Updated in 5/5/2012 2:07:04 PM      Viewed: 134 times      (Journal Article)
PLoS genetics 7 (3): e1001332 (2011)

A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs.

Mia Olsson , Jennifer R S Meadows , Katarina Truvé , Gerli Rosengren Pielberg , Francesca Puppo , Evan Mauceli , Javier Quilez , Noriko Tonomura , Giordana Zanna , Maria José Docampo , Anna Bassols , Anne C Avery , Elinor K Karlsson , Anne Thomas , Daniel L Kastner , Erik Bongcam-Rudloff , Matthew T Webster , Armand Sanchez , Ake Hedhammar , Elaine F Remmers , Leif Andersson , Lluis Ferrer , Linda Tintle , Kerstin Lindblad-Toh
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.
DOI: 10.1371/journal.pgen.1001332      ISSN: 1553-7390     
[Original String]: Mia Olsson, Katarina Truvé, Gerli Rosengren Pielberg, Jennifer R.S. Meadows, Francesca Puppo, Evan Mauceli, Javier Quilez, Giordana Zanna, Maria José Docampo, Noriko Tonomura, Anne Avery, Elinor K. Karlsson, Anne Thomas, Daniel L. Kastner, Matthew T. Webster, Armand Sanchez, Åke Hedhammar, Elaine F. Remmers, Leif Andersson, Lluis Ferrer, Linda Tintle, Kerstin Lindblad-Toh: A novel unstable duplication upstream of HAS2 predisposes to a breed-specific skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. PLoS Genet 7(3): e1001332.doi:10.1371/journal.pgen.1001332.