Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome

The functional impact of genetic variation has been extensively surveyed, revealing that genetic changes correlated to phenotypes lie mostly in non-coding genomic regions. Studies have linked allele-specific genetic changes to gene expression, DNA methylation, and histone marks but these investigations have only been carried out in a limited set of samples. We describe a large-scale coordinated study of allelic and non-allelic effects on DNA methylation, histone mark deposition, and gene expression, detecting the interrelations between epigenetic and functional features at unprecedented resolution. We use information from whole genome and targeted bisulfite sequencing from 910 samples to perform genotype-dependent analyses of allele-specific methylation (ASM) and non-allelic methylation (mQTL). In addition, we introduce a novel genotype-independent test to detect methylation imbalance between chromosomes. Of the ~2.2 million CpGs tested for ASM, mQTL, and genotype-independent effects, we identify ~32% as being genetically regulated (ASM or mQTL) and ~14% as being putatively epigenetically regulated. We also show that epigenetically driven effects are strongly enriched in repressed regions and near transcription start sites, whereas the genetically regulated CpGs are enriched in enhancers. Known imprinted regions are enriched among epigenetically regulated loci, but we also observe several novel genomic regions (e.g., HOX genes) as being epigenetically regulated. Finally, we use our ASM datasets for functional interpretation of disease-associated loci and show the advantage of utilizing naïve T cells for understanding autoimmune diseases. Our rich catalogue of haploid methylomes across multiple tissues will allow validation of epigenome association studies and exploration of new biological models for allelic exclusion in the human genome.

• Publication year

  2017

• Venue

  Genome Biology

• Publication date

  2017-03-10

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1186/s13059-017-1173-7PMID 28283040PMCID 5346261
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• ASM datasets support functional interpretation of disease-associated loci, and naïve T cells improve interpretation for autoimmune disease loci.

  Confidence 0.87

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• Known imprinted regions are enriched among epigenetically regulated loci, and additional epigenetically regulated regions include HOX genes.

  Confidence 0.90

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• Epigenetically driven CpGs are enriched in repressed regions and near transcription start sites, whereas genetically regulated CpGs are enriched in enhancers.

  Confidence 0.96

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• About 32% of the ~2.2 million tested CpGs were classified as genetically regulated through ASM or mQTL, and about 14% were classified as putatively epigenetically regulated.

  Confidence 0.98

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review

• allele-specific methylation (asm)

  epigenetic feature

  An allele-resolved methylation measurement that compares methylation between the two chromosomes at the same locus.

  Aliases: ASM

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• autoimmune diseases

  disease category

  Immune-mediated diseases used as the disease context for interpreting the ASM data.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• disease-associated loci

  genomic locus

  Genomic loci implicated by disease-association studies and used for functional interpretation of methylation signals.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• enhancers

  regulatory element

  Regulatory DNA elements that increase transcription of target genes and were used as an enrichment context.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• epigenetically regulated cpgs

  genomic feature

  CpG sites whose methylation imbalance is inferred to arise without a detectable genetic effect in the analysis.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• genetically regulated cpgs

  genomic feature

  CpG sites whose methylation levels are associated with inherited genetic variation in the analysis.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• hox genes

  gene family

  A cluster of homeobox developmental regulator genes examined as genomic regions in the methylation analysis.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• imprinted regions

  genomic region

  Genomic regions with parent-of-origin-specific regulation that were evaluated among epigenetically regulated loci.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• methylation quantitative trait loci (mqtl)

  genetic association

  Genetic loci in which DNA variants are associated with methylation differences at CpG sites.

  Aliases: mQTL

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• naive t cells

  cell type

  A T-cell subset used as a cellular context for interpreting methylation patterns relevant to disease.

  Aliases: naïve T cells

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• repressed regions

  genomic region

  Genomic regions annotated as transcriptionally repressed chromatin contexts in the methylation analyses.

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review
• transcription start sites

  genomic feature

  Genomic positions where transcription initiates and where CpG enrichment was assessed.

  Aliases: TSS

  박진우 (dztg5apj7m) extractionB (s683577b42) reviewAnonymous (12632b8b5f) reviewAK (4715169a40) review

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