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.
Highlights
Shar-Pei dogs have been companion animals for centuries within China where they were commissioned to guard and hunt, and to sometimes serve as fighting animals
The strongest signal of reduced heterozygosity appeared within a 3.7 Mb stretch on chromosome 13 (CanFam 2.0 Chr13: 23,487,992–27,227,623) near the Hyaluronic Acid Synthase 2 (HAS2) gene, where almost complete homozygosity was observed in Shar Pei (Figure 2C)
We have identified a 16.1 Kb duplication located approximately 350 Kb upstream of HAS2. This is clearly a derived mutation since it occurs as a single copy sequence in other dog breeds. We postulate that this is a causative mutation associated with both hyaluronanosis and Shar-Pei fever, as the observed correlation between copy number and susceptibility to Shar-Pei fever was not expected if this was a linked, neutral polymorphism
Summary
Shar-Pei dogs have been companion animals for centuries within China where they were commissioned to guard and hunt, and to sometimes serve as fighting animals. A few Chinese Shar-Pei dogs were exported to the United States in the early 1970’s and Shar-Pei descending from this limited number of animals have undergone strong selection for a wrinkled skin phenotype and heavily padded muzzle and are called the ‘‘meatmouth’’ type (Figure 1A–1C) and have found global popularity. Shar-Pei dogs have two unique features: a breed defining ‘‘wrinkled’’ skin phenotype and a genetic disorder called Familial Shar-Pei Fever (FSF). HAS2 was previously not known to associate with autoinflammatory disease, and this finding is of wide interest since approximately 60% of human patients with periodic fever syndrome remain genetically unexplained. This investigation demonstrates how strong artificial selection may affect desired and selected phenotypes, and the health of domestic animals
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