggtag cagcggtggctccagcggctcggaaactccgggcacctccgagtcagcga ccccggaatctggaagtgagacacccgggacttcagaatccgcgaccccg gagtctgga  76 Deaminase evoCDA1 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaacagatgctgaatatgtaaggatacacgagaagctggacatc tacacctttaaaaagcagttctccaacaataaaaaatctgtcagccatcg ttgctacgtgttgtttgaactcaagcgtcgtggcgaacgccgtgcgtgct tttggggttacgctgtgaacaaaccgcagagcggtacggaacgtggtatt catgcggagatcttcagcatccgcaaggtggaagagtatctgcgcgataa cccgggtcaattcaccattaactggtacagcagctggtcaccgtgcgccg actgtgctgagaagattttggagtggtataaccaagaattgcgcggtaat ggccatactctgaagatctgggtgtgtaaactttattacgaaaagaacgc gcgtaatcaaattggtctgtggaatctgagagataacggcgttggtctga atgttatggtttccgagcactatcagtgctgccgtaaaatcttcattcag tccagccacaaccaactgaacgagaaccgttggctggaaaagaccctgaa gcgcgcggagaaacgtcgtagcgagctgagcattatgtttcaggttaaaa tcttacacaccaccaaatcgccggcagtctctggcggttcctcgggcggc agctctggctccgaaaccccaggtacgagcgagagcgcaaccccggaatc tggaagtgagacacccgggacttcagaatccgcgaccccggagtctgga 77 Deaminase evoFERNY atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcatttgagaggaattatgatcccagagaattgcgcaaagagacg tacctgctgtatgaaatcaagtggggtaaaagcggcaagctgtggcgtca ttggtgtcaaaacaaccgcacccaacacgcggaagtttatttcctcgaga atattttcaacgcccgtcgttttaacccgagcacccactgctccatcacc tggtatctttcttggtcgccgtgtgcggagtgctcgcaaaaaatcgtgga cttcctgaaagaacatccgaatgtgaacctggagatctatgttgcgagat tgtactatccggagaacgaacgtaatcgtcagggcctgcgcgacttggtc aacagcggggtgaccattcgtattatggatctgccggattacaattactg ctggaaaacctttgtttccgatcagggtggcgacgaagactactggcctg gtcactttgctccgtggattaagcagtacagcctgaagctgagcggtggt tcttccggcggtagcagtggctccgagactccaggtacgagcgagagcgc aaccccggaatctggaagtgagacacccgggacttcagaatccgcgaccc cggagtctgga 78 Deaminase hA3G-CTD atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggatcccccaacatttactttcaactttaataacgaaccgtgggtt cgcggtcgccacgaaacctacctgtgctatgaggtggaacgtatgcataa tgatacttgggttctgctgaatcaacgtagaggctttttatgcaaccaag ctccgcataaacatggttttctggaaggccgtcacgccgagctgtgcttc cttgacgtgatcccattctggaaactggacttggaccaggattatcgtgt gacctgtttcaccagctggtcgccgtgcttcagctgtgcgcaggagatgg cgaagttcatctccaaaaacaagcacgttagcttgtgcatttttaccgcg cgtatttacgatgatcaaggtcgctgccaagagggcctgcgtaccctggc agaggctggtgcgaagatctctatcatgacgtacagcgaatttaaacact gctgggacacgtttgtcgatcaccagggttgtccgttccagccgtgggac ggcttggacgaacatagccaggatttgtccggtcgtctgcgcgcaattct acagaatcaagagaactctggaagtgagacacccgggacttcagaatccg cgaccccggagtctgga 79 Deaminase minStart atgggcagccaccaccaccaccaccacagcggcgagaacctgtacttcca gtccatggctccaaagaagaagagaaaggttggaatccacggagttccag cttctgga 80 Deaminase mTadA8e atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgagcggattagtaatgcaaaattataggctaatagacgctacgttgtat gtgacctttgaaccgtgcgttatgtgcgctggtgcaatgattcattctcg tatcggccgtgtcgtgttcggcgtgagaaacagcaagcgcggtgcggcgg gtagcctgatgaatgttctgaactacccgggtatgaaccaccgtgttgaa attaccgagggtatcttggcagacgagtgcgccgccctgctgtgtgattt ctaccgcatgccgcgtcaggtttttaacgcgcagaaaaaggcgcaaagca gcatcaatagcggcggtagctctggcggctcctccggttcggagtctgga agtgagacacccgggacttcagaatccgcgaccccggagtctgga  81 Deaminase pmCDA1 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgacagatgctgaatatgtaaggatacacgagaagttggacatctac acctttaaaaagcagttctttaacaacaaaaagagcgtcagccatcgttg ctatgttctgtttgagttgaagcgccgtggcgaacgtcgtgcgtgctttt ggggttatgctgtgaacaaaccgcagtctggtactgaacgcggtattcat gcagaaattttcagcattcgtaaggtggaagaatacctgcgcgataaccc aggtcagttcaccattaactggtacagcagctggtccccgtgcgcggatt gcgctgagaagatcttggagtggtacaatcaagagctgcgtggtaatggc cataccctgaaaatctgggcgtgcaaactgtattacgaaaagaacgcgcg taatcaaattggtctgtggaatctgcgtgacaacggcgtgggcctgaatg ttatggtttccgagcactatcagtgttgtcgtaaaatcttcatccaatcc tctcacaaccaattgaacgagaaccgctggctggagaagaccctgaagcg cgccgagaaaagacgtagcgaactctcgatcatgattcaggttaaaatct tacacacgaccaaaagcccggcagtgtctggaagtgagacacccgggact tcagaatccgcgaccccggagtctgga 82 Deaminase PpA1-R33A atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgacaagtgaaaaaggaccctcaactggggacccaaccctgcgtcgt cgcattgaaagctgggagttcgacgttttttatgatccgcgtgagctggc gaaagagacgtgcctgttgtacgagatcaaatggggtatgagccgtaaaa tctggagatccagcggtaaaaacaccaccaatcacgtggaagtgaatttt atcaagaagttcaccagcgaacgtcgtttccacagctccatttcttgttc tattacctggtttctgtcttggtcgccgtgttgggagtgctcccaggcaa ttcgtgaattccttagtcaacatccgggcgtgaccctggtcatctacgtc gcccgtttgttttggcatatggaccagcgcaatcgtcagggtttgcgcga tctggttaacagcggcgttacgatccaaattatgcgtgcgagcgagtatt accactgctggcgcaacttcgtgaactatccaccgggcgatgaagcacat tggccgcaatatccgccgctgtggatgatgctgtacgcgctggaactcca ctgcattatcctgtcgctgccgccttgtctgaagatcagccgacgctggc agaaccacctcgcgtttttccgcctgcacttgcaaaactgccattaccag accatcccgccgcatatcctgttagctaccggtctgattcacccgagcgt tacttggcgttctggaagtgagacacccgggacttcagaatccgcgaccc cggagtctgga 83 Deaminase rA1 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgaccctgcgtcgc cgcattgagccgcacgagttcgaagtcttttttgatccgcgtgaactgcg caaagaaacctgtctgctgtatgaaattaactggggtggccgtcacagca tttggcgtcacactagtcaaaacaccaataaacacgtggaagttaacttc atcgagaaatttaccaccgagcgctacttctgcccgaatactcgttgttc tattacgtggtttctctcttggtcgccgtgcggcgagtgcagccgtgcga ttaccgagttcctgagccgttacccgcacgttaccctgtttatctatatc gcgcgtctgtaccatcatgcggacccgcgtaaccgtcaaggtctgcgtga tctgatcagcagcggtgttacgatccagattatgacggagcaggagtccg gctattgctggcgcaacttcgtgaactatagcccatccaatgaagctcat tggccgcgctacccgcacctgtgggtacgtttgtacgtgctggaactcta ctgcatcatccttggcctgccaccgtgcttgaatattttgagacgcaagc agccgcaactgaccttcttcaccatcgccctgcaaagctgtcattatcag cgtttgccgcctcacatcttatgggcaaccggtttgaagtctggaagtga gacacccgggacttcagaatccgcgaccccggagtctgga 84 Deaminase rA1-YE1 atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgagttcagaaacaggacccgttgctgtagacccgaccttgcgcaga cgtattgagccgcacgaattcgaggtgtttttcgacccgagagaattgcg caaagaaacctgtctgctgtacgagatcaactggggtggtcgtcatagca tctggcgtcacacctctcagaatacgaacaaacacgtggaagtcaatttc atcgagaagttcacgaccgagcgctacttctgtccgaacacccgttgttc gatcacgtggtttctgagctattctccgtgcggcgaatgcagccgtgcaa ttaccgagttcctgtcacgttacccgcacgtaactctgtttatctacatt gcgcgtctctaccatcatgctgatccggaaaaccgtcaaggtttacgcga tctgattagctccggcgtgaccatccagattatgactgagcaggagagcg gctattgctggcgcaactttgttaactattccccgtccaatgaggcgcat tggcctcgttatccgcacctgtgggttcgtctatacgttctggaattgta ctgcattatcctgggcctgccaccatgcttgaatattctgcgtcgcaagc agccgcaattgacctttttcaccatcgccctgcaaagctgccattatcag cgccttccgccgcacatcctgtgggcgaccggtctgaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctgga 85 Deaminase rA1-YEE atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgtcaagtgaaacaggacccgttgctgtagacccgaccttgagacgc