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PMID: 21852959 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Analysis of DNA methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation.

PLoS genetics ·Vol. 7 ·No. 8 ·2011-08-00 ·Pages e1002228

Gertz J, Varley KE, Reddy TE, Bowling KM, Pauli F, Parker SL, Kucera KS, Willard HF, Myers RM

Abstract

The methylation of cytosines in CpG dinucleotides is essential for cellular differentiation and the progression of many cancers, and it plays an important role in gametic imprinting. To assess variation and inheritance of genome-wide patterns of DNA methylation simultaneously in humans, we applied reduced representation bisulfite sequencing (RRBS) to somatic DNA from six members of a three-generation family. We observed that 8.1% of heterozygous SNPs are associated with differential methylation in cis, which provides a robust signature for Mendelian transmission and relatedness. The vast majority of differential methylation between homologous chromosomes (>92%) occurs on a particular haplotype as opposed to being associated with the gender of the parent of origin, indicating that genotype affects DNA methylation of far more loci than does gametic imprinting. We found that 75% of genotype-dependent differential methylation events in the family are also seen in unrelated individuals and that overall genotype can explain 80% of the variation in DNA methylation. These events are under-represented in CpG islands, enriched in intergenic regions, and located in regions of low evolutionary conservation. Even though they are generally not in functionally constrained regions, 22% (twice as many as expected by chance) of genes harboring genotype-dependent DNA methylation exhibited allele-specific gene expression as measured by RNA-seq of a lymphoblastoid cell line, indicating that some of these events are associated with gene expression differences. Overall, our results demonstrate that the influence of genotype on patterns of DNA methylation is widespread in the genome and greatly exceeds the influence of imprinting on genome-wide methylation patterns.

MeSH Terms
Alleles Base Sequence Chromosomes, Human, Pair 21/genetics Chromosomes, Human, Pair 8/genetics Chromosomes, Human, X/genetics CpG Islands DNA Methylation Epigenesis, Genetic Female Gene Expression Gene Silencing Heredity Humans Male Molecular Sequence Data Pedigree Polymorphism, Single Nucleotide Sequence Analysis, DNA
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Gertz Jason
HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, United States of America.
Varley Katherine E
Reddy Timothy E
Bowling Kevin M
Pauli Florencia
Parker Stephanie L
Kucera Katerina S
Willard Huntington F
Myers Richard M
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1002228
Published
2011-08-00
Epub
2011-00-11
Pages
e1002228
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3154961
Subset
IM
Grants
NHGRI NIH HHS · U54 HG004576 · United States
NHGRI NIH HHS · 5U54HG004576 · United States
External Links
PubMed source DOI: 10.1371/journal.pgen.1002228 PMC Full Text View journal details
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