Genetic sources of population epigenomic variation

• Published in: Nature reviews. Genetics Vol. 17; no. 6; pp. 319 - 332
• Main Authors: Taudt, Aaron, Colomé-Tatché, Maria, Johannes, Frank
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2016; Nature Publishing Group
• Subjects: 631/208/176/1988; 631/208/177; 631/208/2491; 631/208/457; 631/208/457/649; Agriculture; Animal Genetics and Genomics; Biomedicine; Cancer Research; DNA methylation; Epigenesis, Genetic - genetics; Epigenetic inheritance; Epigenetics; Epigenomics - methods; Evolution, Molecular; Gene Function; Genetic research; Genetic variation; Genetic Variation - genetics; Genetics, Population; Genomes; Human Genetics; Humans; Identification and classification; Observations; Phenotype; review-article; Germany
• ISSN: 1471-0056; 1471-0064
• DOI: 10.1038/nrg.2016.45

Key Points Computationally integrated chromatin state maps define 'epigenomes' and provide a snapshot of the functional state of the genome. Comparisons of reference epigenomes across different tissues, developmental stages, disease states and environmental treatments show that enhancer elements are the most variable, whereas transcription start sites (TSSs) and repressive regions vary the least. Human population genetic studies of chromatin state maps involving up to five histone modifications show that the most variable regions correspond to enhancer states. A relatively small proportion of variable regions are associated with genetic variation, in which individual single-nucleotide polymorphisms (SNPs) can act as histone quantitative trait loci (hQTL) and affect multiple levels of local chromatin organization as well as expression levels of proximal or distal genes, most likely through a combination of differential transcription factor binding and chromatin looping. In humans, DNA methylation variation within and between populations is depleted in CpG islands and enriched in active chromatin states such as enhancers (weak and active) and active TSSs. Variation in DNA methylation correlates, locally, with variability in other epigenetic marks. In humans, array-based heritability estimates of DNA methylation variation at single CpG sites is about 0.2, and only a small proportion of CpGs can be associated with methylation QTL (meQTL). The majority of meQTL are strictly local and seem to involve mutations that impair DNA methylation itself or that disrupt transcription factor binding. The impact of genetic variation in DNA methylation is probably biased downward as current array technologies undersample distal enhancer elements. In plants, many cis -meQTL seem to be due to SNPs tagging structural variants such as transposable element (TE) insertions that spread DNA methylation into flanking regions or facilitate siRNA silencing of downstream homologous sequences. Trans -acting meQTL are prevalent and often involve variants in chromatin control genes. As a result, trans -acting meQTL can affect methylation levels at the genome-wide scale, and some evidence indicates that such effects can be adaptive. In plants, the interpretation of detected cis associations is complicated by the fact that alternative DNA methylation states (epialleles) can be inherited across generations, so that cis association may reflect linkage disequilibrium rather than active genetic regulation. Conversely, epialleles can also become disassociated from their underlying sequence haplotypes through high epimutation rates, and thus contribute to population epigenomic variation independently of DNA sequence variants. Scaling up current studies to include more epigenetic marks, cell types and individuals promises to provide deeper insights into the heritable basis underlying population epigenomic variation and will clarify its implications for biomedical, agricultural and evolutionary research. The authors review recent studies into the heritable basis of population epigenomic variation and discuss important challenges when interpreting results from these genetic studies in different species to highlight the state of knowledge regarding how genetic variation can influence differences in chromatin states between individuals. The field of epigenomics has rapidly progressed from the study of individual reference epigenomes to surveying epigenomic variation in populations. Recent studies in a number of species, from yeast to humans, have begun to dissect the cis - and trans -regulatory genetic mechanisms that shape patterns of population epigenomic variation at the level of single epigenetic marks, as well as at the level of integrated chromatin state maps. We show that this information is paving the way towards a more complete understanding of the heritable basis underlying population epigenomic variation. We also highlight important conceptual challenges when interpreting results from these genetic studies, particularly in plants, in which epigenomic variation can be determined both by genetic and epigenetic inheritance.