cgcattgagccgcacgaatttgaagttttcttcgacccgcgtgaattgcg taaagagacgtgcttgctgtacgagattaactggggtggccgtcacagca tttggcgccacaccagccaaaacaccaacaaacatgtggaagtcaacttc atcgagaagttcactaccgagcgttacttttgtccgaatacgcgttgttc gatcacctggtttctgtcctattccccgtgcggtgaatgctcacgcgcaa tcactgagttcctgtctcgttacccgcacgtaaccctgtttatctatatc gcgcgtttgtaccatcatgcggatccggagaaccgccagggtctggaaga tttaattagcagcggcgttacgatccagattatgaccgagcaggagagcg gctattgctggcgtaatttcgtgaactattccccgtctaatgaagcgcat tggccgcgttacccacacctgtgggttcgtctctacgtgctggaattgta ctgcattatcctgggtttaccgccttgcctgaatattctacgtcgcaagc aaccgcagctgacctttttcaccatcgccctgcaaagctgtcattatcag cgtctgccgccacacatcctgtgggctaccggccttaaatctggaagtga gacacccgggacttcagaatccgcgaccccggagtctgga 86 Deaminase RrA3F-F130L atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatgaaacctcagattcgcgatcatcgtccgaatcctatggaggcgatg tatccgcatattttctactttcattttgaaaacttagaaaaagcctatgg ccgtaacgaaacttggctgtgctttaccgtagagattatcaaacaatatt taccggtaccctggaaaaaaggtgttttccgtaatcaggttgatccggag acacattgtcatgcagagaagtgcttcctgtcctggttctgcaataacac ccttagcccgaaaaagaattaccaagttacttggtacacgagctggtcgc catgtccagagtgcgcaggagaagtagcagaattcttagctgaacattcg aacgtaaaattgacaatctacaccgcccgtctctactacctgtgggacac cgactatcaggaaggcctgcgctcattgtctgaggagggcgcatcggtcg aaatcatggattatgaagattttcagtattgttgggaaaatttcgtatac gacgatggtgagccttttaaacgttggaaaggcctgaagtacaactttca gtctttgacccgtcgcttgcgcgaaattctgcaatctggaagtgagacac ccgggacttcagaatccgcgaccccggagtctgga 87 Deaminase SsA3B-R54Q atgggaagtcatcaccaccaccaccattcaggtgagaacctgtacttcca gagcatggctccgaaaaagaaacgtaaggtgggtatccacggcgttccgg cgatggatccacagaggctaagacaatggcccggtccgggtccggcgagc cgcggtggctacggccagcgtccgcgtatccgcaatccggaagagtggtt ccacgaactgagtccgagaacctttagcttccactttcgtaacctgcgtt ttgctagcggtcagaatcgcagctatatctgctgccaggtggaaggcaag aactgcttcttccaaggtatttttcaaaaccaggttccgccggacccacc ttgtcatgctgaactttgctttttgtcctggttccaaagctggggtttgt cgccggacgagcactattacgtgacctggttcatctcctggtccccgtgc tgtgaatgtgcggcgaaagtcgcccaatttctggaagagaaccgcaacgt gagcttgtctttgtctgcggcgcgtctgtactacttctggaaaagcgagt cccgtgagggcctgcgccgtctgtccgatctgggtgcacaggttggtatt atgtcgttccaagattttcagcattgttggaataactttgttcataatct gggcatgccgttccagccgtggaagaaattgcacaaaaactaccaacgtc tggtgaccgaattaaaacagattctccgcgaggagccggctacctatggc tctccacaggcgcaaggtaaggtgcgcatcggcagcaccgcggcgggtct gcgtcacagccatagccacacccgtagcgaggcgcatctgcgtcccaacc actcatctcgtcagcaccgtatcctgaatccgccgcgcgaggcccgtgcg cgtacgtgcgttctggtagacgcatcctggatttgctatcgttctggaag tgagacacccgggacttcagaatccgcgaccccggagtctgga 88 Nuclease dCas9 atggataaaaagtattcaataggactagctattggcaccaacagcgttgg ttgggcagttatcaccgatgaatataaggtcccgagcaagaagtttaagg tcctgggcaacaccgatcgccacagcataaaaaagaaccttattggtgcg ctgctgttcgattctggtgagactgccgaagcgacccgtctgaagagaac cgcgcgtcgtagatacacccggcgcaagaaccgtatctgctatctgcaag aaattttcagcaacgagatggctaaggtcgacgactccttctttcatcgc ctggaggaaagctttctggttgaggaagacaaaaagcacgagcgtcatcc gattttcggtaacattgttgatgaagttgcctaccacgaaaaatacccca caatttatcatctgcgtaaaaaactggtagactccaccgataaggcggat ttacgccttatctatttggcgctggcgcatatgattaagttccgcggtca ttttttgatcgagggcgacctgaatccggataacagcgacgttgacaaac tgtttatccagctggtgcagacctataaccagttgttcgaagagaacccg attaatgcgtctggcgtggacgcgaaggcgatcctgagcgctcgtctgtc caagtcacgccgcctggagaacttgatcgcgcaactgccgggtgagaaga aaaacggcttgttcggcaatctgattgctctgtccctaggtttgaccccg aatttcaaatctaattttgatctggcggaagatgcgaaattacagttgag caaggacacttacgatgacgatctggacaacctgctcgctcagatcggcg atcagtatgccgatcttttcctggccgcgaagaacctgagcgatgccatc ttgctatcggacatcttacgtgttaacaccgaaatcaccaaagctccgct aagcgcgtccatgattaaacgttacgatgaacaccaccaggatctgacgc tgctgaaagcgttggtgcgccagcaactgccggaaaaatacaaggaaatt ttcttcgaccaaagcaagaacggttatgcaggctatatcgacggtggtgc gtcgcaagaagaattttataaattcatcaaaccgattttggagaagatgg atggtaccgaggagctgctggtaaaattgaatcgggaagacctcttgcga aagcagcgtactttcgataatggtagcatcccgcaccagattcatctggg cgaacttcacgcaatcctacgtcgtcaagaggatttctacccgtttctga aggataaccgtgaaaagatcgagaagattctgacctttcgtattccgtat tatgtgggtccgctggcgagaggcaacagccgttttgcgtggatgacccg caagtcggaagagactatcacgccgtggaatttcgaggaggtcgtggaca agggtgcatcagcgcaatcttttattgaacgtatgaccaattttgataaa aaccttccaaatgaaaaagtgttgccgaagcacagcttgctgtacgagta tttcaccgtttacaatgaactgacgaaagtcaagtacgttaccgaaggta tgcgtaagccagcctttctgtctggggagcaaaaaaaagccattgtggat ctgctgttcaagaccaatcgcaaggttaccgtcaagcaactgaaagagga ttacttcaaaaaaatcgaatgttttgactccgtggaaatcagcggcgttg aagaccgctttaatgcatctctgggcacctaccacgatctactcaagatc atcaaggataaggacttcctggacaacgaagaaaatgaggatatcttgga agatattgtgctgactttaacgttgttcgaggatcgtgagatgattgaag aacgcctcaaaacgtacgcacatctgtttgacgataaggtgatgaaacag ctaaagcgccgtcgttacaccggttggggtcgtctgtctagaaagctgat taacggcattcgtgacaaacaatctggcaagaccatcctggacttcctca aatccgacggcttcgcaaatcgtaatttcatgcaactgatccatgatgat agcctgacctttaaagaagatattcagaaggctcaagtgtccggccaggg tgactcgctgcatgagcatatcgcgaatctggctggctcccctgcgataa aaaaaggtattctccaaacggtgaaagttgtggatgaactggttaaagtc atgggtcgtcataaaccggaaaacatcgtgattgagatggcacgtgagaa ccagaccacccagaaaggtcaaaaaaacagtcgtgagcgtatgaaacgta tcgaagaggggattaaggagttaggcagccagattctgaaggagcacccg gttgagaacacccagctgcaaaacgagaagctctacctgtattacctgca aaacggccgtgacatgtatgttgaccaggagctggacatcaatcgtctca gcgactacgacgtggatgctatcgtgccgcagagctttctaaaagatgat tccatcgacaataaagtgctcacccgtagcgacaagaaccgtggtaaaag cgacaacgtgccgagcgaggaagtagttaagaaaatgaaaaactactggc gtcagctattgaacgccaagcttatcacccagcgtaagtttgacaacttg acgaaggcagagcgtggcggcctgagcgagctagacaaggcgggttttat taaacgccagctggtggaaactcgccagattaccaaacacgttgcgcaaa tcttggactcacgcatgaatacgaagtacgacgaaaacgataaattgatc cgcgaggtgaaggtcataaccctgaaatctaaactggttagcgatttccg gaaggactttcaattttataaagtccgggagattaacaactatcaccatg cacacgacgcttacttaaatgcggttgttggcacggccctgatcaagaag tacccgaaactggaaagcgagtttgtttatggtgactacaaggtgtatga cgttcgcaagatgattgcaaaatccgaacaagagattggtaaggcgacgg ctaagtattttttctacagcaatatcatgaacttcttcaagactgaaatc accctggcgaacggtgaaattcgtaaacgtccgttgatcgaaaccaacgg tgaaaccggtgaaatcgtttgggataaaggtagggattttgcgaccgttc gtaaggtcctgagcatgccgcaggttaacatcgtgaaaaagaccgaagtg cagaccggcggtttctccaaggagagtatcttaccgaagcgcaacagtga caagctgatcgcgcgtaaaaaagactgggatccgaaaaaatacggcggct ttgactccccgaccgtcgcgtacagcgtactggtcgtggctaaagtggag aaaggcaaatcgaaaaagctgaaatccgttaaagagttgctgggtattac gattatggaacgttcgagcttcgagaaaaatccgatcgacttcctggagg ccaaaggctacaaggaagttaaaaaagacctgatcattaaactgccgaag tacagcctgttcgagctcgagaacggtcgcaaacgcatgctggcgagcgc gggtgagctccaaaaaggcaacgaattggctctgccgagcaagtacgtga acttcctgtatctggcctcccattatgaaaaactgaagggtagcccggaa