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Sequence-level mechanisms of human epigenome evolution.

ABSTRACT: DNA methylation and chromatin states play key roles in development and disease. However, the extent of recent evolutionary divergence in the human epigenome and the influential factors that have shaped it are poorly understood. To determine the links between genome sequence and human epigenome evolution, we examined the divergence of DNA methylation and chromatin states following segmental duplication events in the human lineage. Chromatin and DNA methylation states were found to have been generally well conserved following a duplication event, with the evolution of the epigenome largely uncoupled from the total number of genetic changes in the surrounding DNA sequence. However, the epigenome at tissue-specific, distal regulatory regions was observed to be unusually prone to diverge following duplication, with particular sequence differences, altering known sequence motifs, found to be associated with divergence in patterns of DNA methylation and chromatin. Alu elements were found to have played a particularly prominent role in shaping human epigenome evolution, and we show that human-specific AluY insertion events are strongly linked to the evolution of the DNA methylation landscape and gene expression levels, including at key neurological genes in the human brain. Studying paralogous regions within the same sample enables the study of the links between genome and epigenome evolution while controlling for biological and technical variation. We show DNA methylation and chromatin divergence between duplicated regions are linked to the divergence of particular genetic motifs, with Alu elements having played a disproportionate role in the evolution of the epigenome in the human lineage.

SUBMITTER: Prendergast JG

PROVIDER: S-EPMC4122940 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Sequence-level mechanisms of human epigenome evolution.

Prendergast James G D JG Chambers Emily V EV Semple Colin A M CA

Genome biology and evolution 20140624 7

DNA methylation and chromatin states play key roles in development and disease. However, the extent of recent evolutionary divergence in the human epigenome and the influential factors that have shaped it are poorly understood. To determine the links between genome sequence and human epigenome evolution, we examined the divergence of DNA methylation and chromatin states following segmental duplication events in the human lineage. Chromatin and DNA methylation states were found to have been gener ...[more]

PMID: 24966180

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Project description:While many authors have discussed models and tools for studying protein evolution at the sequence level, molecular function is usually mediated by complex, higher order features such as independently folding domains and linear motifs that are based on or embedded in a particular arrangment of features such as secondary structure elements, transmembrane domains and regions with intrinsic disorder. This 'protein architecture' can, in its most simplistic representation, be visualized as domain organization cartoons that can be used to compare proteins in terms of the order of their mostly globular domains.Here, we describe a visual approach and a webserver for protein comparison that extend the domain organization cartoon concept. By developing an information-rich, compact visualization of different protein features above the sequence level, potentially related proteins can be compared at the level of propensities for secondary structure, transmembrane domains and intrinsic disorder, in addition to PFAM domains. A public Web server is available at www.proteinarchitect.net, while the code is provided at protarchitect.sourceforge.net.Due to recent advances in sequencing technologies we are now flooded with millions of predicted proteins that await comparative analysis. In many cases, mature tools focused on revealing hits with considerable global or local similarity to well-characterized proteins will not be able to lead us to testable hypotheses about a protein's function, or the function of a particular region. The visual comparison of different types of protein features with ProteinArchitect will be useful when assessing the relevance of similarity search hits, to discover subgroups in protein families and superfamilies, and to understand protein regions with conserved features outside globular regions. Therefore, this approach is likely to help researchers to develop testable hypotheses about a protein's function even if is somewhat distant from the more characterized proteins, by facilitating the discovery of features that are conserved above the sequence level for comparison and further experimental investigation.

Project description:Previous reports link differential DNA methylation (DNAme) to environmental exposures that are associated with lung function. Direct evidence on lung function DNAme is, however, limited. We undertook an agnostic epigenome-wide association study (EWAS) on pre-bronchodilation lung function and its change in adults.In a discovery-replication EWAS design, DNAme in blood and spirometry were measured twice, 6-15 years apart, in the same participants of three adult population-based discovery cohorts (n=2043). Associated DNAme markers (p<5×10-7) were tested in seven replication cohorts (adult: n=3327; childhood: n=420). Technical bias-adjusted residuals of a regression of the normalised absolute β-values on control probe-derived principle components were regressed on level and change of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and their ratio (FEV1/FVC) in the covariate-adjusted discovery EWAS. Inverse-variance-weighted meta-analyses were performed on results from discovery and replication samples in all participants and never-smokers.EWAS signals were enriched for smoking-related DNAme. We replicated 57 lung function DNAme markers in adult, but not childhood samples, all previously associated with smoking. Markers not previously associated with smoking failed replication. cg05575921 (AHRR (aryl hydrocarbon receptor repressor)) showed the statistically most significant association with cross-sectional lung function (FEV1/FVC: pdiscovery=3.96×10-21 and pcombined=7.22×10-50). A score combining 10 DNAme markers previously reported to mediate the effect of smoking on lung function was associated with lung function (FEV1/FVC: p=2.65×10-20).Our results reveal that lung function-associated methylation signals in adults are predominantly smoking related, and possibly of clinical utility in identifying poor lung function and accelerated decline. Larger studies with more repeat time-points are needed to identify lung function DNAme in never-smokers and in children.

Dataset Information

Sequence-level mechanisms of human epigenome evolution.

Publications

Sequence-level mechanisms of human epigenome evolution.

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