title: 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 (p(raw) = 2.3 × 10⁻⁶, p(genome) = 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.
authors: Science for Life Laboratory, Department of Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden. mia.olsson@imbim.uu.se
authors: Mia
authors: M
authors: Olsson
authors: Jennifer R S
authors: JR
authors: Meadows
authors: Katarina
authors: K
authors: Truvé
authors: Gerli
authors: G
authors: Rosengren Pielberg
authors: Francesca
authors: F
authors: Puppo
authors: Evan
authors: E
authors: Mauceli
authors: Javier
authors: J
authors: Quilez
authors: Noriko
authors: N
authors: Tonomura
authors: Giordana
authors: G
authors: Zanna
authors: Maria José
authors: MJ
authors: Docampo
authors: Anna
authors: A
authors: Bassols
authors: Anne C
authors: AC
authors: Avery
authors: Elinor K
authors: EK
authors: Karlsson
authors: Anne
authors: A
authors: Thomas
authors: Daniel L
authors: DL
authors: Kastner
authors: Erik
authors: E
authors: Bongcam-Rudloff
authors: Matthew T
authors: MT
authors: Webster
authors: Armand
authors: A
authors: Sanchez
authors: Ake
authors: A
authors: Hedhammar
authors: Elaine F
authors: EF
authors: Remmers
authors: Leif
authors: L
authors: Andersson
authors: Lluis
authors: L
authors: Ferrer
authors: Linda
authors: L
authors: Tintle
authors: Kerstin
authors: K
authors: Lindblad-Toh
mesh_terms: D000818:Animals; D001947:Breeding; D004283:Dog Diseases / Q000235:genetics* / Q000473:pathology; D004285:Dogs / Q000235:genetics*; D005334:Fever / Q000235:genetics / Q000662:veterinary*; D020440:Gene Duplication / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism; D006820:Hyaluronic Acid / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012867:Skin / Q000201:enzymology / Q000473:pathology; D013577:Syndrome
chemical_list: D006820:Hyaluronic Acid; D014453:Glucuronosyltransferase