gataacgaacaaaagcagctgttcgtggaacaacataaacactatctgga cgagattattgagcaaatcagcgagttcagcaaacgcgtgattctggcgg atgctaatctggacaaggttctttcagcctataataaacaccgtgataag ccgatccgtgaacaggcagaaaatattattcacctgttcaccctgacgaa cctgggtgcgccagcagcgtttaaatacttcgacacaacgatcgaccgga agcgttataccagcaccaaagaggttcttgacgccaccttgattcaccaa agcatcacgggtctgtatgaaacccgtattgacttgagccagttgggcgg agattcagggggaagtggcggaagcggtgggtctacgaacctgagcgaca ttattgaaaaagaaactggtaaacagttggtgatccaagaatccattctg atgttaccggaggaagtggaagaggtgatcggcaacaagccggagtccga catcctggttcacaccgcgtatgatgagtcgaccgatgagaatgttatgc tgctgaccagcgacgccccagagtacaaaccgtgggcgctcgtcatccag gatagcaatggcgaaaacaagatcaagatgttgtctggcggtagcatggc tccgaaaaagaagcgtaaagtaggtattcatggtgttccggcatcaggt 89 Nuclease dCasPhi-2 atgccaaaacccgctgtagagtcagaattttcaaaagttttgaaaaagca ctttccgggagaacgtttccgctcgagctatatgaaaagaggcggtaaga tcctggctgcccaaggcgaagaggcagttgttgcgtatctacagggcaag tccgaggaggagcctccgaacttccagccaccggcgaagtgccacgtggt gaccaaatcccgtgacttcgcggaatggccgatcatgaaggcgtcggaag cgattcaacgttatatctatgcactgtcgaccaccgaacgcgcggcctgt aaaccgggcaaaagtagtgagagccatgcagcgtggttcgccgctaccgg tgtcagcaaccacggctacagccacgttcagggtctgaacctgatttttg atcataccttgggccgttacgatggtgttctgaaaaaggtccaactgcgc aacgaaaaggcgagagcgcgtttagagagcattaacgcgtctagagcaga tgaaggtttaccggagattaaagccgaggaggaagaagtggctacgaacg aaaccggccacctgttgcaaccgccgggtatcaatccgagcttttacgtg tatcagaccattagcccgcaggcataccgtccgcgtgacgagatcgtgct gccgccggagtacgcaggttacgtacgtgacccgaatgctccgattccgc tgggtgtggtgcgtaaccgttgcgatatccaaaaagggtgcccgggctac atcccggaatggcagcgtgaagcaggtaccgcgatcagcccgaaaacagg caaggccgtaactgtgccgggcctgtctccgaagaaaaacaaacgtatgc gtaggtactggcgctctgagaaggagaaagctcaagatgcgctgttggtt accgtacgcattggtaccgattgggttgtcatcgacgtgcgcggtctgtt gcgcaacgcccgttggcgcaccatcgctcccaaggacatcagcctgaatg cgctcctcgatttgtttaccggtgatccggtgatcgatgtgcgtcgcaat attgttacctttacgtacaccctcgacgcctgtggtacctacgcccgtaa atggaccttgaaaggcaaacagacgaaagcgaccctggacaaactgacgg ccactcagacggttgcgttggttgcgattgcgcttggtcagaccaacccg atttccgctggcattagccgtgttacacaagaaaatggtgcactgcaatg cgaaccgctggaccggttcaccctgccggatgacctgttgaaggacatca gcgcatatcgcattgcttgggacagaaacgaagaggaactacgcgctcgc agcgtcgaggccctgccggaggcgcaacaagcggaggtccgtgcgctgga cggggtgtccaaagaaaccgcgcgtacccaactgtgcgcagatttcggcc tggacccgaaacgtctgccgtgggataaaatgagctccaatactaccttt atcagcgaagccttgctgtctaacagcgtgagccgtgatcaggttttttt cactccggctccgaagaagggtgctaagaaaaaagcgcctgttgaagtta tgcgtaaagaccgcacttgggcacgtgcgtacaagccgcgtctgagcgtc gaagctcagaaactgaagaacgaagccctgtgggcacttaagcgcacctc cccggagtatttgaagctgagccgtcgcaaagaggagctgtgtcgtcgta gcatcaactatgttatcgaaaagacccgtcgccgtacgcaatgtcagatt gtgatcccggtgatcgaggatctgaatgttcgcttctttcatggttctgg taagagactgcccggttgggataatttcttcaccgctaaaaaagagaacc gttggttcatccagggcctgcacaaagcgtttagcgatctgcgtacgcac cgttccttctatgtttttgaagttcgtccggagcgcacctctattacctg tccaaagtgcggtcattgcgaggtgggtaatcgtgacggtgaggcgtttc agtgcctgagctgcggcaagacgtgcaacgcagatcttgacgtcgcgacc cataatctgacccaagtggcgttgaccggtaagaccatgccgaagcgcga ggagccgcgtgacgctcagggtacagcgccagcgcgcaagactaagaagg cgagcaaatcaaaggcgccaccggcggagcgcgaagaccagaccccggcg caagagccaagccagaccagttctggaggtagcgggggtagcggtggtag cactaacttaagtgatattatcgagaaagaaaccgggaaacagctggtga tccaagaaagcattctgatgctgcccgaagaagttgaagaagtgattggt aacaagcctgagtcggacatcttagtgcacaccgcgtacgatgaaagcac ggatgagaatgtgatgctgctcacctctgatgcccccgaatacaagccgt gggctctggtgatccaggactctaacggagaaaacaaaattaagatgctc tctggcggctccatggcgcctaaaaaaaaacgcaaagtggggattcacgg ggttccggcgtcaggt 90 Nuclease dLbCas12a atgtcaaaactagaaaagtttacaaattgttactccctgtcgaaaaccct gagattcaaagcgatcccggtgggtaaaactcaagagaacattgataaca aacgtctgctggttgaggacgaaaagcgcgcggaggattacaaaggcgtt aaaaagctgttggaccgttattacctgtcctttattaatgatgttctgca cagcattaaattaaagaacctaaacaattacatctccctcttccgtaaaa agacccgcaccgaaaaggaaaataaagaactggagaaccttgagattaat ctgcgtaaagaaatcgctaaagcgtttaaaggcaacgagggttataaatc cttatttaaaaaagacatcatcgaaacgattctcccagaattcctggacg acaaagacgagatcgcgctggttaattccttcaacggctttaccaccgca ttcaccggcttttttgataaccgcgaaaacatgttctctgaagaggccaa aagcacctcaattgcgtttcgctgcattaacgaaaatctgacgcgttata tctctaacatggatatcttcgagaaggttgacgctatctttgataaacat gaagtccaggagatcaaggagaagatcctgaacagcgactacgacgtgga ggatttcttcgagggtgagttcttcaattttgttttgacccaagaaggca tcgatgtctacaatgcgataattggtggttttgttaccgagagcggggag aaaattaagggtctgaacgaatatatcaacttgtacaaccagaaaaccaa acaaaaactgccgaagtttaagccgctgtacaagcaagtcttgtcggatc gtgaatcgctgagcttttacggcgaaggctacaccagcgatgaggaggtg ttggaggtgttccgcaatacgttgaataagaactctgaaattttttccag cattaagaagctggaaaaactattcaagaacttcgacgagtatagcagcg caggtatctttgtgaaaaacggtccggctattagcaccatctcgaaagac attttcggcgaatggaatgttattcgtgataagtggaatgccgaatacga cgacattcatctgaagaaaaaggcggttgtaactgaaaagtacgaggacg atcgtcgtaagtcgttcaaaaagatcggctccttctctctggagcaactg caagagtacgccgatgccgatttgtcagtcgtggagaagctgaaagagat catcattcaaaaagttgacgaaatctataaggtctatggtagcagtgaaa aactgtttgacgcggacttcgtgctggagaaaagcctgaagaaaaatgac gccgtggtggcaatcatgaaagatcttctggatagcgtcaagtctttcga aaactacatcaaagcgtttttcggtgaaggcaaggaaacgaatcgtgacg agagcttctatggtgatttcgtcctagcctatgatatcctgcttaaggtg gatcacatctatgatgccatccgcaactatgttacccagaaaccgtactc aaaggacaagttcaagttatacttccagaatccgcagtttatgggtggct gggataaagataaggaaaccgactatcgcgccaccattttacgttacggt agtaagtactatctggcaatcatggataaaaaatatgcgaaatgcctgca aaagatcgacaaggacgatgttaacggcaattatgagaagatcaactaca aactgctgccgggcccaaataagatgctgccgaaggtgtttttcagcaaa aaatggatggcgtattacaatccgagcgaggacatccaaaagatctacaa aaacggtacgtttaagaagggtgatatgttcaacctcaacgattgtcata aacttattgacttcttcaaggatagcatatctcgttatccgaagtggagc aacgcgtatgactttaactttagcgaaaccgagaaatacaaagatatcgc gggtttctatcgtgaagttgaagaacagggttacaaagtgtccttcgagt ccgcgagcaagaaggaggtagacaagctggtcgaggagggtaagttgtac atgtttcagatttacaataaggacttttccgacaagtcccatggtacacc gaatttgcacaccatgtatttcaagcttctgttcgacgagaacaaccacg gccagatccgtctgagcggtggtgcagagctgttcatgcgtagagctagc ctgaagaaagaagagttggtcgttcatccggctaattcgccgatcgcgaa caaaaatccagataaccctaaaaagactacgaccctgagctatgatgtgt ataaagacaaacgctttagcgaagaccagtatgagttacacattccgatc gctatcaacaagtgcccgaagaatattttcaagatcaacaccgaagtgcg tgttcttttgaagcacgatgacaacccgtatgtgattggtattgctcgtg gtgaacgtaatctgctgtacattgtggttgtggacggcaaaggaaacatc gtggaacagtacagcctgaacgaaatcattaacaatttcaacggcattcg cattaagacggattaccattctttgctggacaaaaaggagaaagagcgtt tcgaggcccgtcagaactggacctccatcgagaacattaaggagctgaag gcgggttacatcagccaggtggtgcacaaaatctgcgaactggtggagaa gtacgacgcggtgattgctttggcggatttgaactccggttttaagaaca gccgcgttaaagtggaaaagcaggtttatcagaaattcgaaaaaatgctg