Academic journal article Genetics

Variation in Crossover Frequencies Perturb Crossover Assurance without Affecting Meiotic Chromosome Segregation in Saccharomyces Cerevisiae

Academic journal article Genetics

Variation in Crossover Frequencies Perturb Crossover Assurance without Affecting Meiotic Chromosome Segregation in Saccharomyces Cerevisiae

Article excerpt

SEXUALLY reproducing organisms undergo meiosis to produce haploid gametes from diploid progenitor cells (Roeder 1997; Zickler and Kleckner 1999). This reduction in ploidy is achieved through the segregation of homologous chromosomes at the first meiotic division (MI). Accurate homolog segregation is facilitated by crossovers that establish physical connections between homolog pairs and provide tension necessary for generation of the bipolar spindle (Petronczki et al. 2003). Meiotic crossing over is highly regulated to ensure at least one crossover per homolog pair (crossover assurance) despite limited number of crossovers per meiosis (Berchowitz and Copenhaver 2010; Rosu et al. 2011).

Although crossovers are thought to be essential for accurate meiotic chromosome segregation, population genetic studies in humans suggest that there is considerable variation in crossover frequencies between populations, sexes, and individuals (Cheung et al. 2007; Chowdhury et al. 2009; FledelAlon et al. 2009; Kong et al. 2010; Kong et al. 2014). Analysis of meiotic crossovers in single sperm cells using wholegenome sequencing reinforces the fact that within individuals, crossover numbers per meiosis vary widely (Lu et al. 2012). The average number of crossovers per sperm was observed to be 26, but with a large variation from 17 to 35 crossovers per sperm (Lu et al. 2012). Although a lower frequency of crossovers increases the chances of aneuploidy in sperm, studies in Saccharomyces cerevisiae, Drosophila, and humans have shown that nonexchange chromosomes can undergo accurate segregation frequently (Dawson et al. 1986; Mann and Davis 1986; Guacci and Kaback 1991; Demburg et al. 1996; Karpen et al. 1996; Kemp et al. 2004; Cheslock et al. 2005; Fledel-Alon et al. 2009; Gladstone et al. 2009; Newnham et al. 2010). Identification of genetic variants associated with such Variation in crossover frequencies is of considerable interest.

Meiotic crossovers are initiated by the programmed introduction of DNA double-strand breaks (DSBs) (Keeney et al. 1997). Repair of meiotic DSBs results in the formation of crossover as well as noncrossover products through distinct pathways (Allers and Lichten 2001; Hunter and Kleckner 2001). In S. cerevisiae and mammals, a majority of the crossovers are formed through a pathway mediated by the MutS mismatch repair homologs Msh4, Msh5, and MutL mismatch repair homologs Mlh1, Mlh3 (RossMacdonald and Roeder 1994; Hollingsworth et al. 1995; Baker et al. 1996; Barlow and Hulten 1998; De Vries et al. 1999; Edelmann et al. 1999; Woods et al. 1999; Kneitz et al. 2000; Novak et al. 2001; Lipkin et al. 2002; SantucciDarmanin et al. 2002; Argueso et al. 2004; Guillon et al. 2005; Kolas et al. 2005; Lynn et al. 2007; Cole et al. 2012). The Msh4/5 proteins are part of an ensemble of proteins called the ZMM complex that stabilizes single end invasion intermediates generated during invasion of an intact homolog by a resected DSB end (Chua and Roeder 1998; Agarwal and Roeder 2000; Borner et al. 2004; Tsubouchi et al. 2006; Shinohara et al. 2008). The Msh4/ 5 complex also binds and stabilizes double Holliday junctions and promotes their resolution into crossover products in association with other repair factors that include Mlh1/3, Exo1, and Sgs1 (Borner et al. 2004; Snowden et al. 2004; Nishant et al. 2008; Snowden et al. 2008; Zakharyevich et al. 2010; De Muyt et al. 2012; Zakharyevich et al. 2012).

Recent human studies have implicated polymorphisms in ZMM genes such as RNF212 (putative S. cerevisiae ZIP3 ortholog) and MSF14 with genome-wide crossover frequency variation (Kong et al. 2014). Similar observations have been made in S. cerevisiae, where a series of msh4/5 hypomorphic alleles that showed up to twofold reduction in crossovers at specific loci on chromosomes VII, VIII, and XV with high spore viability were identified (Nishant et al. 2010). The high spore viability observed in S. cerevisiae msh4/5 hypomorphs and in other mutants like mlh3D mms4D (Brown et al. …

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