Parallel mapping and simultaneous sequencing reveals deletions in BCAN and FAM83H associated with discrete inherited disorders in a domestic dog breed |
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Authors: | Forman Oliver P Penderis Jacques Hartley Claudia Hayward Louisa J Ricketts Sally L Mellersh Cathryn S |
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Institution: | Kennel Club Genetics Centre, Animal Health Trust, Kentford, United Kingdom. oliver.forman@aht.org.uk |
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Abstract: | The domestic dog (Canis familiaris) segregates more naturally-occurring diseases and phenotypic variation than any other species and has become established as an unparalled model with which to study the genetics of inherited traits. We used a genome-wide association study (GWAS) and targeted resequencing of DNA from just five dogs to simultaneously map and identify mutations for two distinct inherited disorders that both affect a single breed, the Cavalier King Charles Spaniel. We investigated episodic falling (EF), a paroxysmal exertion-induced dyskinesia, alongside the phenotypically distinct condition congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID), commonly known as dry eye curly coat syndrome. EF is characterised by episodes of exercise-induced muscular hypertonicity and abnormal posturing, usually occurring after exercise or periods of excitement. CKCSID is a congenital disorder that manifests as a rough coat present at birth, with keratoconjunctivitis sicca apparent on eyelid opening at 10–14 days, followed by hyperkeratinisation of footpads and distortion of nails that develops over the next few months. We undertook a GWAS with 31 EF cases, 23 CKCSID cases, and a common set of 38 controls and identified statistically associated signals for EF and CKCSID on chromosome 7 (Praw 1.9×10?14; Pgenome?=?1.0×10?5) and chromosome 13 (Praw 1.2×10?17; Pgenome?=?1.0×10?5), respectively. We resequenced both the EF and CKCSID disease-associated regions in just five dogs and identified a 15,724 bp deletion spanning three exons of BCAN associated with EF and a single base-pair exonic deletion in FAM83H associated with CKCSID. Neither BCAN or FAM83H have been associated with equivalent disease phenotypes in any other species, thus demonstrating the ability to use the domestic dog to study the genetic basis of more than one disease simultaneously in a single breed and to identify multiple novel candidate genes in parallel.Authors SummaryThe Cavalier King Charles Spaniel (CKCS) is popular as a companion breed of dog in many countries worldwide. However, in common with other breeds, it is documented to suffer from a high frequency of inherited disorders, which are largely the result of routine breeding practices. The homogeneous population structure of individual breeds is advantageous for mapping inherited conditions, and we sought to utilise this by mapping two disorders, episodic falling (EF) and congenital keratoconjunctivitis sicca and ichthyosiform dermatosis (CKCSID), using a genome-wide association study approach comprising a set of cases for each condition and a single set of common controls. Independent disease-associated regions were identified for EF and CKCSID, both containing approximately 100 genes. In the absence of any provocative candidate genes, we resequenced both entire regions simultaneously using two cases for each disease and one clinically unaffected control. A 15.7 kb deletion in the BCAN gene was associated with EF and a 1 bp deletion in FAM83H was associated with CKCSID. Neither gene has been associated with similar conditions previously. This investigation highlights how multiple disease-associated mutations can be simultaneously identified in the dog with a minimal set of individuals. |
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