Genetic factors underlying discordance in chromatin accessibility between monozygotic twins

BackgroundOpen 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.ResultsWe 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′-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.ConclusionOur observations illustrate how somatic mutations and genetic polymorphisms may contribute to regulatory, and ultimately phenotypic, discordance.

[1]  Alain Arneodo,et al.  Open chromatin encoded in DNA sequence is the signature of ‘master’ replication origins in human cells , 2009, Nucleic acids research.

[2]  Inkyung Jung,et al.  Genetic Landscape of Open Chromatin in Yeast , 2013, PLoS genetics.

[3]  W. J. Kent,et al.  The UCSC Genome Browser , 2003, Current protocols in bioinformatics.

[4]  Ken Chen,et al.  VarScan: variant detection in massively parallel sequencing of individual and pooled samples , 2009, Bioinform..

[5]  S. Rafii,et al.  Directional DNA methylation changes and complex intermediate states accompany lineage specificity in the adult hematopoietic compartment. , 2011, Molecular cell.

[6]  E. Birney,et al.  Heritable Individual-Specific and Allele-Specific Chromatin Signatures in Humans , 2010, Science.

[7]  Luke E. Berchowitz,et al.  A positive but complex association between meiotic double-strand break hotspots and open chromatin in Saccharomyces cerevisiae. , 2009, Genome research.

[8]  P. Visscher,et al.  DNA methylation profiles in monozygotic and dizygotic twins , 2009, Nature Genetics.

[9]  C. Glass,et al.  Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. , 2010, Molecular cell.

[10]  Zachary D. Smith,et al.  DNA methylation dynamics during in vivo differentiation of blood and skin stem cells. , 2012, Molecular cell.

[11]  Shane J. Neph,et al.  Systematic Localization of Common Disease-Associated Variation in Regulatory DNA , 2012, Science.

[12]  Xin Chen,et al.  TRANSFAC: an integrated system for gene expression regulation , 2000, Nucleic Acids Res..

[13]  Karen L. Mohlke,et al.  A map of open chromatin in human pancreatic islets , 2010, Nature Genetics.

[14]  Nathan C. Sheffield,et al.  Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity. , 2011, Genome research.

[15]  H. Aburatani,et al.  Global Mapping of Cell Type–Specific Open Chromatin by FAIRE-seq Reveals the Regulatory Role of the NFI Family in Adipocyte Differentiation , 2011, PLoS genetics.

[16]  Leighton J. Core,et al.  Coordinated Effects of Sequence Variation on DNA Binding, Chromatin Structure, and Transcription , 2013, Science.

[17]  Timothy J. Durham,et al.  "Systematic" , 1966, Comput. J..

[18]  J. Ibrahim,et al.  ZINBA integrates local covariates with DNA-seq data to identify broad and narrow regions of enrichment, even within amplified genomic regions , 2011, Genome Biology.

[19]  Z. Weng,et al.  High-Resolution Mapping and Characterization of Open Chromatin across the Genome , 2008, Cell.

[20]  B. Han,et al.  Sustained viral activity of epstein-Barr virus contributes to cellular immortalization of lymphoblastoid cell lines , 2009, Molecules and cells.

[21]  Young-Joon Kim,et al.  Nucleosome deposition and DNA methylation at coding region boundaries , 2009, Genome Biology.

[22]  T. Spector,et al.  Epigenetic differences arise during the lifetime of monozygotic twins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Shane J. Neph,et al.  An expansive human regulatory lexicon encoded in transcription factor footprints , 2012, Nature.

[24]  Sonia Shah,et al.  Use of Allele-Specific FAIRE to Determine Functional Regulatory Polymorphism Using Large-Scale Genotyping Arrays , 2012, PLoS genetics.

[25]  Jonathan K. Pritchard,et al.  Identification of Genetic Variants That Affect Histone Modifications in Human Cells , 2013, Science.

[26]  J. Choi.  Contrasting chromatin organization of CpG islands and exons in the human genome , 2010, Genome Biology.

[27]  Aaron R. Quinlan,et al.  BIOINFORMATICS APPLICATIONS NOTE , 2022 .

[28]  Terrence S. Furey,et al.  F-Seq: a feature density estimator for high-throughput sequence tags , 2008, Bioinform..

[29]  Tim D. Spector,et al.  A twin approach to unraveling epigenetics , 2011, Trends in genetics : TIG.

[30]  Randy D Ernst,et al.  Paleoradiology: advanced CT in the evaluation of nine Egyptian mummies. , 2002, Radiographics : a review publication of the Radiological Society of North America, Inc.

[31]  Alexander E. Kel,et al.  TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes , 2005, Nucleic Acids Res..

[32]  Joseph K. Pickrell,et al.  DNaseI sensitivity QTLs are a major determinant of human expression variation , 2011, Nature.

[33]  Nathan C. Sheffield,et al.  The accessible chromatin landscape of the human genome , 2012, Nature.

[34]  M. Ernstoff,et al.  Maximum androgen-blockade with medical or surgical castration in advanced prostate cancer: A meta-analysis of nine published randomized controlled trials and 4128 patients using flutamide , 1999, Prostate Cancer and Prostatic Diseases.

[35]  V. Iyer,et al.  FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) isolates active regulatory elements from human chromatin. , 2007, Genome research.

[36]  James A. Cuff,et al.  A Bivalent Chromatin Structure Marks Key Developmental Genes in Embryonic Stem Cells , 2006, Cell.

[37]  Vijay K. Tiwari,et al.  DNA-binding factors shape the mouse methylome at distal regulatory regions , 2011, Nature.

[38]  Identification of human mitochondrial DNA fragments corresponding to the genes for ATPase, cytochrome C oxidase, and nine tRNAs in a denaturing gradient gel electrophoresis system. , 1994, Analytical biochemistry.

[39]  Dustin E. Schones,et al.  High-Resolution Profiling of Histone Methylations in the Human Genome , 2007, Cell.

[40]  Martin J. Aryee,et al.  Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in Rheumatoid Arthritis , 2013, Nature Biotechnology.

[41]  Michael Q. Zhang,et al.  Combinatorial patterns of histone acetylations and methylations in the human genome , 2008, Nature Genetics.

[42]  Dan Xie,et al.  Extensive Variation in Chromatin States Across Humans , 2013, Science.

[43]  Christopher A. Miller,et al.  VarScan 2: somatic mutation and copy number alteration discovery in cancer by exome sequencing. , 2012, Genome research.