attgataaattgaattacatggttgacaaaaagtctaacccgtgtgcaac cggcggtgcgctgaagggctaccaaatcaccaataagtttgaaagcttta agagcatgagcacgcaaaatggcttcattttttacattccggcgtggctg accagcaagatcgatccgtcaaccggctttgttaatttactgaagacgaa gtatacctctattgccgactctaaaaaatttattagttccttcgatagaa tcatgtatgttccggaagaggacctgttcgaatttgcactggactacaag aactttagccgtaccgatgctgattatataaagaaatggaaactctacag ctatggcaaccgcatccgtatctttcgcaacccgaaaaaaaacaacgtgt tcgactgggaagaggtatgtctgacttcagcgtacaaggagcttttcaat aaatatggtatcaactaccagcagggtgatatccgtgcactgctttgcga gcaaagcgataaagcgttctattcaagcttcatggcgctgatgagcctga tgctgcaaatgcgcaacagcatcaccggtcgtaccgatgttgcatttctg atttctccagtaaaaaacagcgatggtatcttttacgacagccgtaatta cgaggcccaagaaaatgcgattttgccgaagaacgctgacgcgaatggtg catacaacattgcaaggaaagttctgtgggcaatcggccaatttaaaaaa gcggaagatgagaagctggacaaagtgaaaattgcgattagcaacaagga gtggctggagtatgcgcagacctccgttaaatcagggggaagtggcggaa gcggtgggtctacgaacctgagcgacattattgaaaaagaaactggtaaa cagttggtgatccaagaatccattctgatgttaccggaggaagtggaaga ggtgatcggcaacaagccggagtccgacatcctggttcacaccgcgtatg atgagtcgaccgatgagaatgttatgctgctgaccagcgacgccccagag tacaaaccgtgggcgctcgtcatccaggatagcaatggcgaaaacaagat caagatgttgtctggcggtagcatggctccgaaaaagaagcgtaaagtag gtattcatggtgttccggcatcaggt 91 Protospacer AsCas12-pS taatttctactcttgtagatgtcagcaacgacaggcagctggg 92 Protospacer CasPhi-pS caacgattgcccctcacgaggggacgtcagcaacgacaggcagctggg 93 Protospacer dCas9-pS gtcagcaacgacaggcagctgttttagagctagaaatagcaagttaaaat aaggctagtccgttatcaacttgaaaaagtggcaccgagtcggtgctttt tt 94 Protospacer ErCas12-pS gtcaaaagacctttttaatttctactcttgtagatgtcagcaacgacagg cagctggg 95 Protospacer FnCas12-pS aatttctactgttgtagatgtcagcaacgacaggcagctggg 96 Protospacer LbCas12-pS aatttctactaagtgtagatgtcagcaacgacaggcagctggg 97 Protospacer MbCas12-pS aatttctactgtttgtagatgtcagcaacgacaggcagctgggcgacccc 98 Functional- XTEN-NG-N7 ggatctggaagtgagacacccgggacttcagaatccggtctatggtgag ization 1-48:xten caagggcgaggaggataacatggcctctctcccagcgacacatgagtta component 49-756:NG cacatctttggctccatcaacggtgtggactttgacatggtgggtcaggg 757-1011:N7 caccggcaatccaaatgatggttatgaggagttaaacctgaagtccacca 1012-1012:Stop agggtgacctccagttctccccctggattctggtccctcatatcgggtat ggcttccatcagtacctgccctaccctgacgggatgtcgcctttccaggc cgccatggtagatggctccggataccaagtccatcgcacaatgcagtttg aagatggtgcctcccttactgttaactaccgctacacctacgagggaagc cacatcaaaggagaggcccaggtgaaggggactggtttccctgctgacgg tcctgtgatgaccaactcgctgaccgctgcggactggtgcaggtcgaaga agacttaccccaacgacaaaaccatcatcagtacctttaagtggagttac accactggaaatggcaagcgctaccggagcactgcgcggaccacctacac ctttgccaagccaatggcggctaactatctgaagaaccagccgatgtacg tgttccgtaagacggagctcaagcactccaagaccgagctcaacttcaag gagtggcaaaaggcctttaccgatgtgatgggcatggacgagctgtacaa gtcaggtgctgcagcggccgaattcaagcgtgaagaacaagcaaggaaag ctaaggtgaacaatgagaaaaagacggaaatagtgaaaccagagagttgt agcaatgaaggagatgtcaaggatctgaaaagaaaggactctgaggatgg aaacgagggtgaggaagaagaagcttcttcgaaaccgaaaaagccaaaag ttgctctttctcatcttcaggacattgacgacacagaagctgatcaagaa gaagagtaa 99 Promoter pCmYLCV tggcagacatactgtcccacaaatgaagatggaatctgtaaaagaaaacg cgtgaaataatgcgtctgacaaaggttaggtcggctgcctttaatcaata ccaaagtggtccctaccacgatggaaaaactgtgcagtcggtttggcttt ttctgacgaacaaataagattcgtggccgacaggtgggggtccaccatgt gaaggcatcttcagactccaataatggagcaatgacgtaagggcttacga aataagtaagggtagtttgggaaatgtccactcacccgtcagtctataaa tacttagcccctccctcattgttaagggagcaaaatctcagagagatagt cctagagagagaaagagagcaagtagcctagaagtagtcaaggcggcgaa gtattcaggcacgtggccaggaagaagaaaagccaagacgacgaaaacag gtaagagctaagctta 100 Promoter p35S agattagccttttcaatttcagaaagaatgctaacccacagatggttaga gaggcttacgcagcaagtctcatcaagacgatctacccgagcaataatct acaggaaatcaaataccttcccaagaaggttaaagatgcagtcaaaagat tcaggactaactgcatcaagaacacagagaaagatatatttctcaagatc agaagtactattccagtatggacgattcaaggcttgcttcacaaaccaag gcaagtaatagagattggagtctctaaaaaggtagttcccactgaatcaa aggccatggagtcaaagattcaaatagaggacctaacagaactcgccgta aagactggcgaacagttcatacagagtctcttacgactcaatgacaagaa gaaaatcttcgtcaacatggtggagcacgacacacttgtctactccaaaa atatcaaagatacagtctcagtagaccaaagggcaattgagacttttcaa caaagggtaatatccggaaacctcctcggattccattgcccagctatctg tcactttattgtgaagatagtggaaaaggaaggtggctcctacaaatgcc atcattgcgataaaggaaaggccatcgttgaagatgcctctgccgacagt ggtcccaaagatggacccccacccacgaggagcatcgtggaaaaagaaaa cgttccaaccacgtctacaaagcaagtggattgatgtgatatctccactg acgtaagggatgacgcacaatcccactatccttcgcaagacccttcctct atataaggaagttcatttcatttggagagaacacgggggactctagagga tccaaca 101 Functional- pCmYLCV- tggcagacatactgtcccacaaatgaagatggaatctgtaaaagaaaacg ized base A3A-dCas9- cgtgaaataatgcgtctgacaaaggttaggtcggctgcctttaatcaata editor NG ccaaagtggtccctaccacgatggaaaaactgtgcagtcggtttggcttt 1-466:pCmYLCV ttctgacgaacaaataagattcgtggccgacaggtgggggtccaccatgt 467-5671:A3A- gaaggcatcttcagactccaataatggagcaatgacgtaagggcttacg dCas9 aaataagtaagggtagtttgggaaatgtccactcacccgtcagtctata 5672:6730:-NG aatacttagcccctccctcattgttaagggagcaaaatctcagagagata gtcctagagagagaaagagagcaagtagcctagaagtagtcaaggcggcg aagtattcaggcacgtggccaggaagaagaaaagccaagacgacgaaaac aggtaagagctaagcttaatgggaagtcatcaccaccaccaccattcagg tgagaacctgtacttccagagcatggctccgaaaaagaaacgtaaggtgg gtatccacggcgttccggcgatggaagcaagtccagcttcaggacccagg cacctgatggacccgcatattttcacctctaattttaacaacggtattgg ccgtcacaagacgtacctgtgttatgaagtggaacgtcttgacaacggca cctccgtgaaaatggaccagcatcgtggtttcttgcataatcaagctaaa aacctgctgtgcggtttctacggccgtcacgcggaactgcgttttttgga cctggttccgagcctgcaactggacccggcacagatttatcgtgttactt ggttcatcagctggtcgccgtgttttagctggggttgcgccggcgaggta cgcgcgtttttgcaagagaacacccacgtgcgtttgcgcatcttcgccgc tcgtatctacgattatgacccactgtataaagaagcgctccagatgctgc gcgatgcaggcgcgcaggtttccatcatgacctacgacgagttcaagcac tgctgggatacctttgtcgatcatcagggctgcccgttccagccgtggga tggtctggatgagcacagccaggcgttaagcggtcgcctcagagcgattc tgcaaaaccaaggtaattctggaagtgagacacccgggacttcagaatcc gcgaccccggagtctggaatggataaaaagtattcaataggactagctat tggcaccaacagcgttggttgggcagttatcaccgatgaatataaggtcc cgagcaagaagtttaaggtcctgggcaacaccgatcgccacagcataaaa aagaaccttattggtgcgctgctgttcgattctggtgagactgccgaagc gacccgtctgaagagaaccgcgcgtcgtagatacacccggcgcaagaacc gtatctgctatctgcaagaaattttcagcaacgagatggctaaggtcgac gactccttctttcatcgcctggaggaaagctttctggttgaggaagacaa aaagcacgagcgtcatccgattttcggtaacattgttgatgaagttgcct accacgaaaaataccccacaatttatcatctgcgtaaaaaactggtagac tccaccgataaggcggatttacgccttatctatttggcgctggcgcatat gattaagttccgcggtcattttttgatcgagggcgacctgaatccggata acagcgacgttgacaaactgtttatccagctggtgcagacctataaccag ttgttcgaagagaacccgattaatgcgtctggcgtggacgcgaaggcgat cctgagcgctcgtctgtccaagtcacgccgcctggagaacttgatcgcgc