Cut Thy Neighbor: Cyclic Birth and Death of Recombination Hotspots via Genetic Conflict

Abstract

Most recombination takes place in numerous, localized regions called hotspots. However, empirical evidence indicates that nascent hotspots are susceptible to removal due to biased gene conversion, so it is paradoxical that they should be so widespread. Previous modeling work has shown that hotspots can evolve due to genetic drift overpowering their intrinsic disadvantage. Here we synthesize recent theoretical and empirical results to show how natural selection can favor hotspots. We propose that hotspots are part of a cycle of antagonistic coevolution between two tightly linked chromosomal regions: an inducer region that initiates recombination during meiosis by cutting within a nearby region of DNA and the cut region itself, which can evolve to be resistant to cutting. Antagonistic coevolution between inducers and their cut sites is driven by recurrent episodes of Hill-Robertson interference, genetic hitchhiking, and biased gene conversion.

The Red Queen theory of recombination hotspots

“…In a population fixed at the target locus for a resistant allele, negative linkage disequilibrium between flanking regions is built up because of the lack of local recombination. When negative linkage disequilibrium is large enough, alleles at the modifier locus coding for tolerance to DSBs will be favoured by hitchhiking with the most fit genetic background (Friberg & Rice, 2008). The argument of Friberg & Rice (2008) requires that the modifier locus be far enough from the target site to avoid gene conversion, but close enough to hitchhike with its genetic background.…”

“…Similarly, Friberg & Rice (2008) consider a trans ‐acting modifier that determines the susceptibility of the target locus to DSBs. In a population fixed at the target locus for a resistant allele, negative linkage disequilibrium between flanking regions is built up because of the lack of local recombination.…”

Nonparadoxical evolutionary stability of the recombination initiation landscape in yeast

“…However, theoretical studies have considered this implausible as a mechanism to preserve hotspots (3, 10). Instead, many studies start from the assumption that hotspot lifespan must always be short and that the fine-scale recombination initiation landscape will always be highly dynamic over evolutionary scales (4, 6, 7, 16). This assumption is appropriate for primates and mice because they use PRDM9, but has not been evaluated for other taxa.…”

Distribution of Recombination Hotspots in the Human Genome – A Comparison of Computer Simulations with Real Data

“…The problem of recombination hotspots has also been a subject of theoretical studies [28]–[31]. Most of them focused on the explanation of hotspot survival in the context of the biased transmission caused by gene conversion.…”