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Science. 2018 Sep 28;361(6409). pii: eaar3146. doi: 10.1126/science.aar3146. Epub 2018 Aug 23.

Allele-specific epigenome maps reveal sequence-dependent stochastic switching at regulatory loci.

Onuchic V1,2,3,4, Lurie E1,3,4, Carrero I1,3, Pawliczek P1,3, Patel RY1,3, Rozowsky J5,6, Galeev T5,6, Huang Z1,7, Altshuler RC4,8,9, Zhang Z8,9, Harris RA1,3,4, Coarfa C1,3,4, Ashmore L1,2,3, Bertol JW10, Fakhouri WD10, Yu F1,2,7, Kellis M4,8,9, Gerstein M5,6, Milosavljevic A11,2,3,4.

Author information

1
Molecular and Human Genetics Department, Baylor College of Medicine, Houston, TX, USA.
2
Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, USA.
3
Epigenome Center, Baylor College of Medicine, Houston, TX, USA.
4
NIH Roadmap Epigenomics Project.
5
Program in Computational Biology and Bioinformatics, Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT, USA.
6
Department of Computer Science, Yale University, New Haven, CT, USA.
7
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
8
Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA, USA.
9
Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA, USA.
10
Center for Craniofacial Research, Department of Diagnostic and Biomedical Sciences, School of Dentistry, University of Texas Health Science Center at Houston, Houston, TX, USA.
11
Molecular and Human Genetics Department, Baylor College of Medicine, Houston, TX, USA. amilosav@bcm.edu.

Abstract

To assess the impact of genetic variation in regulatory loci on human health, we constructed a high-resolution map of allelic imbalances in DNA methylation, histone marks, and gene transcription in 71 epigenomes from 36 distinct cell and tissue types from 13 donors. Deep whole-genome bisulfite sequencing of 49 methylomes revealed sequence-dependent CpG methylation imbalances at thousands of heterozygous regulatory loci. Such loci are enriched for stochastic switching, which is defined as random transitions between fully methylated and unmethylated states of DNA. The methylation imbalances at thousands of loci are explainable by different relative frequencies of the methylated and unmethylated states for the two alleles. Further analyses provided a unifying model that links sequence-dependent allelic imbalances of the epigenome, stochastic switching at gene regulatory loci, and disease-associated genetic variation.

PMID:
30139913
PMCID:
PMC6198826
DOI:
10.1126/science.aar3146
[Indexed for MEDLINE]
Free PMC Article

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