Polymorphic tandem repeats within gene promoters act as modifiers of gene expression and DNA methylation in humans

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dc.contributor.authorQuilez, Javieren
dc.contributor.authorGuilmatre, Audreyen
dc.contributor.authorGarg, Parasen
dc.contributor.authorHighnam, Garethen
dc.contributor.authorGymrek, Melissaen
dc.contributor.authorErlich, Yaniven
dc.contributor.authorJoshi, Ricky S.en
dc.contributor.authorMittelman, Daviden
dc.contributor.authorSharp, Andrew J.en
dc.contributor.departmentBiological Sciencesen
dc.contributor.departmentFralin Life Sciences Instituteen
dc.date.accessioned2019-04-11T18:07:53Zen
dc.date.available2019-04-11T18:07:53Zen
dc.date.issued2016-05-05en
dc.description.abstractDespite representing an important source of genetic variation, tandem repeats (TRs) remain poorly studied due to technical difficulties. We hypothesized that TRs can operate as expression (eQTLs) and methylation (mQTLs) quantitative trait loci. To test this we analyzed the effect of variation at 4849 promoter-associated TRs, genotyped in 120 individuals, on neighboring gene expression and DNA methylation. Polymorphic promoter TRs were associated with increased variance in local gene expression and DNA methylation, suggesting functional consequences related to TR variation. We identified >100 TRs associated with expression/methylation levels of adjacent genes. These potential eQTL/mQTL TRs were enriched for overlaps with transcription factor binding and DNaseI hypersensitivity sites, providing a rationale for their effects. Moreover, we showed that most TR variants are poorly tagged by nearby single nucleotide polymorphisms (SNPs) markers, indicating that many functional TR variants are not effectively assayed by SNP-based approaches. Our study assigns biological significance to TR variations in the human genome, and suggests that a significant fraction of TR variations exert functional effects via alterations of local gene expression or epigenetics. We conclude that targeted studies that focus on genotyping TR variants are required to fully ascertain functional variation in the genome.en
dc.description.notesNIH [DA033660, HG006696, HD073731, MH097018 to A.J.S.]; March of Dimes Research Grant [6-FY13-92 to A.J.S.]; Scientific Interface from the Burroughs Wellcome Fund Career Award (to Y.E.); Gift from Andria and Paul Heafy; NIJ [2014-DN-BX-K089]; Department of Scientific Computing at the Icahn School of Medicine at Mount Sinai (in part). Funding for open access charge: NIH [DA033660, HG006696, HD073731, MH097018 to A.J.S.]; March of Dimes Research Grant [6-FY13-92 to A.J.S.]; Scientific Interface from the Burroughs Wellcome Fund Career Award (to Y.E.); Gift from Andria and Paul Heafy; NIJ [2014-DN-BX-K089].en
dc.description.sponsorshipNIH [DA033660, HG006696, HD073731, MH097018]; March of Dimes Research Grant [6-FY13-92]; Scientific Interface from the Burroughs Wellcome Fund Career Award; NIJ [2014-DN-BX-K089]; Department of Scientific Computing at the Icahn School of Medicine at Mount Sinaien
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1093/nar/gkw219en
dc.identifier.eissn1362-4962en
dc.identifier.issn0305-1048en
dc.identifier.issue8en
dc.identifier.pmid27060133en
dc.identifier.urihttp://hdl.handle.net/10919/88889en
dc.identifier.volume44en
dc.language.isoen_USen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjecthuman genomeen
dc.subjectcopy numberen
dc.subjectarabidopsis-thalianaen
dc.subjectstr variationen
dc.subjectmutationen
dc.subjectmicrosatelliteen
dc.subjectassociationen
dc.subjectvariabilityen
dc.subjectnucleotideen
dc.subjectpopulationen
dc.titlePolymorphic tandem repeats within gene promoters act as modifiers of gene expression and DNA methylation in humansen
dc.title.serialNucleic Acids Researchen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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