aactgccgggtgagaagaaaaacggcttgttcggcaatctgattgctctg tccctaggtttgaccccgaatttcaaatctaattttgatctggcggaaga tgcgaaattacagttgagcaaggacacttacgatgacgatctggacaacc tgctcgctcagatcggcgatcagtatgccgatcttttcctggccgcgaag aacctgagcgatgccatcttgctatcggacatcttacgtgttaacaccga aatcaccaaagctccgctaagcgcgtccatgattaaacgttacgatgaac accaccaggatctgacgctgctgaaagcgttggtgcgccagcaactgccg gaaaaatacaaggaaattttcttcgaccaaagcaagaacggttatgcagg ctatatcgacggtggtgcgtcgcaagaagaattttataaattcatcaaac cgattttggagaagatggatggtaccgaggagctgctggtaaaattgaat cgggaagacctcttgcgaaagcagcgtactttcgataatggtagcatccc gcaccagattcatctgggcgaacttcacgcaatcctacgtcgtcaagagg atttctacccgtttctgaaggataaccgtgaaaagatcgagaagattctg acctttcgtattccgtattatgtgggtccgctggcgagaggcaacagccg ttttgcgtggatgacccgcaagtcggaagagactatcacgccgtggaatt tcgaggaggtcgtggacaagggtgcatcagcgcaatcttttattgaacgt atgaccaattttgataaaaaccttccaaatgaaaaagtgttgccgaagca cagcttgctgtacgagtatttcaccgtttacaatgaactgacgaaagtca agtacgttaccgaaggtatgcgtaagccagcctttctgtctggggagcaa aaaaaagccattgtggatctgctgttcaagaccaatcgcaaggttaccgt caagcaactgaaagaggattacttcaaaaaaatcgaatgttttgactccg tggaaatcagcggcgttgaagaccgctttaatgcatctctgggcacctac cacgatctactcaagatcatcaaggataaggacttcctggacaacgaaga aaatgaggatatcttggaagatattgtgctgactttaacgttgttcgagg atcgtgagatgattgaagaacgcctcaaaacgtacgcacatctgtttgac gataaggtgatgaaacagctaaagcgccgtcgttacaccggttggggtcg tctgtctagaaagctgattaacggcattcgtgacaaacaatctggcaaga ccatcctggacttcctcaaatccgacggcttcgcaaatcgtaatttcatg caactgatccatgatgatagcctgacctttaaagaagatattcagaaggc tcaagtgtccggccagggtgactcgctgcatgagcatatcgcgaatctgg ctggctcccctgcgataaaaaaaggtattctccaaacggtgaaagttgtg gatgaactggttaaagtcatgggtcgtcataaaccggaaaacatcgtgat tgagatggcacgtgagaaccagaccacccagaaaggtcaaaaaaacagtc gtgagcgtatgaaacgtatcgaagaggggattaaggagttaggcagccag attctgaaggagcacccggttgagaacacccagctgcaaaacgagaagct ctacctgtattacctgcaaaacggccgtgacatgtatgttgaccaggagc tggacatcaatcgtctcagcgactacgacgtggatgctatcgtgccgcag agctttctaaaagatgattccatcgacaataaagtgctcacccgtagcga caagaaccgtggtaaaagcgacaacgtgccgagcgaggaagtagttaaga aaatgaaaaactactggcgtcagctattgaacgccaagcttatcacccag cgtaagtttgacaacttgacgaaggcagagcgtggcggcctgagcgagct agacaaggcgggttttattaaacgccagctggtggaaactcgccagatta ccaaacacgttgcgcaaatcttggactcacgcatgaatacgaagtacgac gaaaacgataaattgatccgcgaggtgaaggtcataaccctgaaatctaa actggttagcgatttccggaaggactttcaattttataaagtccgggaga ttaacaactatcaccatgcacacgacgcttacttaaatgcggttgttggc acggccctgatcaagaagtacccgaaactggaaagcgagtttgtttatgg tgactacaaggtgtatgacgttcgcaagatgattgcaaaatccgaacaag agattggtaaggcgacggctaagtattttttctacagcaatatcatgaac ttcttcaagactgaaatcaccctggcgaacggtgaaattcgtaaacgtcc gttgatcgaaaccaacggtgaaaccggtgaaatcgtttgggataaaggta gggattttgcgaccgttcgtaaggtcctgagcatgccgcaggttaacatc gtgaaaaagaccgaagtgcagaccggcggtttctccaaggagagtatctt accgaagcgcaacagtgacaagctgatcgcgcgtaaaaaagactgggatc cgaaaaaatacggcggctttgactccccgaccgtcgcgtacagcgtactg gtcgtggctaaagtggagaaaggcaaatcgaaaaagctgaaatccgttaa agagttgctgggtattacgattatggaacgttcgagcttcgagaaaaatc cgatcgacttcctggaggccaaaggctacaaggaagttaaaaaagacctg atcattaaactgccgaagtacagcctgttcgagctcgagaacggtcgcaa acgcatgctggcgagcgcgggtgagctccaaaaaggcaacgaattggctc tgccgagcaagtacgtgaacttcctgtatctggcctcccattatgaaaaa ctgaagggtagcccggaagataacgaacaaaagcagctgttcgtggaaca acataaacactatctggacgagattattgagcaaatcagcgagttcagca aacgcgtgattctggcggatgctaatctggacaaggttctttcagcctat aataaacaccgtgataagccgatccgtgaacaggcagaaaatattattca cctgttcaccctgacgaacctgggtgcgccagcagcgtttaaatacttcg acacaacgatcgaccggaagcgttataccagcaccaaagaggttcttgac gccaccttgattcaccaaagcatcacgggtctgtatgaaacccgtattga cttgagccagttgggcggagattcagggggaagtggcggaagcggtgggt ctacgaacctgagcgacattattgaaaaagaaactggtaaacagttggtg atccaagaatccattctgatgttaccggaggaagtggaagaggtgatcgg caacaagccggagtccgacatcctggttcacaccgcgtatgatgagtcga ccgatgagaatgttatgctgctgaccagcgacgccccagagtacaaaccg tgggcgctcgtcatccaggatagcaatggcgaaaacaagatcaagatgtt gtctggcggtagcatggctccgaaaaagaagcgtaaagtaggtattcatg gtgttccggcatcaggttcaggttctggaagtgagacacccgggacttca gaatccgcgaccccggagtctatggtgagcaagggcgaggaggataacat ggcctctctcccagcgacacatgagttacacatctttggctccatcaacg gtgtggactttgacatggtgggtcagggcaccggcaatccaaatgatggt tatgaggagttaaacctgaagtccaccaagggtgacctccagttctcccc ctggattctggtccctcatatcgggtatggcttccatcagtacctgccct accctgacgggatgtcgcctttccaggccgccatggtagatggctccgga taccaagtccatcgcacaatgcagtttgaagatggtgcctcccttactgt taactaccgctacacctacgagggaagccacatcaaaggagaggcccagg tgaaggggactggtttccctgctgacggtcctgtgatgaccaactcgctg accgctgcggactggtgcaggtcgaagaagacttaccccaacgacaaaac catcatcagtacctttaagtggagttacaccactggaaatggcaagcgct accggagcactgcgcggaccacctacacctttgccaagccaatggcggct aactatctgaagaaccagccgatgtacgtgttccgtaagacggagctcaa gcactccaagaccgagctcaacttcaaggagtggcaaaaggcctttaccg atgtgatgggcatggacgagctgtacaagtcaggtgctgcagcggccgaa ttcaagcgtgaagaacaagcaaggaaagctaaggtgaacaatgagaaaaa gacggaaatagtgaaaccagagagttgtagcaatgaaggagatgtcaagg atctgaaaagaaaggactctgaggatggaaacgagggtgaggaagaagaa gcttcttcgaaaccgaaaaagccaaaagttgctctttctcatcttcagga cattgacgacacagaagctgatcaagaagaagagtaagcttctctagcta gagtcgatcgacaagctcgagtttctccataataatgtgtgagtagttcc cagataagggaattagggttcctatagggtttcgctcatgtgttgagcat ataagaaacccttagtatgtatttgtatttgtaaaatacttctatcaata aaatttctaattcctaaaaccaaaatccagtactaaaatccagatcgct 102 Functional- p35S-A3A- agattagccttttcaatttcagaaagaatgctaacccacagatggt ized base dCas9-NG tagagaggcttacgcagcaagtctcatcaagacgatctacccgagcaat  editor 1-857:p35S aatctacaggaaatcaaataccttcccaagaaggttaaagatgcagtca  858-6062:A3A- aaagattcaggactaactgcatcaagaacacagagaaagatatatttct  dCas9 caagatcagaagtactattccagtatggacgattcaaggcttgcttcac  6063-7076:NG aaaccaaggcaagtaatagagattggagtctctaaaaaggtagttcccac tgaatcaaaggccatggagtcaaagattcaaatagaggacctaacagaac tcgccgtaaagactggcgaacagttcatacagagtctcttacgactcaat gacaagaagaaaatcttcgtcaacatggtggagcacgacacacttgtcta ctccaaaaatatcaaagatacagtctcagtagaccaaagggcaattgaga cttttcaacaaagggtaatatccggaaacctcctcggattccattgccca gctatctgtcactttattgtgaagatagtggaaaaggaaggtggctccta caaatgccatcattgcgataaaggaaaggccatcgttgaagatgcctctg ccgacagtggtcccaaagatggacccccacccacgaggagcatcgtggaa aaagaaaacgttccaaccacgtctacaaagcaagtggattgatgtgatat ctccactgacgtaagggatgacgcacaatcccactatccttcgcaagacc cttcctctatataaggaagttcatttcatttggagagaacacgggggact ctagaggatccaacaatgggaagtcatcaccaccaccaccattcaggtga gaacctgtacttccagagcatggctccgaaaaagaaacgtaaggtgggta tccacggcgttccggcgatggaagcaagtccagcttcaggacccaggcac ctgatggacccgcatattttcacctctaattttaacaacggtattggccg tcacaagacgtacctgtgttatgaagtggaacgtcttgacaacggcacct