Specific modifications of histone tails, but not DNA methylation, mirror the temporal variation of mammalian recombination hotspots.

Jia Zeng,Soojin V Yi

doi:10.1093/gbe/evu230

Abstract

Recombination clusters nonuniformly across mammalian genomes at discrete genomic loci referred to as recombination hotspots. Despite their ubiquitous presence, individual hotspots rapidly lose their activities, and the molecular and evolutionary mechanisms underlying such frequent hotspot turnovers (the so-called “recombination hotspot paradox”) remain unresolved. Even though some sequence motifs are significantly associated with hotspots, multiple lines of evidence indicate that factors other than underlying sequences, such as epigenetic modifications, may affect the evolution of recombination hotspots. Thus, identifying epigenetic factors that covary with recombination at fine-scale is a promising step for this important research area. It was previously reported that recombination rates correlate with indirect measures of DNA methylation in the human genome. Here, we analyze experimentally determined DNA methylation and histone modification of human sperms, and show that the correlation between DNA methylation and recombination in long-range windows does not hold with respect to the spatial and temporal variation of recombination at hotspots. On the other hand, two histone modifications (H3K4me3 and H3K27me3) overlap extensively with recombination hotspots. Similar trends were observed in mice. These results indicate that specific histone modifications rather than DNA methylation are associated with the rapid evolution of recombination hotspots. Furthermore, many human recombination hotspots occupy “bivalent” chromatin regions that harbor both active (H3K4me3) and repressive (H3K27me3) marks. This may explain why human recombination hotspots tend to occur in nongenic regions, in contrast to yeast and Arabidopsis hotspots that are characterized by generally active chromatins. Our results highlight the dynamic epigenetic underpinnings of recombination hotspot evolution.

Highlights

One of the most fascinating aspects of mammalian recombination is that recombination events are highly localized in short genomic regions known as “recombination hotspots” (Steinmetz et al 1982; Jeffreys et al 2001, 2004; Arnheim et al 2003)
We first analyzed the relationship between experimentally determined DNA methylation levels and recombination rates in 500-kb nonoverlapping windows in the human genome
As expected, human-specific recombination hotspots are significantly overrepresented in H3K4me3enriched regions in sperm: 816 human recombination hotspots overlap with H3K4me3-enriched regions in sperm genomic DNA, whereas the expected number of overlap is 229

Summary

Introduction

One of the most fascinating aspects of mammalian recombination is that recombination events are highly localized in short genomic regions known as “recombination hotspots” (referred to as “hotspots” ) (Steinmetz et al 1982; Jeffreys et al 2001, 2004; Arnheim et al 2003). These hotspots change rapidly in evolutionary timescale.

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