Natural selection acts on epigenetic marks

Abstract

<jats:title>ABSTRACT</jats:title><jats:p>A fundamental component of molecular evolution are the rules that govern when, and why, a given change (allele) is deleterious or neutral. The ability to define such rules for epialleles – analogous to the rules at the DNA sequence level – would thus have profound implications for our understanding of epigenetic variation and evolution. Here, we focus on promoter methylation in the male human germline, which – apart from its role in gene regulation – is also known to greatly increase the mutation rate of CpG dinucleotides. We first develop a simple but general approach for detecting selection on epialleles, which does not require populationscale data. We then show that germline promoter methylation is deleterious at loss-of-function intolerant genes, but neutral at loss-of-function tolerant ones. In concordance with this, a human-mouse comparative analysis of sperm methylomes reveals strong suppression of methylation acquisition at loss-of-function intolerant promoters. We demonstrate that this selection is neither a secondary consequence of germline gene expression levels, nor of promoter H3K4me3 levels. Rather, the deleteriousness of promoter methylation is explained by its mutagenic effect on the underlying CpGs. Our results thus address a long-standing open question in molecular evolution, providing the first demonstration of selection acting on an epigenetic mutation rate modifier to locally dictate the mutation rate in humans. They also suggest the existence of a mechanism that preferentially protects loss-of-function intolerant promoters from methylation in the germline. Finally, they directly refute the prevailing dogma that CpG islands are not under active selection.</jats:p>

Gene body methylation is under selection in Arabidopsis thaliana

“…In the first, Vidalis et al (2016) estimated the SFS of cytosine sites within genes of a sample of 92 A. thaliana individuals, but they did not detect a deviation from neutrality. More recently, studies have hinted at selection on methylation, because an SFS analysis at the level of 100 bp regions detected weak but significant selection on methylation levels ( Xu et al 2020 ) and because germline promoter methylation was inferred to be deleterious in humans ( Boukas et al 2020 ).…”

Investigation Gene body methylation is under selection inArabidopsis thaliana

“…In the first, Vidalis et al (2016) estimated the SFS of cytosine sites within genes of a sample of 92 A. thaliana individuals, but they did not detect a deviation from neutrality. More recently, studies have hinted at selection on methylation, because an SFS analysis at the level of 100bp regions detected weak but significant selection on methylation levels (Xu et al 2020) and because germline promoter methylation was inferred to be deleterious in humans (Boukas et al 2020).…”

Report of mutation biases mirroring selection in Arabidopsis thaliana unlikely to be entirely due to variant calling errors

“…4). In humans, H3K36me3 is the most highly enriched feature of coding sequences, and is especially enriched in genes subject to the strongest constraints [4,45].…”

“…How well the effects of increased mutation due to transcription are compensated by transcription-coupled DNA repair may depend on transcription rate [70][71][72]. Of note, Boukas and colleagues [45] recently leveraged a very large de novo mutation data set [73], finding that more evolutionary constrained genes have a lower rate of synonymous mutation in humans, which is consistent with at least one previous report [74]. Specifically, these authors reported that the synonymous mutation rate of genes under least constraint, as determined from their LOEUF ("loss-of-function observed/expected upper bound fraction" [75]) decile, is almost twice as high as that of genes under the strongest constraint [45].…”

“…4). In humans, H3K36me3 is the most highly enriched feature of coding sequences, and is especially enriched in genes subject to the strongest constraints [4,45]. The drift barrier exists when N e * u * s * d u * p d * L segment < 1, where N e is the effective population size, u is the mutation rate, s is the average selection coefficient on deleterious mutations, d u is the degree of change in mutation rate, p d is the proportion of sites subject to purifying selection, and L segment is the absolute size of the affected genomic regions [3].…”