A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs.
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2011-03-01
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| Series: | PLoS Genetics |
| Online Access: | http://europepmc.org/articles/PMC3060080?pdf=render |
| _version_ | 1828351746284453888 |
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| author | Mia Olsson Jennifer R S Meadows Katarina Truvé Gerli Rosengren Pielberg Francesca Puppo Evan Mauceli Javier Quilez Noriko Tonomura Giordana Zanna Maria José Docampo Anna Bassols Anne C Avery Elinor K Karlsson Anne Thomas Daniel L Kastner Erik Bongcam-Rudloff Matthew T Webster Armand Sanchez Ake Hedhammar Elaine F Remmers Leif Andersson Lluis Ferrer Linda Tintle Kerstin Lindblad-Toh |
| author_facet | Mia Olsson Jennifer R S Meadows Katarina Truvé Gerli Rosengren Pielberg Francesca Puppo Evan Mauceli Javier Quilez Noriko Tonomura Giordana Zanna Maria José Docampo Anna Bassols Anne C Avery Elinor K Karlsson Anne Thomas Daniel L Kastner Erik Bongcam-Rudloff Matthew T Webster Armand Sanchez Ake Hedhammar Elaine F Remmers Leif Andersson Lluis Ferrer Linda Tintle Kerstin Lindblad-Toh |
| author_sort | Mia Olsson |
| collection | DOAJ |
| description | 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 × 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. |
| first_indexed | 2024-04-14T01:43:44Z |
| format | Article |
| id | doaj.art-0fc34a2c6193493c831dd107ce05bb30 |
| institution | Directory Open Access Journal |
| issn | 1553-7390 1553-7404 |
| language | English |
| last_indexed | 2024-04-14T01:43:44Z |
| publishDate | 2011-03-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Genetics |
| spelling | doaj.art-0fc34a2c6193493c831dd107ce05bb302022-12-22T02:19:37ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-03-0173e100133210.1371/journal.pgen.1001332A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs.Mia OlssonJennifer R S MeadowsKatarina TruvéGerli Rosengren PielbergFrancesca PuppoEvan MauceliJavier QuilezNoriko TonomuraGiordana ZannaMaria José DocampoAnna BassolsAnne C AveryElinor K KarlssonAnne ThomasDaniel L KastnerErik Bongcam-RudloffMatthew T WebsterArmand SanchezAke HedhammarElaine F RemmersLeif AnderssonLluis FerrerLinda TintleKerstin Lindblad-TohHereditary 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 × 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.http://europepmc.org/articles/PMC3060080?pdf=render |
| spellingShingle | Mia Olsson Jennifer R S Meadows Katarina Truvé Gerli Rosengren Pielberg Francesca Puppo Evan Mauceli Javier Quilez Noriko Tonomura Giordana Zanna Maria José Docampo Anna Bassols Anne C Avery Elinor K Karlsson Anne Thomas Daniel L Kastner Erik Bongcam-Rudloff Matthew T Webster Armand Sanchez Ake Hedhammar Elaine F Remmers Leif Andersson Lluis Ferrer Linda Tintle Kerstin Lindblad-Toh 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 |
| title | A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. |
| title_full | A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. |
| title_fullStr | A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. |
| title_full_unstemmed | A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. |
| title_short | A novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. |
| title_sort | novel unstable duplication upstream of has2 predisposes to a breed defining skin phenotype and a periodic fever syndrome in chinese shar pei dogs |
| url | http://europepmc.org/articles/PMC3060080?pdf=render |
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