Whole Genome Sequencing Reveals Multiple Linked Genetic Variants on Canine Chromosome 12 Associated with Risk for Symmetrical Lupoid Onychodystrophy (SLO) in the Bearded Collie

Abstract

In dogs, symmetrical lupoid onychodystrophy (SLO) results in nail loss and an abnormal regrowth of the claws. In Bearded Collies, an autoimmune nature has been suggested because certain dog leukocyte antigen (DLA) class II haplotypes are associated with the condition. A genome-wide association study of the Bearded Collie revealed two regions of association that conferred risk for disease: one on canine chromosome (CFA) 12 that encompasses the DLA genes, and one on CFA17. Case-control association was employed on whole genome sequencing data to uncover putative causative variants in SLO within the CFA12 and CFA17 associated regions. Genotype imputation was then employed to refine variants of interest. Although no SLO-associated protein-coding variants were identified on CFA17, multiple variants, many with predicted damaging effects, were identified within potential candidate genes on CFA12. Furthermore, many potentially damaging alleles were fully correlated with the presence of DLA class II risk haplotypes for SLO, suggesting that the variants may reflect DLA class II haplotype association with disease or vice versa. Strong linkage disequilibrium in the region precluded the ability to isolate and assess the individual or combined effect of variants on disease development. Nonetheless, all were predictive of risk for SLO and, with judicious assessment, their application in selective breeding may prove useful to reduce the incidence of SLO in the breed.

Validation of a Chromosome 14 Risk Haplotype for Idiopathic Epilepsy in the Belgian Shepherd Dog Found to Be Associated with an Insertion in the RAPGEF5 Gene

“…The regions immediately adjacent to the SNPs on CFA14 that comprise the ACTG haplotype and those adjacent to the CFA37 haplotype were explored in the whole genome sequence data, as previously described [ 17 ]. The ACTG risk haplotype falls 17,855 bases upstream of the Rap Guanine Nucleotide Exchange Factor 5 ( RAPGEF5 ) gene, which has a role during neurogenesis [ 21 ] and alterations in expression are associated with seizures such as temporal lobe epilepsy [ 22 , 23 ].…”

“…Whole genome data from three IE dogs having the ACTG high-risk haplotype on CFA14 and four control dogs homozygous for the low-risk CTCT haplotype were explored for potential causal variants in the risk haplotype region. A whole genome analysis pipeline for quality checks, trimming, and mapping of raw reads was performed, as previously described [ 17 ]. The FreeBayes [ 18 ] haplotype-based caller was then used to call variants across all samples.…”

Special Issue: “Canine Genetics 2”

“…A global RNA-seq experiment revealed transcriptomic changes in the skin of alopecic Bohemian Wire-haired Pointing Griffon dogs [22]. Whole genome sequencing experiments enabled the identification of new potential risk variants for symmetrical lupoid onychodystrophy (SLO) in Bearded collies [23]. Norton et al report the first heritability estimate and GWAS for episodic exercise-induced collapse in Border Collies [24].…”