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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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نویسنده
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olsson m. ,meadows j.r.s. ,truvé k. ,pielberg g.r. ,puppo f. ,mauceli e. ,quilez j. ,tonomura n. ,zanna g. ,docampo m.j. ,bassols a. ,avery a.c. ,karlsson e.k. ,thomas a. ,kastner d.l. ,bongcam-rudloff e. ,webster m.t. ,sanchez a. ,hedhammar å. ,remmers e.f. ,andersson l. ,ferrer l. ,tintle l. ,lindblad-toh k.
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منبع
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plos genetics - 2011 - دوره : 7 - شماره : 3
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چکیده
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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 (praw = 2.3×10-6,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 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.
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آدرس
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science for life laboratory,department of medical biochemistry and microbiology,uppsala university,uppsala, Sweden, science for life laboratory,department of medical biochemistry and microbiology,uppsala university,uppsala, Sweden, department of animal breeding and genetics,swedish university of agricultural sciences,uppsala, Sweden, science for life laboratory,department of medical biochemistry and microbiology,uppsala university,uppsala, Sweden, national human genome research institute,bethesda,md, United States, broad institute of harvard,massachusetts institute of technology (mit),cambridge,ma, United States, department of animal and food science,veterinary molecular genetics service,universitat autònoma de barcelona,barcelona, Spain, broad institute of harvard,massachusetts institute of technology (mit),cambridge,ma, United States, department of animal medicine and surgery,universitat autònoma de barcelona,barcelona, Spain, department of biochemistry and molecular biology,universitat autònoma de barcelona,barcelona, Spain, department of biochemistry and molecular biology,universitat autònoma de barcelona,barcelona, Spain, department of microbiology,immunology,and pathology,colorado state university,fort collins,co, United States, broad institute of harvard,massachusetts institute of technology (mit),cambridge,ma,united states,fas center for systems biology,harvard university,cambridge,ma, United States, antagene laboratory,limonest, France, national human genome research institute,bethesda,md, United States, linnaeus centre for bioinformatics,uppsala university,uppsala, Sweden, science for life laboratory,department of medical biochemistry and microbiology,uppsala university,uppsala, Sweden, department of animal and food science,veterinary molecular genetics service,universitat autònoma de barcelona,barcelona, Spain, department of clinical sciences,swedish university of agricultural sciences,uppsala, Sweden, national human genome research institute,bethesda,md, United States, science for life laboratory,department of medical biochemistry and microbiology,uppsala university,uppsala,sweden,department of animal breeding and genetics,swedish university of agricultural sciences,uppsala, Sweden, department of animal medicine and surgery,universitat autònoma de barcelona,barcelona, Spain, wurtsboro veterinary clinic,wurtsboro,ny, United States, science for life laboratory,department of medical biochemistry and microbiology,uppsala university,uppsala,sweden,broad institute of harvard,massachusetts institute of technology (mit),cambridge,ma, United States
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Authors
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