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Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation

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 r...

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Autores principales: Gertz, Jason, Varley, Katherine E., Reddy, Timothy E., Bowling, Kevin M., Pauli, Florencia, Parker, Stephanie L., Kucera, Katerina S., Willard, Huntington F., Myers, Richard M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154961/
https://www.ncbi.nlm.nih.gov/pubmed/21852959
http://dx.doi.org/10.1371/journal.pgen.1002228
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author Gertz, Jason
Varley, Katherine E.
Reddy, Timothy E.
Bowling, Kevin M.
Pauli, Florencia
Parker, Stephanie L.
Kucera, Katerina S.
Willard, Huntington F.
Myers, Richard M.
author_facet Gertz, Jason
Varley, Katherine E.
Reddy, Timothy E.
Bowling, Kevin M.
Pauli, Florencia
Parker, Stephanie L.
Kucera, Katerina S.
Willard, Huntington F.
Myers, Richard M.
author_sort Gertz, Jason
collection PubMed
description 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.
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spelling pubmed-31549612011-08-18 Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation Gertz, Jason Varley, Katherine E. Reddy, Timothy E. Bowling, Kevin M. Pauli, Florencia Parker, Stephanie L. Kucera, Katerina S. Willard, Huntington F. Myers, Richard M. PLoS Genet Research Article 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. Public Library of Science 2011-08-11 /pmc/articles/PMC3154961/ /pubmed/21852959 http://dx.doi.org/10.1371/journal.pgen.1002228 Text en Gertz et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Gertz, Jason
Varley, Katherine E.
Reddy, Timothy E.
Bowling, Kevin M.
Pauli, Florencia
Parker, Stephanie L.
Kucera, Katerina S.
Willard, Huntington F.
Myers, Richard M.
Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation
title Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation
title_full Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation
title_fullStr Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation
title_full_unstemmed Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation
title_short Analysis of DNA Methylation in a Three-Generation Family Reveals Widespread Genetic Influence on Epigenetic Regulation
title_sort analysis of dna methylation in a three-generation family reveals widespread genetic influence on epigenetic regulation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154961/
https://www.ncbi.nlm.nih.gov/pubmed/21852959
http://dx.doi.org/10.1371/journal.pgen.1002228
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