ccgtgaaaatggaccagcatcgtggtttcttgcataatcaagctaaaaac ctgctgtgcggtttctacggccgtcacgcggaactgcgttttttggacct ggttccgagcctgcaactggacccggcacagatttatcgtgttacttggt tcatcagctggtcgccgtgttttagctggggttgcgccggcgaggtacgc gcgtttttgcaagagaacacccacgtgcgtttgcgcatcttcgccgctcg tatctacgattatgacccactgtataaagaagcgctccagatgctgcgcg atgcaggcgcgcaggtttccatcatgacctacgacgagttcaagcactgc tgggatacctttgtcgatcatcagggctgcccgttccagccgtgggatgg tctggatgagcacagccaggcgttaagcggtcgcctcagagcgattctgc aaaaccaaggtaattctggaagtgagacacccgggacttcagaatccgcg accccggagtctggaatggataaaaagtattcaataggactagctattgg caccaacagcgttggttgggcagttatcaccgatgaatataaggtcccga gcaagaagtttaaggtcctgggcaacaccgatcgccacagcataaaaaag aaccttattggtgcgctgctgttcgattctggtgagactgccgaagcgac ccgtctgaagagaaccgcgcgtcgtagatacacccggcgcaagaaccgta tctgctatctgcaagaaattttcagcaacgagatggctaaggtcgacgac tccttctttcatcgcctggaggaaagctttctggttgaggaagacaaaaa gcacgagcgtcatccgattttcggtaacattgttgatgaagttgcctacc acgaaaaataccccacaatttatcatctgcgtaaaaaactggtagactcc accgataaggcggatttacgccttatctatttggcgctggcgcatatgat taagttccgcggtcattttttgatcgagggcgacctgaatccggataaca gcgacgttgacaaactgtttatccagctggtgcagacctataaccagttg ttcgaagagaacccgattaatgcgtctggcgtggacgcgaaggcgatcct gagcgctcgtctgtccaagtcacgccgcctggagaacttgatcgcgcaac tgccgggtgagaagaaaaacggcttgttcggcaatctgattgctctgtcc ctaggtttgaccccgaatttcaaatctaattttgatctggcggaagatgc gaaattacagttgagcaaggacacttacgatgacgatctggacaacctgc tcgctcagatcggcgatcagtatgccgatcttttcctggccgcgaagaac ctgagcgatgccatcttgctatcggacatcttacgtgttaacaccgaaat caccaaagctccgctaagcgcgtccatgattaaacgttacgatgaacacc accaggatctgacgctgctgaaagcgttggtgcgccagcaactgccggaa aaatacaaggaaattttcttcgaccaaagcaagaacggttatgcaggcta tatcgacggtggtgcgtcgcaagaagaattttataaattcatcaaaccga ttttggagaagatggatggtaccgaggagctgctggtaaaattgaatcgg gaagacctcttgcgaaagcagcgtactttcgataatggtagcatcccgca ccagattcatctgggcgaacttcacgcaatcctacgtcgtcaagaggatt tctacccgtttctgaaggataaccgtgaaaagatcgagaagattctgacc tttcgtattccgtattatgtgggtccgctggcgagaggcaacagccgttt tgcgtggatgacccgcaagtcggaagagactatcacgccgtggaatttcg aggaggtcgtggacaagggtgcatcagcgcaatcttttattgaacgtatg accaattttgataaaaaccttccaaatgaaaaagtgttgccgaagcacag cttgctgtacgagtatttcaccgtttacaatgaactgacgaaagtcaagt acgttaccgaaggtatgcgtaagccagcctttctgtctggggagcaaaaa aaagccattgtggatctgctgttcaagaccaatcgcaaggttaccgtcaa gcaactgaaagaggattacttcaaaaaaatcgaatgttttgactccgtgg aaatcagcggcgttgaagaccgctttaatgcatctctgggcacctaccac gatctactcaagatcatcaaggataaggacttcctggacaacgaagaaaa tgaggatatcttggaagatattgtgctgactttaacgttgttcgaggatc gtgagatgattgaagaacgcctcaaaacgtacgcacatctgtttgacgat aaggtgatgaaacagctaaagcgccgtcgttacaccggttggggtcgtct gtctagaaagctgattaacggcattcgtgacaaacaatctggcaagacca tcctggacttcctcaaatccgacggcttcgcaaatcgtaatttcatgcaa ctgatccatgatgatagcctgacctttaaagaagatattcagaaggctca agtgtccggccagggtgactcgctgcatgagcatatcgcgaatctggctg gctcccctgcgataaaaaaaggtattctccaaacggtgaaagttgtggat gaactggttaaagtcatgggtcgtcataaaccggaaaacatcgtgattga gatggcacgtgagaaccagaccacccagaaaggtcaaaaaaacagtcgtg agcgtatgaaacgtatcgaagaggggattaaggagttaggcagccagatt ctgaaggagcacccggttgagaacacccagctgcaaaacgagaagctcta cctgtattacctgcaaaacggccgtgacatgtatgttgaccaggagctgg acatcaatcgtctcagcgactacgacgtggatgctatcgtgccgcagagc tttctaaaagatgattccatcgacaataaagtgctcacccgtagcgacaa gaaccgtggtaaaagcgacaacgtgccgagcgaggaagtagttaagaaaa tgaaaaactactggcgtcagctattgaacgccaagcttatcacccagcgt aagtttgacaacttgacgaaggcagagcgtggcggcctgagcgagctaga caaggcgggttttattaaacgccagctggtggaaactcgccagattacca aacacgttgcgcaaatcttggactcacgcatgaatacgaagtacgacgaa aacgataaattgatccgcgaggtgaaggtcataaccctgaaatctaaact ggttagcgatttccggaaggactttcaattttataaagtccgggagatta acaactatcaccatgcacacgacgcttacttaaatgcggttgttggcacg gccctgatcaagaagtacccgaaactggaaagcgagtttgtttatggtga ctacaaggtgtatgacgttcgcaagatgattgcaaaatccgaacaagaga ttggtaaggcgacggctaagtattttttctacagcaatatcatgaacttc ttcaagactgaaatcaccctggcgaacggtgaaattcgtaaacgtccgtt gatcgaaaccaacggtgaaaccggtgaaatcgtttgggataaaggtaggg attttgcgaccgttcgtaaggtcctgagcatgccgcaggttaacatcgtg aaaaagaccgaagtgcagaccggcggtttctccaaggagagtatcttacc gaagcgcaacagtgacaagctgatcgcgcgtaaaaaagactgggatccga aaaaatacggcggctttgactccccgaccgtcgcgtacagcgtactggtc gtggctaaagtggagaaaggcaaatcgaaaaagctgaaatccgttaaaga gttgctgggtattacgattatggaacgttcgagcttcgagaaaaatccga tcgacttcctggaggccaaaggctacaaggaagttaaaaaagacctgatc attaaactgccgaagtacagcctgttcgagctcgagaacggtcgcaaacg catgctggcgagcgcgggtgagctccaaaaaggcaacgaattggctctgc cgagcaagtacgtgaacttcctgtatctggcctcccattatgaaaaactg aagggtagcccggaagataacgaacaaaagcagctgttcgtggaacaaca taaacactatctggacgagattattgagcaaatcagcgagttcagcaaac gcgtgattctggcggatgctaatctggacaaggttctttcagcctataat aaacaccgtgataagccgatccgtgaacaggcagaaaatattattcacct gttcaccctgacgaacctgggtgcgccagcagcgtttaaatacttcgaca caacgatcgaccggaagcgttataccagcaccaaagaggttcttgacgcc accttgattcaccaaagcatcacgggtctgtatgaaacccgtattgactt gagccagttgggcggagattcagggggaagtggcggaagcggtgggtcta cgaacctgagcgacattattgaaaaagaaactggtaaacagttggtgatc caagaatccattctgatgttaccggaggaagtggaagaggtgatcggcaa caagccggagtccgacatcctggttcacaccgcgtatgatgagtcgaccg atgagaatgttatgctgctgaccagcgacgccccagagtacaaaccgtgg gcgctcgtcatccaggatagcaatggcgaaaacaagatcaagatgttgtc tggcggtagcatggctccgaaaaagaagcgtaaagtaggtattcatggtg ttccggcatcaggttcaggttctggaagtgagacacccgggacttcagaa tccgcgaccccggagtctatggtgagcaagggcgaggaggataacatggc ctctctcccagcgacacatgagttacacatctttggctccatcaacggtg tggactttgacatggtgggtcagggcaccggcaatccaaatgatggttat gaggagttaaacctgaagtccaccaagggtgacctccagttctccccctg gattctggtccctcatatcgggtatggcttccatcagtacctgccctacc ctgacgggatgtcgcctttccaggccgccatggtagatggctccggatac caagtccatcgcacaatgcagtttgaagatggtgcctcccttactgttaa ctaccgctacacctacgagggaagccacatcaaaggagaggcccaggtga aggggactggtttccctgctgacggtcctgtgatgaccaactcgctgacc gctgcggactggtgcaggtcgaagaagacttaccccaacgacaaaaccat catcagtacctttaagtggagttacaccactggaaatggcaagcgctacc ggagcactgcgcggaccacctacacctttgccaagccaatggcggctaac tatctgaagaaccagccgatgtacgtgttccgtaagacggagctcaagca ctccaagaccgagctcaacttcaaggagtggcaaaaggcctttaccgatg tgatgggcatggacgagctgtacaagtcaggtgctgcagcggccgaattc aagcgtgaagaacaagcaaggaaagctaaggtgaacaatgagaaaaagac ggaaatagtgaaaccagagagttgtagcaatgaaggagatgtcaaggatc tgaaaagaaaggactctgaggatggaaacgagggtgaggaagaagaagct tcttcgaaaccgaaaaagccaaaagttgctctttctcatcttcaggacat tgacgacacagaagctgatcaagaagaagagtaagcttctctagctagag tcgatcgacaagctcgagtttctccataataatgtgtgagtagttcccag ataagggaattagggttcctatagggtttcgctcatgtgttgagcatata agaaacccttagtatgtatttgtatttgtaaaatacttctatcaataaaa tttctaattcctaaaaccaaaatccagtactaaaatccagatcgct

