ENAapplication/xmlftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR031/ERR031014/ERR031014.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR031/ERR031016/ERR031016.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR031/ERR031011/ERR031011.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR031/ERR031012/ERR031012.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR031/ERR031013/ERR031013.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR031/ERR031010/ERR031010.fastq.gzftp://ftp.sra.ebi.ac.uk/vol1/fastq/ERR031/ERR031015/ERR031015.fastq.gzprimaryOK200GenomicsSwedish University of Agricultural SciencesSLUhttps://www.ebi.ac.uk/ena/browser/view/PRJEB2448Abstract 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 1 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=2.3x10-6, 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 folded 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 less than 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.ENAdermis plus epidermis plus hypodermis, the integument, region of skin, Oct-11a, pelt, Canis familiaris, DP, Otf-11, Skn-li, Asian, skin zone, integumental organ, dogs, East Asian, Far East, Dog, epidermis, skin plus hypodermis, Oct11, skin region, BC033609, animal breed, Skin-1a, tegument, Skin, Eastern, East, East Asian Peoples, dog, integumentum commune, Skn-1a, Asian People, skin benign neoplasm, Eastern Asian Peoples, skin, vertebrate integument, dermoid system, entire skin, Canis canis., Eastern Asian People, SKIN, mKIAA0493, Epoc-1, Far East Asian, Phenotypes, skin organ, portion of skin, Canis domesticus, East Asians, vertebrate epidermis, Far East Asians, People, integument, Eastern Asians, Fam91a1, Otf11, Canis borealis, Eastern Asian, Canis lupus borealis, entire integument, Chinese, AV220772, dermal system, skin and subcutaneous tissuedermis plus epidermis plus hypodermis, the integument, Controlling, preventive therapy, region of skin, Oct-11a, pelt, Canis familiaris, Otf-11, Skn-li, Asian, skin zone, integumental organ, dogs, East Asian, Far East, Dog, prevention, epidermis, skin plus hypodermis, Oct11, skin region, Canis canis, BC033609, Skin-1a, tegument, Eastern, prevention and control, Skin, East, East Asian Peoples, dog, integumentum commune, Asian People, Skn-1a, skin benign neoplasm, Eastern Asian Peoples, skin, reference sample, prophylaxis, vertebrate integument, dermoid system, entire skin, Eastern Asian People, SKIN, mKIAA0493, Far East Asian, Epoc-1, Illumina Genome Analyzer I., preventive measures, Phenotypes, Canis domesticus, skin organ, portion of skin, East Asians, Far East Asians, vertebrate epidermis, People, integument, control, Eastern Asians, Fam91a1, Otf11, Canis borealis, Eastern Asian, Canis lupus borealis, entire integument, Chinese, AV220772, dermal system, skin and subcutaneous tissue, ControlledfalseSequencing Chinese Sharpei dogs and control breeds for skin phenotype using the Illumina Genome AnalyzerA Novel Unstable Duplication upstream of HAS2 predisposes to a Breed-defining Skin Phenotype and a Periodic Fever Syndrome in Chinese Shar-Pei Dogs2016-05-202011-03-18PRJEB2448