A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs
Olsson, Mia (Uppsala University. Department of Medical Biochemistry and Microbiology)
Meadows, Jennifer R. S. (Uppsala University. Department of Medical Biochemistry and Microbiology)
Truvé, Katarina (Swedish University of Agricultural Sciences. Department of Animal Breeding and Genetics)
Rosengren Pielberg, Gerli (Uppsala University. Department of Medical Biochemistry and Microbiology)
Puppo, Francesca (National Human Genome Research Institute (Bethesda, Estats Units d'Amèrica))
Mauceli, Evan (Massachusetts Institute of Technology (Cambridge, Estats Units d'Amèrica))
Quílez Oliete, Javier (Universitat Autònoma de Barcelona. Departament de Ciència Animal i dels Aliments)
Tonomura, Noriko (Massachusetts Institute of Technology (Cambridge, Estats Units d'Amèrica))
Zanna, Giordana (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia Animals)
Docampo, María José (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Bassols Teixidó, Anna Maria (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Avery, Anne C. (Colorado State University. Department of Microbiology, Immunology, and Pathology)
Thomas, Anne (ANTAGENE Laboratory (França))
Kastner, Daniel L. (National Human Genome Research Institute (Bethesda, Estats Units d'Amèrica))
Bongcam-Rudloff, Erik (Uppsala University. Linnaeus Centre for Bioinformatics)
Webster, Matthew T. (Uppsala University. Department of Medical Biochemistry and Microbiology (Uppsala, Suècia))
Sánchez Bonastre, Armando (Universitat Autònoma de Barcelona. Departament de Ciència Animal i dels Aliments)
Hedhammar, Åke (Swedish University of Agricultural Sciences)
Remmers, Elaine F. (National Human Genome Research Institute (Bethesda, Estats Units d'Amèrica))
Andersson, Leif (Uppsala University. Department of Medical Biochemistry and Microbiology (Uppsala, Suècia))
Ferrer i Caubet, Lluís (Universitat Autònoma de Barcelona. Departament de Medicina i Cirurgia Animals)
Tintle, Linda (Wurtsboro Veterinary Clinic (Nova York, Estats Units d'Amèrica))
Lindblad-Toh, Kerstin (Uppsala University. Department of Medical Biochemistry and Microbiology (Uppsala, Suècia))

Data:	2011
Resum:	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.
Ajuts:	European Commission 201370
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; Versió publicada
Matèria:	Sequence analysis ; Genomic signal processing ; Fevers ; Mammalian genomics ; DNA sequence analysis ; Polymerase chain reaction amplification
Publicat a:	PLoS Genetics, Vol. 7, Issue 3 (March 2011) , p. e1001332, ISSN 1553-7404

DOI: 10.1371/journal.pgen.1001332
PMID: 21437276

11 p, 2.1 MB

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