EXAMPLES

[0251] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.

Example 1

[0252] Selection of Nucleases and Deaminases

[0253] The selection of nucleases and deaminases was conducted by performing a literature search of reported CBE base-editors. Along with other novel nucleases or deaminases not reported in their application as base-editor, a selection was performed based on their efficiency, PAM requirement, enzyme substrate and size to encompass the editing space. Sequences for all reported variants were obtained through the NCBI nucleotide sequence database and collected for further processing. Sequences for cognate deaminase fusion partners were also collected, and design considerations were determined from reported literature of functional activity. Sequences were codon-optimised using GenSmart™ Codon Optimization (GenScript).

[0254] Modular Assembly

[0255] Design of assemblies was established using a modular cloning strategy with standardised overhangs (Weber et al., 2011, A modular cloning system for standardized assembly of multigene constructs, PLoS ONE 6(2): e16765; Patron et al., 2015 “Standards for plant synthetic biology: A common syntax for exchange of DNA parts”, New Phytologist 208(1):13-19 (2015); EP2580332B1). An adaptation was made to enable CDS to be composed from 3 different modular parts by including an additional overhang situated between the deaminase and the Cas protein that enables placing serine-glycine amino acids between both modules. Using the proposed standardised overhangs, the promoter is situated between A (GGAG) and B (TACT), the 5′UTR/RBS sequence between B and C (AATG), the deaminase module between C and X (TGGA), the Cas protein between X and D (AGGT), an additional coding C-terminus module between D and E (GCTT) and finally a 3′UTR and terminator sequence between E and F (CGCT) overhangs (FIG. 2).

[0256] The Deaminase module comprises a DNA sequence encoding a His purification tag with a TEV cleavage site and a SV40 nuclear localisation sequence designed and added to the 5′ of the codon-optimised deaminases (at the N-terminus) and DNA sequence encoding a XTEN linker with additional flexible amino acids at the 3′ of the codon-optimised deaminases (at the C-terminus). The Nuclease module comprises a DNA sequence encoding a UGI, a small flexible SGGS linker and a nucleoplasmin bipartite nuclear localisation signal at the 3′ of the codon-optimized site-directed nucleases (at the C-terminus).

[0257] The vector backbones in which these modular components are situated, contain convergent flanking BsaI sites that enable release of the part for consequent directional ligation with compatible overhangs into the destination vector.

[0258] Vector Design for Detection of Activity

[0259] The Destination vectors (pBE-entry) were prepared in order to perform a phenotypic assay of function of cloned base-editors using a constitutively expressed fluorescent protein. These vectors contain three main components (FIG. 3): [0260] I) Divergent BsaI restriction sites that enable cloning of base-editor cassette: promoter (AB), 5′UTR/RBS (BC), deaminase module (CX), nuclease module (XD), C-terminus module (DE) and 3′UTR and terminator sequence (EF). [0261] II) Constitutive or regulable cassettes for expression of nuclease gRNA. AarI restriction sites in this component allow cloning of gRNA protospacer sequences to target pre-sfGFP regions for CBEs composed by Cas9-based base-editors. [0262] III) A cassette for constitutive expression of sfGFP. Additionally, this component contains a pre-sfGFP region (5′ of sfGFP sequence) that, for CBEs, is composed of multiple putative stop codons at the 5′ section of the coding sequence for early protein termination upon CBE editing event (FIG. 4). [0263] In vitro construction of vectors encoding editors

[0264] The three main components described before along with the deaminase and nuclease modules were synthesized by Twist Bioscience. Components of destination vectors (pBE-entry) contain SapI flanking sites. In vitro construction of these destination vectors was performed by SapI-mediated Golden Gate assembly using synthesized fragments (Twist Bioscience) and a PCR-amplified pCAodd-1 vector backbone (Pollak, B. et al., 2020, Universal loop assembly: open, efficient and cross-kingdom DNA fabrication, Synth Biol (Oxf). 5(1), ysaa001) with flanking SapI restriction sites. Cloning of base-editors to destination vectors (pBE-entry) was performed as described in Pollak et al. (2019, Loop assembly: a simple and open system for recursive fabrication of DNA circuits. New Phytologist 222(1), 628-640) by odd level (BsaI) ligation.

