Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7

Abstract

BackgroundThe 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.MethodsThe 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.ResultsA stop gain was identified at position c.577C > T in cat AIPL1, a predicted p.Arg193*. A c.5A > G variant causing a p.V2A was identified in HES7. The variants segregated concordantly in a Persian – Japanese bobtail pedigree. Over 1700 cats from 40 different breeds and populations were genotyped for the AIPL1 variant, defining an allelic frequency in only Persian –related breeds of 1.15 %. A sub-set of cats was genotyped for the HES7 variant, supporting the variant as private to the Japanese bobtail breed. Approximately 18 million SNPs were identified for application in cat research. The cat AIPL1 variant would have been considered a high priority variant for evaluation, regardless of a priori knowledge from previous genetic studies.ConclusionsThis 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 this AIPL1 variant. The HES7 variant should further calibrate the somite segmentation clock.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2595-4) contains supplementary material, which is available to authorized users.

Whole Genome Sequencing Identifies a Missense Mutation in HES7 Associated with Short Tails in Asian Domestic Cats

“…During the preparation of this manuscript, an independent study has reported that the bobbed tail trait of Japanese Bobtail is associated with the same HES7 mutation, thus giving further support to the results of this study34.…”

Localization of a feline autosomal dominant dwarfism locus: a novel model of chondrodysplasia

“…Three unrelated dwarf cats were submitted for whole genome sequencing as part of the 99 Lives Cat Genome Sequencing Consortium as previously described [23][24][25][26] (BioProject PRJNA308208, PRJNA288177; BioSamples: SAMN05980349, SAMN05980348, SAMN05980352). Reads were mapped to Felis_catus_9.0 (GCF_000181335.3/) and assigned to read groups using BWA-MEM from Burrows-Wheeler Aligner version 0.7.17 27 .…”

Early-Onset Progressive Retinal Atrophy Associated with an IQCB1 Variant in African Black-Footed Cats (Felis nigripes)

“…The cats were confirmed to be wild type for the variants known to cause PRA in Abyssinian type domestic cats, specifically the variants within CRX 27 and CEP290 26, and in Persian type domestic cats within the AIPL1 gene12.…”