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Parent-of-Origin Effects Implicate Epigenetic Regulation of Experimental Autoimmune Encephalomyelitis and Identify Imprinted as a Novel Risk Gene


Even with recent progress in determining the genetic basis of complex diseases, the issue of ‘missing heritability’ remains and its potential sources are frequently speculated about but rarely explained. Parent-of-origin effects might contribute to the ‘missing heritability’ and involve genetic and epigenetic mechanisms of inheritance. Our study is the first that establishes (i) the magnitude and (ii) the type of parent-of-origin effects in the pathogenesis of a multiple sclerosis-like disease, experimental autoimmune encephalomyelitis (EAE) in rat, using a strategy designed to identify genes that confer risk only when inherited from either mother or father. A striking 37-54% of all risk loci depended on parental origin. Accounting for parent-of-origin enabled more powerful and precise identification of novel risk factors for EAE, such as the imprinted Dlk1gene. Disease-predisposing alleles conferred lower Dlk1 expression in rats and transgenic Dlk1 mice demonstrated that lower Dlk1 drives more severe EAE and modulates adaptive immune responses. Because parental-origin effects are epigenetically regulated, our data implicate a contributory role for epigenetic mechanisms in complex diseases. Considering parent-of-origin effects in complex disease has enabled more powerful and precise identification of novel risk factors.


Vyšlo v časopise: Parent-of-Origin Effects Implicate Epigenetic Regulation of Experimental Autoimmune Encephalomyelitis and Identify Imprinted as a Novel Risk Gene. PLoS Genet 10(3): e32767. doi:10.1371/journal.pgen.1004265
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004265

Souhrn

Even with recent progress in determining the genetic basis of complex diseases, the issue of ‘missing heritability’ remains and its potential sources are frequently speculated about but rarely explained. Parent-of-origin effects might contribute to the ‘missing heritability’ and involve genetic and epigenetic mechanisms of inheritance. Our study is the first that establishes (i) the magnitude and (ii) the type of parent-of-origin effects in the pathogenesis of a multiple sclerosis-like disease, experimental autoimmune encephalomyelitis (EAE) in rat, using a strategy designed to identify genes that confer risk only when inherited from either mother or father. A striking 37-54% of all risk loci depended on parental origin. Accounting for parent-of-origin enabled more powerful and precise identification of novel risk factors for EAE, such as the imprinted Dlk1gene. Disease-predisposing alleles conferred lower Dlk1 expression in rats and transgenic Dlk1 mice demonstrated that lower Dlk1 drives more severe EAE and modulates adaptive immune responses. Because parental-origin effects are epigenetically regulated, our data implicate a contributory role for epigenetic mechanisms in complex diseases. Considering parent-of-origin effects in complex disease has enabled more powerful and precise identification of novel risk factors.


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