title: Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7.
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 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.
  
  
  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 this AIPL1 variant. The HES7 variant should further calibrate the somite segmentation clock.
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, E109 Vet Med Building, 1600 E. Rollins Street, Columbia, MO, 65211, USA. lyonsla@missouri.edu.
authors.forename: Leslie A
authors.initials: LA
authors.lastname: Lyons
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, E109 Vet Med Building, 1600 E. Rollins Street, Columbia, MO, 65211, USA.
authors.forename: Erica K
authors.initials: EK
authors.lastname: Creighton
authors.affiliation: College of Science, Kuwait University, Safat, 13060, Kuwait.
authors.forename: Hasan
authors.initials: H
authors.lastname: Alhaddad
authors.affiliation: Maverix Biomics, Inc., San Mateo, CA, 94402, USA.
authors.forename: Holly C
authors.initials: HC
authors.lastname: Beale
authors.affiliation: Veterinary Genetics Laboratory, School of Veterinary Medicine, University of California - Davis, Davis, CA, 95616, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Grahn
authors.affiliation: Graduate School of Health Science Business Convergence, College of Medicine, Chungbuk National University, Chongju, Chungbuk Province, 28644, South Korea.
authors.forename: HyungChul
authors.initials: H
authors.lastname: Rah
authors.affiliation: Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California - Davis, Davis, CA, 95616, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Maggs
authors.affiliation: Langford Veterinary Services, University of Bristol, Langford, Bristol, BS40 5DU, UK.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Helps
authors.affiliation: Department of Veterinary Medicine and Surgery, College of Veterinary Medicine, University of Missouri - Columbia, E109 Vet Med Building, 1600 E. Rollins Street, Columbia, MO, 65211, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Gandolfi
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D001766:Blindness / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D002415:Cats; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics*; D016678:Genome; D060005:Genotyping Techniques; D006239:Haplotypes; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019170:Somites / Q000473:pathology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002352:Carrier Proteins; D005136:Eye Proteins
keywords: Aryl-hydrocarbon-interacting receptor protein-like 1; Domestic cat; Felis silvestris catus; Hairy and Enhancer of Split 7; LCA4; Progressive retinal atrophy