Academic journal article Genetics

Persistence and Loss of Meiotic Recombination Hotspots

Academic journal article Genetics

Persistence and Loss of Meiotic Recombination Hotspots

Article excerpt

ABSTRACT

The contradiction between the long-term persistence of the chromosomal hotspots that initiate meiotic recombination and the self-destructive mechanism by which they act strongly suggests that our understanding of recombination is incomplete. This "hotspot paradox" has been reinforced by the finding that biased gene conversion also removes active hotspots from human sperm. To investigate the requirements for hotspot persistence, we developed a detailed computer simulation model of their activity and its evolutionary consequences. With this model, unopposed hotspot activity could drive strong hotspots from 50% representation to extinction within 70 generations. Although the crossing over that hotspots cause can increase population fitness, this benefit was always too small to slow the loss of hotspots. Hotspots could not be maintained by plausible rates of de novo mutation, nor by crossover interference, which alters the frequency and/or spacing of crossovers. Competition among hotspots for activity-limiting factors also did not prevent their extinction, although the rate of hotspot loss was slowed. Key factors were the probability that the initiating hotspot allele is destroyed and the nonmeiotic contributions hotspots make to fitness. Experimental investigation of these deserves high priority, because until the paradox is resolved all components of the mechanism are open to doubt.

SEXUAL recombination is one of the main forces shaping eukaryote evolution, but implicit in its mechanism is a serious paradox. The mechanism, called double-strand break repair, was first proposed for fungi in 1983 (SZOSTAK et al. 1983). It has become increasingly well understood and well supported in a wide variety of organisms, and double-strand DNA breaks (DSBs) are now thought to be the primary initiators of meiotic recombination in eukaryotes (KEENEY 2001; PETES 2001). DSBs usually occur at chromosomal sites called recombination hotspots, whose evolutionary persistence is at the heart of the paradox. DSBs appear to frequently cause destruction of the DNA sequence specifying the hotspot and replacement of this sequence by the sequence of its homolog (NICOLAS et al 1989; KAUPPI et al. 2004). Over many generations this self-destructive mechanism is expected to cause all active hotspot alleles to be replaced by alleles incapable of initiating DSBs (BouLTON et al. 1997). The paradox is that this has not happened.

Recombination hotspots are defined as short segments (usually < 1 kb) with a much higher probability of undergoing a meiotic DSB than surrounding sequences. Each chromosome typically has many such hotspots; for example, 177 were identified in a genome-wide screen of the 16 yeast chromosomes (GERTON et al. 2000). Only a fraction of the available hotspots initiate recombination in any single meiosis, and not all of these initiation events lead to crossing over; usually most resolve as simple patches of gene conversion or heteroduplex DNA (BoWRING and CATCHESIDE 1996; JEFFREYS and MAY 2004).

The crossing over that hotspots cause plays two important roles in meiosis, one physical and one genetic. First, it creates covalent bonds between homologous chromosomes and thus physically connects the homologs at meiosis. In most organisms such connections are required for accurate chromosome alignment on the metaphase plate and segregation into the haploid daughter cells (ZiCKLER and RLECKNER 1999; WALKER and HAWLEY 2000; PETRONCZKI et al 2003). second, these new connections create new combinations of alleles on each chromosome, greatly increasing the diversification of haplotypes that is thought to be meiosis's primary function.

The double-strand break repair (DSBR) model for DSB-initiated meiotic recombination is illustrated in Figure 1 (SzOSTAK et al. 1983) and described in the Figure 1 legend. It differs from an earlier model of recombination (HOLLIDAY 1964) in its asymmetry-DNA is cut and degraded at the initiation site in only one of the interacting homologs-and this asymmetry is the source of the paradox. …

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