A Combination of cis and trans Control Can Solve the Hotspot Conversion Paradox

Abstract

There is growing evidence that in a variety of organisms the majority of meiotic recombination events occur at a relatively small fraction of loci, known as recombination hotspots. If hotspot activity results from the DNA sequence at or near the hotspot itself (in cis), these hotspots are expected to be rapidly lost due to biased gene conversion, unless there is strong selection in favor of the hotspot itself. This phenomenon makes it very difficult to maintain existing hotspots and even more difficult for new hotspots to evolve; it has therefore come to be known as the ''hotspot conversion paradox.'' I develop an analytical framework for exploring the evolution of recombination hotspots under the forces of selection, mutation, and conversion. I derive the general conditions under which cis-and trans-controlled hotspots can be maintained, as well as those under which new hotspots controlled by both a cis and a trans locus can invade a population. I show that the conditions for maintenance of and invasion by trans-or cis-plus-trans-controlled hotspots are broader than for those controlled entirely in cis. Finally, I show that a combination of cis and trans control may allow for long-lived polymorphisms in hotspot activity, the patterns of which may explain some recently observed features of recombination hotspots.T HERE is growing evidence from several model systems across the eukaryotic phylogeny that meiotic recombination events, rather than being distributed uniformly across the genome, are largely concentrated into relatively small regions known as ''recombination hotspots.'' Hotspots in yeast (Malone et al.

Nonparadoxical evolutionary stability of the recombination initiation landscape in yeast

“…Furthermore, such large-scale domains presumably reflect factors — such as attachment of chromatin loops to chromosome axes — that work in cis but at a distance from DSB hotspots. Because such factors are too far to be frequently included in gene conversion tracts and are thus not subject to loss through biased gene conversion, they are not expected to evolve as rapidly as hotspots (3, 5, 16, 31). …”

The Red Queen theory of recombination hotspots

“…Mathematical models show that the strength of selection (either fertility or viability) necessary to prevent biased gene conversion from removing hot alleles from the population is far too strong to be realistic, and the chromosomal crossover rate declines rapidly under realistic parameter values (Boulton et al. , 1997; Pineda‐Krch & Redfield, 2005; Peters, 2008).…”

“…By acting on its neighbour, this modifier gains the individual advantage derived from crossing over, but limits the cost of under‐transmission to the cases in which it lies close enough to its target site to be affected by gene conversion. This form of action reduces the strength of selection necessary to maintain recombination hotspots in the population (Peters, 2008). However, this model cannot explain either the over‐transmission of a particular sequence (there are no hot or cold alleles at the target site) or the transient nature of recombination hotspots (each hotspot remains hot indefinitely, and the recombinatorial landscape is static).…”

“…A final class of mathematical models considers an allelic sequence acting in cis to determine its own resistance to DSBs and a modifier acting in trans to modify the resistance of its target (Peters, 2008) (Fig. 3c4).…”

Characterization of the nonallelic homologous recombination hotspot PRS3 associated with type-3NF1deletions

“…NAHRassociated crossovers, in common with AHR-associated crossovers, are known to cluster within narrow hotspot regions of 500 bp to 2 kb [Coop et al, 2008;Crawford et al, 2004;Jeffreys et al, 2001;McVean et al, 2004;Webb et al, 2008]. Cis-and trans-acting factors are known to activate AHR hotspots [Peters, 2008;Ubeda and Wilkins, 2011]. SNPs have been identified within human AHR hotspots that influence the recombination intensity in cis Neumann, 2002, 2005;Zheng et al, 2010].…”