A transgenic mouse comprising T30A, S32P, Q33L, N39D, and M470Q mutations in GPIIIa, as well as methods for making the transgenic mouse and methods for using the transgenic mouse to screen test compounds are described.

The present invention comprises non-human vertebrate cells and non-human mammals having a genome comprising an introduced partially human immunoglobulin region, said introduced region comprising human V.sub.H coding sequences and non-coding V.sub.H sequences based on the endogenous genome of the non-human mammal.

Non-human animals, cells, methods and compositions for making and using the same are provided, wherein the non-human animals and cells comprise a humanized a proliferation-inducing ligand gene. Non-human animals and cells that express a human or humanized a proliferation-inducing ligand protein from an endogenous a proliferation-inducing ligand locus are described.

Transgenic silkworms stably expressing hagfish thread keratin genes or composite silkworm/hagfish thread keratin genes are disclosed. The exogenous hagfish thread keratin genes are stably integrated into a defined site of the fibroin heavy chain intron or a fibroin light chain intron of silkworms. Synthetic hagfish thread keratin proteins and composite hagfish thread keratin-silkworm genes and proteins are provided. The expression of exogenous hagfish thread keratin genes is driven by the endogenous fibroin heavy chain promoter, improving the genetic stability of transgenic silkworms. The composite silkworm/hagfish thread keratin fibers exhibit exceptional mechanical performance, compared to normal silkworm silk fibers and other transgenic silkworm fibers.

Variant immunoglobulins with one or more amino acid modifications in the Fe region that have increased in vivo half-lives, and methods of using the same are provided.

The present invention comprises non-human vertebrate cells and non-human mammals having a genome comprising an introduced partially human immunoglobulin region, said introduced region comprising human V.sub.H coding sequences and non-coding V.sub.H sequences based on the endogenous genome of the non-human mammal.

Methods and compositions for introducing genetic mutations into non-human animal cells are provided. These cells can be used to produce animal models of human disease. In some embodiments, the genetic mutations are flanked by DNA sequences that are humanized to match homologous DNA sequences. In some embodiments, the animal model is a large mammalian model for an inherited metabolic disorder. In some embodiments, the animal model is a pig model for phenylketonuria (PKU) created by introducing a missense mutation into exon 8 of the Pah gene.

The invention provides for systems, methods, and compositions for altering expression of target gene sequences and related gene products. Provided are structural information on the Cas protein of the CRISPR-Cas system, use of this information in generating modified components of the CRISPR complex, vectors and vector systems which encode one or more components or modified components of a CRISPR complex, as well as methods for the design and use of such vectors and components. Also provided are methods of directing CRISPR complex formation in eukaryotic cells and methods for utilizing the CRISPR-Cas system. In particular the present invention comprehends optimized functional CRISPR-Cas enzyme systems, wherein the guide sequence is modified by secondary structure to increase the specificity of the CRISPR-Cas system and whereby the secondary structure can protect against exonuclease activity and allow for 5 additions to the guide sequence.

The present invention relates generally to genetically modified non-human animals and immunodeficient non-human animals characterized by restored complement-dependent cytotoxicity, as well as methods and compositions for assessment of therapeutic antibodies in the genetically modified immunodeficient non-human animals. In specific aspects, the present invention relates to immunodeficient non-obese diabetic (NOD), A/J, A/He, AKR, DBA/2, NZB/B1N, B10.D2/oSn and other mouse strains genetically modified to restore complement-dependent cytotoxicity which is lacking in the unmodified immunodeficient mice. In further specific aspects, the present invention relates to NOD.Cg-Prkdc.sup.scid IL2re.sup.tmlWjl/SzJ (NSG), NOD.Cg-Rag1.sup.tm1Mom Il2rg.sup.tmlWjl/SzJ (NRG) and NOD.Cg-Prkdc.sup.scid Il2rg.sup.tm1Sug/JicTac (NOG) mice genetically modified to restore complement-dependent cytotoxicity which is lacking in unmodified NSG, NRG and NOG mice. Methods for assessment of therapeutic antibodies or putative therapeutic antibodies in the genetically modified immunodeficient mice characterized by an intact complement system are provided according to specific aspects of the present invention.

The present invention relates generally to genetically modified non-human animals and immunodeficient non-human animals characterized by restored complement-dependent cytotoxicity, as well as methods and compositions for assessment of therapeutic antibodies in the genetically modified immunodeficient non-human animals. In specific aspects, the present invention relates to immunodeficient non-obese diabetic (NOD), A/J, A/He, AKR, DBA/2, NZB/BIN, B10.D2/oSn and other mouse strains genetically modified to restore complement-dependent cytotoxicity which is lacking in the unmodified immunodeficient mice. In further specific aspects, the present invention relates to NOD.Cg-Prkdc.sup.scid IL2rg.sup.tm1Wjl/SzJ (NSG), NOD.Cg-Rag1.sup.tm1Mom IL2rg.sup.tm1Wjl/SzJ (NRG) and NOD.Cg-Prkdc.sup.scid IL2rg.sup.tm1Sug/JicTAc (NOG) mice genetically modified to restore complement-dependent cytotoxicity which is lacking in unmodified NSG, NRG and NOG mice. Methods for assessment of therapeutic antibodies or putative therapeutic antibodies in the genetically modified immunodeficient mice characterized by an intact complement system are provided according to specific aspects of the present invention.