Genome Biology, 2014, 01, 1─13

Genetic factors underlying discordance in chromatin accessibility between monozygotic twins

Kim K, Ban HJ, Seo J, Lee K, Kim SC, Park K, Cho SB, Choi JK

Abstract

BACKGROUND
Open chromatin is implicated in regulatory processes; thus, variations in chromatin structure may contribute to variations in gene expression and other phenotypes. In this work, we perform targeted deep sequencing for open chromatin, and array-based genotyping across the genomes of 72 monozygotic twins to identify genetic factors regulating co-twin discordance in chromatin accessibility.
RESULTS
We show that somatic mutations cause chromatin discordance mainly via the disruption of tranion factor binding sites. Structural changes in DNA due to C:G to A:T transversions are under purifying selection due to a strong impact on chromatin accessibility. We show that CpGs whose methylation is specifically regulated during cellular differentiation appear to be protected from high mutation rates of 5'-methylcytosines, suggesting that the spectrum of CpG variations may be shaped fully at the developmental level but not through natural selection. Based on the association mapping of within-pair chromatin differences, we search for cases in which twin siblings with a particular genotype had chromatin discordance at the relevant locus. We identify 1,325 chromatin sites that are differentially accessible, depending on the genotype of a nearby locus, suggesting that epigenetic differences can control regulatory variations via interactions with genetic factors. Poised promoters present high levels of chromatin discordance in association with either somatic mutations or genetic-epigenetic interactions.
CONCLUSION
Our observations illustrate how somatic mutations and genetic polymorphisms may contribute to regulatory, and ultimately phenotypic, discordance

• ISBN or ISSN: 1465-6906

• 본 연구는 질병관리본부 연구개발과제(과제번호 2012-NG72001-00) 연구비를 지원받아 수행되었습니다.
• This research was supported by a fund(code 2012-NG72001-00) by Research of Korea Centers for Disease Control and Prevention.