Show simple item record

dc.contributor.authorOlsson, Mia
dc.contributor.authorMeadows, Jennifer R. S.
dc.contributor.authorRosengren Pielberg, Gerli
dc.contributor.authorPuppo, Francesca
dc.contributor.authorMauceli, Evan
dc.contributor.authorQuilez, Javier
dc.contributor.authorTonomura, Noriko
dc.contributor.authorZanna, Giordana
dc.contributor.authorBassols, Anna
dc.contributor.authorAvery, Anne C.
dc.contributor.authorThomas, Anne
dc.contributor.authorKastner, Daniel L.
dc.contributor.authorBongcam-Rudloff, Erik
dc.contributor.authorWebster, Matthew T.
dc.contributor.authorSanchez, Armand
dc.contributor.authorRemmers, Elaine F.
dc.contributor.authorAndersson, Leif
dc.contributor.authorFerrer, Lluis
dc.contributor.authorTintle, Linda
dc.contributor.authorLindblad-Toh, Kerstin
dc.contributor.authorGeorges, Michel
dc.contributor.authorTruve, Katarina
dc.contributor.authorDocampo, Maria Jose
dc.contributor.authorHedhammar, Ake
dc.contributor.authorKarlsson, Elinor Kathryn
dc.date.accessioned2013-10-25T13:08:57Z
dc.date.issued2011
dc.identifier.citationOlsson, 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.en_US
dc.identifier.issn1553-7390en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:11213335
dc.description.abstractHereditary 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.en_US
dc.description.sponsorshipOrganismic and Evolutionary Biologyen_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi://10.1371/journal.pgen.1001332en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3060080/pdf/en_US
dash.licenseLAA
dc.subjectgenetics and genomicsen_US
dc.subjectanimal geneticsen_US
dc.subjectdisease modelsen_US
dc.subjectgenetics of diseaseen_US
dc.titleA Novel Unstable Duplication Upstream of HAS2 Predisposes to a Breed-Defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogsen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Geneticsen_US
dash.depositing.authorKarlsson, Elinor Kathryn
dc.date.available2013-10-25T13:08:57Z
dc.identifier.doi10.1371/journal.pgen.1001332*
dash.authorsorderedfalse
dash.contributor.affiliatedKarlsson, Elinor K


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record