[0265] Detection and Characterisation of Editors

[0266] A combinatorial experiment comprising four Cas9 nuclease modules and 23 deaminase modules was performed by one-pot odd level (BsaI) ligation of base-editor cassettes as described in Pollak et al. (2019). After ligation, chemically competent TOP10 cells (no. C4040100; ThermoFisher) were transformed and plated into LB containing Kanamycin and a defined concentration of inductor for base editor expression. Edited and unedited colonies (Nonfluorescent/Fluorescent) were grown overnight in 0.5 LB/Kan ml in 2-ml 96-well plates. Fluorescent and nonfluorescent cultures were combined separately and plasmid extracted using the Promega Wizard® Plus SV Minipreps DNA Purification System and further digested by the PstI restriction enzyme. Both linear plasmid combinations were separately sequenced using Oxford Nanopore Technologies Min-lon flow cells (R.9.4.1) and Genomic DNA by Ligation (SQK-LSK109). Single reads were analyzed using bioinformatics for recognition of base editor by BLAST, detection of single edits in the pre-sfGFP region as well as generation of statistics (active base-editor combinations, number of edits for each single base-editor, efficiency estimation) (FIGS. 5 and 6). On-target, off-target, editing window (position and broad), substrate preference and processivity are the main parameters that define the performance of a base-editor. A plasmid-based platform was developed so as to enable the determination of these parameters in a high-throughput experiment by applying the modular design of the base editors assembly, target multiplexing, analysis by sequencing and bioinformatics.

[0267] Expression and Production of Editors

[0268] Vector for expression of A3A (deaminase)+HFnCas9 (nuclease) base-editor under regulation of pBAD promoter were assembled as described in Pollak et al. (2019) by odd level (BsaI) ligation of: AB_pBAD (promoter)+BC_B0034m (RBS)+CX_A3A (deaminase module)+XD_HFnCas9 (nuclease module)+DE_3×Stop (translation stop codons)+EF_B0015 (Terminator) to a pCAodd-1 vector backbone. Ligation product was transformed to chemically competent TOP10 cells (no. C4040100; ThermoFisher). Protein expression was induced by adding 0.1% Arabinose (final concentration) to a 1:100 inoculated LB liquid medium grown at 25° C. for 16h. Total protein was extracted using B-PER (Bacterial Protein Extraction Reagent, no.78243; ThermoFisher), purified using HisPur Cobalt Resin (no.89964; ThermoFisher) and concentrated and buffer exchanged using Pierce concentrators (no.88523; ThermoFisher).

Example 2

[0269] Assembled Base Editors

[0270] Following the methodology described in Example 1, the following base editors were assembled using nuclease dCas9: A3A/dCas9, Anc-rA1/dCas9, eA3A/dCas9, evoCDA1/dCas9, minStart/dCas9, mTadA8e/dCas9, rA1/dCas9, rA1-YE1/dCas9; using nuclease dCasPhi2: A3A/dCasPhi2, A3A-Y130F/dCasPhi2, eA3A/dCasPhi2, evoCDA1/dCasPhi2, minStart/dCasPhi2, mTadA8e/dCasPhi2, rA1/dCasPhi2, rA1-YE1/dCasPhi2; and using nuclease dLbCas12a: A3A/dLbCas12a, A3B/dLbCas12a, AID/dLbCas12a, AmA1/dLbCas12a, evoAPOBEC1/dLbCas12a, evoFERNY/dLbCas12a, hA3G-CTD/dLbCas12a, minStart/dLbCas12a, pmCDA1/dLbCas12a, PpA1-R33A/dLbCas12a, rA1-YEE/dLbCas12a, RrA3F-F130L/dLbCas12a, SsA3B-R54Q/dLbCas12a. The base editors were assembled as follows, from N-terminus to C-terminus: 6×His/TEV-Cleavage site/SV40-NLS/Deaminase/XTEN-Linker/Site-directed nuclease/SGGS-Linker/UGI/Nucleoplasmin-NLS. minStart/Site-directed nuclease was used as a negative control for the nucleotide-modifying enzyme module, which lacks a deaminase and consists of, from N-terminus to C-terminus, 6×His/TEV-Cleavage site/SV40-NLS/XTEN-Linker/Site-directed nuclease/SGGS-Linker/UGI/Nucleoplasmin-NLS. minStart was used as a negative control for the nucleotide-modifying enzyme module, which lacks a deaminase and consists of, from N-terminus to C-terminus, 6×His/TEV-Cleavage site/SV40-NLS/XTEN-Linker. All these base editors were characterized in terms of overall performance and editing window.

[0271] Overall performances of these assembled base editors are depicted in FIGS. 8A-8C. In the case of editors based on dCas9, all editors were able to perform editing at any of the 4 sites within the pre-sfGFP sequence, reaching a maximum with deaminase evoCDA1 and a minimum with the negative control for the deaminase function, minStart (FIG. 8A). On the other hand, editing with editors based on nucleases Cas12a or CasPhi2 was dependent on the deaminase with which these editors were assembled. In the case of Cas12a editors, a maximum percentage of editing was performed when using deaminase evoFERNY, nevertheless when using deaminases hA3G-CTD or rA1-YEE no editing was observed (FIG. 8B). In the case of CasPhi2 editors, they could perform editing on nucleotide sites, but with rates far below those observed with the other editors. When these editors were assembled with deaminases A3A-Y130F or rA1-YE1, no editing was observed (FIG. 8C).

[0272] As depicted in FIGS. 9A-9C, the assembled base editors showed different optimal editing windows. In this case, the editing was performed on the pre-sfGFP region of the assemblies which contains 4 potential sites (per sgRNA), labeled as positions 1-4 in FIGS. 9A-9C. The optimal position is position 1 when using dCas9, but if this nuclease is assembled together with evoCDA1 or A3A deaminases, positions 2 and 3 can be optimal positions as well (FIG. 9A). This means that in the case of dCas9 base editors the target is preferentially edited at sites far from the PAM site of the sgRNA. Regarding the base editors based on nuclease Cas12a, optimal site was reported to be position 3, however for deaminases evoFERNY, pmCDA1 and RrA3F-F130L, the optimal site was position 2 (FIG. 9B). In the case of editors based on nuclease CasPhi2, significant editing was observed when using deaminases A3A or evoCDA1, wherein the optimal sites were position 2 and position 3 of the pre-sfGFP sequence, respectively (FIG. 9C).

Example 3

[0273] Functionalization of Base Editors

[0274] As part of the invention herein disclosed, the methodology comprises the assembly of base editors together with additional functional components to enable the detection of the presence and/or the functioning of the editor in a cell or tissue context. FIGS. 10A-10B present an example of the ability of the methodology to provide such functionalization capabilities. In this case, the base editor (A3A-dCas9) was assembled together with a fluorescent protein (mNeonGreen/NG) as part of the C-terminal of the assembly. The respective vector contained the assembled base editor and its components under the regulation of promoters p35S (FIG. 10A) or pCmYLCV (FIG. 10B). In order to verify the expression as well as localization of the base editor, the vector was introduced into Nicotiana benthamiana tissue using Agrobacterium tumefaciens transformation. Fluorescent cells or tissue showed that the introduced vector bearing the assembled editor was being transcribed and the produced editor was localized to the nucleus, hence accounting for the expression of the editor as well. This example shows that assemblies and methods described herein are able to provide the ability to add functional components accounting for the presence and/or functioning of the assembled base editors.

[0275] Embodiments of the methods and/or systems disclosed herein can include every combination and permutation of the various system components and the various method processes, including any variants (e.g. embodiments, variations, examples, specific examples, figures, etc.), where portions of embodiments of the method and/or processes described herein can be performed asynchronously (e.g. sequentially), concurrently (e.g. in parallel), or in any other suitable order by and/or using one or more instances, elements, components of, and/or other aspects of the systems and/or other entities described herein.

[0276] Any of the variants described herein (e.g., embodiments, variations, examples, specific examples, figures, etc.) and/or any portion of the variants described herein can be additionally or alternatively combined, aggregated, excluded, used, performed serially, performed in parallel, and/or otherwise applied.

[0277] Portions of embodiments of the methods and/or systems can be embodied and/or implemented at least in part as a machine configured to receive a computer-readable medium storing computer-readable instructions. The instructions can be executed by computer-executable components that can be integrated with the system. The computer-readable medium can be stored on any suitable computer-readable media such as RAMs, ROMs, flash memory, EEPROMs, optical devices (CD or DVD), hard drives, floppy drives, or any suitable device. The computer-executable component can be a general or application specific processor, but any suitable dedicated hardware or hardware/firmware combination device can alternatively or additionally execute the instructions.

[0278] As a person skilled in the art will recognize from the previous detailed description and from the figures, modifications and changes can be made to embodiments of the methods, systems, and/or variants without departing from the scope of this invention.

ABBREVIATIONS

[0279] 6×His: Polypeptide composed of 6 Histidines

[0280] A3A: DNA cytidine deaminase APOBEC3A

[0281] AID: Activation-induced cytidine deaminase

[0282] APOBEC: Apolipoprotein B mRNA editing enzyme (cytidine deaminase)

[0283] BE: Base editor

[0284] BLAST: Basic Local Alignment Search Tool

[0285] Cas protein: CRISPR associated protein (RNA-guided DNA endonuclease enzyme)

[0286] CBE: Cytidine base editor

[0287] CDS: Coding sequence

[0288] DNA: Deoxyribonucleic Acid

[0289] NLS: Nuclear localization signal or sequence

[0290] RNA: Ribonucleic Acid

[0291] sfGFP: Superfolder GFP (green fluorescent protein)

[0292] sgRNA: Single guide RNA

[0293] TALEN: Transcription activator-like effector nuclease

[0294] UTR: Untranslated region (of a transcript)