A Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs
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Author
Olsson, Mia
Meadows, Jennifer R. S.
Rosengren Pielberg, Gerli
Puppo, Francesca
Mauceli, Evan
Quilez, Javier
Tonomura, Noriko
Zanna, Giordana
Bassols, Anna
Avery, Anne C.
Thomas, Anne
Kastner, Daniel L.
Bongcam-Rudloff, Erik
Webster, Matthew T.
Sanchez, Armand
Remmers, Elaine F.
Andersson, Leif
Ferrer, Lluis
Tintle, Linda
Lindblad-Toh, Kerstin
Georges, Michel
Truve, Katarina
Docampo, Maria Jose
Hedhammar, Ake
Note: Order does not necessarily reflect citation order of authors.
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https://doi.org/10.1371/journal.pgen.1001332Metadata
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Olsson, Mia, Jennifer R. S. Meadows, Katarina Truve, Gerli Rosengren Pielberg, Francesca Puppo, Evan Mauceli, Javier Quilez, et al. 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. PLoS Genetics 7(3): e1001332.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 (\(p_{raw} = 2.3 \times 10^{-6}, p_{genome}=0.01\)). 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.Other Sources
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060080/pdf/Terms of Use
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