Kwoneel Kim1,† Hyo-Jeong Ban2,3,† Jungmin Seo4 Kibaick Lee1 Maryam Yavartanoo1 Sang Cheol Kim5 Kiejung Park2 Seong Beom Cho2* and Jung Kyoon Choi1*
1 Department of Bio and Brain Engineering, KAIST, Daejeon 305-701, Republic of Korea
2 Department of Biomedical Informatics, Center for Genome Science, National Institute of Health, KCDC, Choongchung-Buk-do 363-951, Republic of Korea
3 Division of Molecular and Life Sciences, Hanyang University, Ansan, Gyeonggi-do 425-791, Republic of Korea
4 Research Institute of Bioinformatics, Omicsis, Inc., Daejeon 305-333, Republic of Korea
5 Samsung Genome Institute, Samsung Medical Center, Seoul 135-710, Republic of Korea
† Equal contributors.
* Corresponding author : Seong Beom Cho, Jung Kyoon Choi
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.
We show that somatic mutations cause chromatin discordance mainly via the disruption of transcription 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[prime]-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.
Our observations illustrate how somatic mutations and genetic polymorphisms may contribute to regulatory, and ultimately phenotypic, discordance.