Regulation of Crossover Frequency and Distribution during Meiotic Recombination

Abstract

Crossover recombination is essential for generating genetic diversity and promoting accurate chromosome segregation during meiosis. The process of crossover recombination is tightly regulated and is initiated by the formation of programmed meiotic DNA double-strand breaks (DSBs). The number of DSBs is around 10-fold higher than the number of crossovers in most species, because only a limited number of DSBs are repaired as crossovers during meiosis. Moreover, crossovers are not randomly distributed. Most crossovers are located on chromosomal arm regions and both centromeres and telomeres are usually devoid of crossovers. Either loss or mislocalization of crossovers frequently results in chromosome nondisjunction and subsequent aneuploidy, leading to infertility, miscarriages, and birth defects such as Down syndrome. Here, we will review aspects of crossover regulation observed in most species and then focus on crossover regulation in the nematode Caenorhabditis elegans in which both the frequency and distribution of crossovers are tightly controlled. In this system, only a single crossover is formed, usually at an off-centered position, between each pair of homologous chromosomes. We have identified C. elegans mutants with deregulated crossover distribution, and we are analyzing crossover control by using an inducible single DSB system with which a single crossover can be produced at specific genomic positions. These combined studies are revealing novel insights into how crossover position is linked to accurate chromosome segregation.Meiosis is a specialized cell division process that generates haploid gametes from diploid parental germ cells. This reduction in the number of chromosomes is achieved by following a single round of DNA replication with two consecutive cell divisions (meiosis I and II). Homologous chromosomes are separated at meiosis I, and sister chromatids are separated at meiosis II. There are unique chromosomal events that need to take place during prophase to ensure that homologs segregate properly at meiosis I (Fig. 1). Homologous chromosomes need to find each other and pair; these pairing interactions need to be stabilized via the formation of a scaffold known as the synaptonemal complex, which assembles at the interface between paired homologs; and interhomolog recombination needs to take place in order to produce crossovers. Crossover formation is one of the sources of genetic diversity in the population. Moreover, crossovers result in physical attachments (chiasmata) between homologs that, underpinned by cohesion, confer the tension required to properly align the attached homologs (bivalents) at the metaphase plate and then orient them toward opposite poles of the meiosis I spindle.Errors in crossover formation result in chromosome nondisjunction leading to aneuploidy, which causes infertility, miscarriages, birth defects, and cancers.Given the impact of crossover formation on human health and reproductive biology, it is therefore not surprising that crossovers are tightly regulated. For e...

Insights about variation in meiosis from 31,228 human sperm genomes

“…7; Supplemental Text). This is consistent with biological constraint on crossover number, a major determinant of which is crossover interference (reviewed in 33,34 ).…”

A rigorous measure of genome-wide genetic shuffling that takes into account crossover positions and Mendel’s second law

“…CO interference, first described more than a century ago (88), is a deeply conserved feature of the meiotic program (128,129). Despite this, its adaptive function, if any, remains unclear (104,130,131). One category of hypotheses invokes mechanical advantages of spread-out COs either to bivalent stability in prophase (132) or to homolog segregation at meiosis I (133).…”

A rigorous measure of genome-wide genetic shuffling that takes into account crossover positions and Mendel’s second law

“…Crossover interference, first described more than a century ago [87], is a deeply conserved feature of the meiotic program [130,131]. Despite this, its adaptive function remains unclear [103,132,133]. One category of hypotheses invokes mechanical advantages of spread-out crossovers, either to bivalent stability in prophase [134] or to homolog segregation at meiosis I [135].…”