A Link between Meiotic Prophase Progression and Crossover Control

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Abstract
During meiosis, most organisms ensure that homologous chromosomes undergo at least one exchange of DNA, or crossover, to link chromosomes together and accomplish proper segregation. How each chromosome receives a minimum of one crossover is unknown. During early meiosis in Caenorhabditis elegans and many other species, chromosomes adopt a polarized organization within the nucleus, which normally disappears upon completion of homolog synapsis. Mutations that impair synapsis even between a single pair of chromosomes in C. elegans delay this nuclear reorganization. We quantified this delay by developing a classification scheme for discrete stages of meiosis. Immunofluorescence localization of RAD-51 protein revealed that delayed meiotic cells also contained persistent recombination intermediates. Through genetic analysis, we found that this cytological delay in meiotic progression requires double-strand breaks and the function of the crossover-promoting heteroduplex HIM-14 (Msh4) and MSH-5. Failure of X chromosome synapsis also resulted in impaired crossover control on autosomes, which may result from greater numbers and persistence of recombination intermediates in the delayed nuclei. We conclude that maturation of recombination events on chromosomes promotes meiotic progression, and is coupled to the regulation of crossover number and placement. Our results have broad implications for the interpretation of meiotic mutants, as we have shown that asynapsis of a single chromosome pair can exert global effects on meiotic progression and recombination frequency. Meiosis is a specialized cell division and an essential component of sexual reproduction. During meiotic prophase, each chromosome must pair with its unique homologous partner and undergo crossing over (genetic exchange) to segregate properly. A major mystery is how the molecular events of meiotic recombination are coupled to the large-scale dynamics of chromosome synapsis. This work reveals a link between the large-scale regulation of chromosome organization and the distribution of crossover events on the chromosomes. In C. elegans, defects in chromosome pairing or synapsis result in an extension of a normally transient stage of meiotic prophase. This study finds that this extension is associated with dysregulation of crossovers, so that more than the usual number of crossovers occur, and their distribution is shifted along the chromosomes. These observations contribute to our understanding of crossover control, which normally ensures accurate transmission of genetic information from parent to progeny.