Читать книгу Pathology of Genetically Engineered and Other Mutant Mice - Группа авторов - Страница 76

Some from the clinical genetics community, seeing successes from genome‐wide association studies (GWAS), claim that with modern genetics and next generation sequencing “the model for the human is now the human” and the use of other organisms is redundant. However, when combined with human genetic studies, such as GWAS for complex genetic diseases, it is now possible to reverse engineer mouse models from development toward validation of the human discoveries. This has been ongoing for many years using traditional recombineering approaches. For example, mutations in the Abcc6, ATP‐binding cassette, sub‐family C (CFTR/MRP), member and member 6 (ABCC6) gene were identified by several groups to cause pseudoxanthoma elasticum (PXE) in humans, a systemic disease characterized by ectopic mineralization. Two groups made null mutations of this gene in mice that recapitulated many of the phenotypes seen in humans [77, 78]. Many other genes produce genocopies of ectopic mineralization, and the discovery of four inbred strains with the same spontaneous Abcc6 hypomorphic allele but very different severity of PXE lesions [79] revealed many modifier genes in the mouse and by extension in humans [42].

Complex human genetic diseases, such as psoriasis, have been difficult to model in mice [80]. However, GWAS studies identified several single nucleotide polymorphisms in the caspase recruitment domain family, member 14 (CARD14) gene [81, 82]. One of these single nucleotide polymorphism (SNPs) was reproduced by three different laboratories in mice, all of which recapitulated the skin disease [83–85]. One lab made the second allelic mutation, which did not have any effect [85]. These are a few of many examples where genetic engineering in mice can either validate or fail to match molecular discoveries in human patient cohorts.