Academic journal article Genetics

High-Resolution Sex-Specific Linkage Maps of the Mouse Reveal Polarized Distribution of Crossovers in Male Germline

Academic journal article Genetics

High-Resolution Sex-Specific Linkage Maps of the Mouse Reveal Polarized Distribution of Crossovers in Male Germline

Article excerpt

(ProQuest: ... denotes formulae omitted.)

RECOMBINATION is a basic biological process that is shared among most sexually reproducing organisms (Morgan 1911; Gerton and Hawley 2005). It plays a key role in genome stability by ensuring the fidelity of chromosome segregation during meiosis (Sears et al. 1992; Hassold and Hunt 2001) and contributes to other processes such as DNA repair (Howard-Flanders and Theriot 1966; Niedzwiedz et al. 2004; Krejci et al. 2012). At the population level, recombination is an important generator of genetic diversity (Feldman et al. 1996; Otto and Lenormand 2002). Abnormal recombination is associated with increased aneuploidy and decreased fitness of offspring and has been associated with several human diseases (Warren et al. 1987; Hassold and Hunt 2001; Kong et al. 2004). Recombination can be exploited experimentally to map loci associated with biological traits: indeed, the construction of linkage maps is among the oldest activities in genetics (Sturtevant 1913). Finally, the recombination machinery can be co-opted for genetic engineering of many organisms (Smithies et al. 1985; Court et al. 2002).

In mammals, many factors-including sex, taxon, and genetics-are known to affect the global, as opposed to local, rate of recombination. The total number of events per meiosis and the recombination rate per unit sequence length vary widely among mammals but are strongly correlated with the fundamental number (number of chromosome arms) present in the karyotype of each species (Pardo-Manuel De Villena and Sapienza 2001). Although the molecular process of recombination can result in either a noncrossover or a crossover event, to date the study of recombination in mammals has been limited almost exclusively to crossovers, which are more readily detected. Previous studies have shown that, as a general rule, the number of crossovers observed in autosomes is higher in female meiosis than in male meiosis and thus the linkage map is longer in the gametes of females (Dunn and Bennett 1967; Broman et al. 1998; Kong et al. 2002; Cox et al. 2009). These same studies demonstrated that the genomic distribution of crossovers between female and male meiosis is significantly different: uniform in females, but subtelomerically enhanced and pericentromerically suppressed in males. Crossover interference (Petkov et al. 2007) and sex-specific patterns of hotspot usage (Paigen et al. 2008; Kong et al. 2010) have been advanced as candidate explanations for these phenomena. Recently, based on evidence from flowering plants, a population genetics basis for the evolution of sex differences in recombination rates-differences in gametic selection between males and females-has been proposed (Lenormand and Dutheil 2005). Despite these advances the presence and causes of sex differences in the overall rate and spatial distribution of recombination remain the object of study and controversy.

Recent studies indicate that recombination rate also varies between closely related species and subspecies and that alleles responsible for these effects may in fact be segregating within species (Dumont et al. 2009; Murdoch et al. 2010; Dumont and Payseur 2011; Auton et al. 2012). In particular, crossover frequency in male mice is known to vary across different inbred strains (Koehler et al. 2002) and these differences have been exploited to map genetic loci affecting recombination rates in F2 intercrosses (Murdoch et al. 2010; Dumont and Payseur 2011). Finally, mutations at several genes are known to lead to pathological changes in recombination (Niedzwiedz et al. 2004; Liebe et al. 2006).

Traditionally recombination has been studied in large pedigrees, using small numbers of informative markers. The first comprehensive linkage map of the laboratory mouse was developed in 1992 by genotyping hundreds of microsatellite markers in an interspecific backcross (Dietrich et al. 1992), work that was crucial to the success of the Mouse Genome Project (Waterston et al. …

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