Academic journal article Genetics

A Combination of Cis and Trans Control Can Solve the Hotspot Conversion Paradox

Academic journal article Genetics

A Combination of Cis and Trans Control Can Solve the Hotspot Conversion Paradox

Article excerpt

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.

(ProQuest: ... denotes formulae omitted.)

THERE is growing evidence from several model systems across the eukaryotic phylogeny that meiotic recombinationevents, 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. 1994; Wu and Lichten 1995; Petes 2001; Cromie et al. 2005), mice (Guillon and De Massy 2002; Kelmenson et al. 2005; Shifman et al. 2006; Baudat and De Massy 2007), and humans( Jeffreyset al.1998,2000,2001,2005;Crawford et al. 2004;McVean et al. 2004;Myers et al. 2005; Conrad et al. 2006; International HapMap Consortium 2007) have now been well characterized, and evidence suggests that hotspots also exist in chimpanzees (Ptak et al. 2005) and several plants (Dooner and Martinez-Ferez 1997; Okagaki and Weil 1997; Yao et al. 2002; Drouaud et al. 2006). While some other well-studied eukaryotes (e.g., Drosophila melanogaster and Caenorhabditis elegans) show no evidence of hotspots (Hey 2004), the phenomenon is widespread enough across the tree of life to merit substantial study.

These hotspots pose a variety of interesting questions for population geneticists, not the least of which is that of their continued existence. One striking characteristic of hotspots is that they are subject to a form of meiotic drive: when a DSB occurs at a hotspot heterozygous for an active ("hot") and an inactive ("cold") hotspot allele, the cold allele tends to appear in a higher proportion of the offspring than does the hot allele (often in an ~3:1 ratio rather than the expected 2:2) (Catcheside 1975; Nicolas et al. 1989; Grimm et al. 1991; Malone et al. 1994; Guillon and De Massy 2002; Jeffreys and Neumann 2002; Jeffreys and May 2004; Cromie et al. 2005). This is likely the result of the mechanism by which recombination is thought to be initiated: a doublestrand break (DSB) forms on one chromatid; this break extends a variable distance in the 59 direction on each strand; and the sequence of the nonsister chromatid is used as a template to repair the gap. The physical connections (Holliday junctions) between the two chromatids that form as a result of this repair often (but not always) result in a crossover event (Szostak et al. 1983); however, a more direct consequence is that a stretch of DNA sequence on the chromatid that experiences the initial DSB is replaced ("converted") by homologous sequence from the nonsister chromatid: while the converted sequence was originally present on two of four chromatids (a 2:2 ratio), after DSB repair it is present on only one of four (a 3:1 ratio). …

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