Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7. (December 2016)

• Record Type: Journal Article
• Authors: Lyons, Leslie; Creighton, Erica; Alhaddad, Hasan; Beale, Holly; Grahn, Robert; Rah, HyungChul; Maggs, David; Helps, Christopher; Gandolfi, Barbara
• Is Part Of: BMC genomics. Volume 17:Number 1(2016)
• Page Start: 1
• Page End: 11
• Publication Date: 2016-12
• Subjects: Aryl-hydrocarbon-interacting receptor protein-like 1 -- Domestic cat -- Felis silvestris catus -- Hairy and Enhancer of Split 7 -- LCA4 -- Progressive retinal atrophy; Genomes -- Periodicals; Gene mapping -- Periodicals; Genomics -- Periodicals; Base Sequence -- Periodicals; Chromosome Mapping -- Periodicals; Genetic Techniques -- Periodicals; Sequence Analysis, DNA -- Periodicals; 572.8605
• DOI: 10.1186/s12864-016-2595-4
• Languages: English
• ISSNs: 1471-2164

Abstract

Abstract Background The reduced cost and improved efficiency of whole genome sequencing (WGS) is drastically improving the development of cats as biomedical models. Persian cats are models for Leber's congenital amaurosis (LCA), the most severe and earliest onset form of visual impairment in humans. Cats with innocuous breed-defining traits, such as a bobbed tail, can also be models for somite segmentation and vertebral column development. Methods The first WGS in cats was conducted on a trio segregating for LCA and the bobbed tail abnormality. Variants were identified using FreeBayes and effects predicted using SnpEff. Variants within a known haplotype block for cat LCA and specific candidate genes for both phenotypes were prioritized by the predicted variant effect on the proteins and concordant segregation within the trio. The efficiency of WGS of a single trio of domestic cats was evaluated. Results A stop gain was identified at position c.577C > T in catAIPL1, a predicted p.Arg193*. A c.5A > G variant causing a p.V2A was identified inHES7 . The variants segregated concordantly in a Persian – Japanese bobtail pedigree. Over 1700 cats from 40 different breeds and populations were genotyped for theAIPL1 variant, defining an allelic frequency in only Persian –related breeds of 1.15 %. A sub-set of cats was genotyped for theHES7 variant, supporting the variant as private to the Japanese bobtail breed. Approximately 18 million SNPs were identified for application in cat research. The catAIPL1 variant would have been considered a high priority variant for evaluation, regardless ofa priori knowledge from previous genetic studies. Conclusions This study represents the first effort of the 99 Lives Cat Genome Sequencing Initiative to identify disease - causing variants in the domestic cat using WGS. The current cat reference assembly is efficient for gene and variant identification. However, as the feline variant database improves, development of cats as biomedical models for human disease will be more efficient, providing an alternative, large animal model for drug and gene therapy trials. Undiagnosed human patients with early-onset blindness should be screened for thisAIPL1 variant. TheHES7 variant should further calibrate the somite segmentation clock.