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PMID: 22615578 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

Genomic hypomethylation in the human germline associates with selective structural mutability in the human genome.

PLoS genetics ·Vol. 8 ·No. 5 ·2012-00-00 ·Pages e1002692

Li J, Harris RA, Cheung SW, Coarfa C, Jeong M, Goodell MA, White LD, Patel A, Kang SH, Shaw C, Chinault AC, Gambin T, Gambin A, Lupski JR, Milosavljevic A

Abstract

The hotspots of structural polymorphisms and structural mutability in the human genome remain to be explained mechanistically. We examine associations of structural mutability with germline DNA methylation and with non-allelic homologous recombination (NAHR) mediated by low-copy repeats (LCRs). Combined evidence from four human sperm methylome maps, human genome evolution, structural polymorphisms in the human population, and previous genomic and disease studies consistently points to a strong association of germline hypomethylation and genomic instability. Specifically, methylation deserts, the ~1% fraction of the human genome with the lowest methylation in the germline, show a tenfold enrichment for structural rearrangements that occurred in the human genome since the branching of chimpanzee and are highly enriched for fast-evolving loci that regulate tissue-specific gene expression. Analysis of copy number variants (CNVs) from 400 human samples identified using a custom-designed array comparative genomic hybridization (aCGH) chip, combined with publicly available structural variation data, indicates that association of structural mutability with germline hypomethylation is comparable in magnitude to the association of structural mutability with LCR-mediated NAHR. Moreover, rare CNVs occurring in the genomes of individuals diagnosed with schizophrenia, bipolar disorder, and developmental delay and de novo CNVs occurring in those diagnosed with autism are significantly more concentrated within hypomethylated regions. These findings suggest a new connection between the epigenome, selective mutability, evolution, and human disease.

MeSH Terms
Animals Comparative Genomic Hybridization DNA Copy Number Variations/genetics DNA Methylation/genetics Disease/genetics Epigenesis, Genetic Evolution, Molecular Genome, Human Genomic Instability Germ Cells/metabolism Homologous Recombination/genetics Humans Male Mutation Rate Segmental Duplications, Genomic Spermatozoa/metabolism
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Li Jian
Bioinformatics Research Laboratory, Epigenome Center, Baylor College of Medicine, Houston, Texas, United States of America.
Harris R Alan
Cheung Sau Wai
Coarfa Cristian
Jeong Mira
Goodell Margaret A
White Lisa D
Patel Ankita
Kang Sung-Hae
Shaw Chad
Chinault A Craig
Gambin Tomasz
Gambin Anna
Lupski James R
Milosavljevic Aleksandar
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.1002692
Published
2012-00-00
Epub
2012-00-17
Pages
e1002692
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC3355074
Subset
IM
Grants
NHGRI NIH HHS · R01 HG004009 · United States
NIDA NIH HHS · U01 DA025956 · United States
External Links
PubMed source DOI: 10.1371/journal.pgen.1002692 PMC Full Text View journal details
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