A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs

Abstract

Hereditary periodic fever syndromes are characterized by recurrent episodes of fever and inflammation with no known pathogenic or autoimmune cause. In humans, several genes have been implicated in this group of diseases, but the majority of cases remain unexplained. A similar periodic fever syndrome is relatively frequent in the Chinese Shar-Pei breed of dogs. In the western world, Shar-Pei have been strongly selected for a distinctive thick and heavily folded skin. In this study, a mutation affecting both these traits was identified. Using genome-wide SNP analysis of Shar-Pei and other breeds, the strongest signal of a breed-specific selective sweep was located on chromosome 13. The same region also harbored the strongest genome-wide association (GWA) signal for susceptibility to the periodic fever syndrome (praw = 2.3×10−6, pgenome = 0.01). Dense targeted resequencing revealed two partially overlapping duplications, 14.3 Kb and 16.1 Kb in size, unique to Shar-Pei and upstream of the Hyaluronic Acid Synthase 2 (HAS2) gene. HAS2 encodes the rate-limiting enzyme synthesizing hyaluronan (HA), a major component of the skin. HA is up-regulated and accumulates in the thickened skin of Shar-Pei. A high copy number of the 16.1 Kb duplication was associated with an increased expression of HAS2 as well as the periodic fever syndrome (p<0.0001). When fragmented, HA can act as a trigger of the innate immune system and stimulate sterile fever and inflammation. The strong selection for the skin phenotype therefore appears to enrich for a pleiotropic mutation predisposing these dogs to a periodic fever syndrome. The identification of HA as a major risk factor for this canine disease raises the potential of this glycosaminoglycan as a risk factor for human periodic fevers and as an important driver of chronic inflammation.

LUPA: A European initiative taking advantage of the canine genome architecture for unravelling complex disorders in both human and dogs

“…Structural changes may underlie phenotypic variation, as extensively documented in domestic animals. For instance, dominant white colour in pigs (Moller et al, 1996), the hair ridge in Rhodesian Ridgeback dogs , greying with age in horses (Rosengren Pielberg et al, 2008) and familial Shar-Pei fever (Olsson et al, 2011) are all caused by duplications.…”

“…A recent LUPA collaborative effort (Olsson et al, 2011) has taken advantage of this selective-sweep approach to identify the region underlying the thickened and wrinkled skin of Chinese Shar-Pei dogs. This approach was combined with a traditional GWAS to identify the gene for familial Shar-Pei fever, a form of periodic fever.…”

Genetic Susceptibility to Rhodococcus equi

“…A 4.6‐kb duplication in an intron has been associated with graying and melanomas in horses 75. A 16.1‐kb duplication has been shown to cause wrinkling of the skin in Shar‐Pei dogs 76. In humans, CNVs are believed to play critical roles in neurodevelopmental disorders, psychiatric disorders, and cancers 77, 78.…”

Le chien dans la pathologie et la génétique comparée: exemples de maladies et de gènes partagés entre l'homme et le chien

“…C'est ainsi que des allèles morbides (responsables de maladies héréditaires simples ou monogéniques) ou des combinaisons d'allèles non adéquates (responsables de maladies héréditaires complexes ou multifactorielles) font désormais partie du patrimoine génétique de pratiquement toutes les races canines. Ces allèles ont été involontairement co-sélectionnés car ils se trouvaient physiquement proches, sur le même chromosome, des allèles gouvernant les caractères désirés, comme cela a été récemment mis en évidence chez le Shar-Pei (Olsson et al 2011). …”