Chromosomes display a different propensity to mis-segregate during meiosis, suggesting that chromosome-specific features influence the pattern of nondisjunction. In humans and many other organisms, the sex chromosomes are distinguished from the autosomes by repetitive elements, sex-specific gene expression, histone modifications and degree of heterochromatinization. In C. elegans these differences have a profound effect on behavior of the X chromosome in the germ line, where the X chromosome is predominantly transcriptionally quiescent and heterochromatic. Studies in Drosophila and mice have shown that heterochromatin presents a barrier to meiotic double-strand break (DSB) formation.

We have identified two genes, xnd-1 and him-5, required specifically for DSB formation on the X chromosome in C. elegans. Recent work in our lab has revealed that xnd-1 regulates specific histone modifications that differentially mark the sex chromosomes. The mouse knockout of the gene required for this modification shows reduced fertility, suggesting that further characterization of this pathway in the nematode will provide insight into mammalian fertility. The xnd-1 therefore provides a molecular handle into the study of how chromatin is regulated during meiosis and how it in turn shapes the genome. 

The recent identification of reproductive abnormalities in mammals exposed to bisphenol A, a plasticizer found in can linings and water bottles, has reawakened interest in the interaction between environmental cues and reproductive outcomes. It has long been appreciated that temperature, stress and age alter recombination rates, but the precise nature of these changes and the mechanisms by which the organism transduces environmental cues to the germline are poorly understood.

We have been developing C. elegans as a system to study germline aging and environmental responses. To begin this work, we developed recombination maps of the nematode third chromosome for both sexes at three growth temperatures, and for young and old hermaphrodites. This work revealed that sex, age and temperature strongly influence the placement of crossovers along the chromosome by shifting the usage of large (Mb) chromosomal domains. This data enhances the emerging hypothesis that recombination in C. elegans, as in humans, is regulated in chromosomal domains, suggesting that chromatin organization is a major determinant of crossover regulation.

We have also performed an RNAi screen for chromatin-related genes that affect crossover formation and placement. This screen identified over 20 genes that affect meiotic recombination. Further analysis of these genes has promise to identify key factors in crossover regulation.

Although xnd-1 exerts controls crossing over formation on the X, XND-1 protein is enriched on autosomes. Therefore, XND-1 protein must be acting at a distance to affect the X chromosome. xnd-1 does function on autosomes:  it influences crossover placement, causing more crossovers in regions that are generally repressed for crossover formation. We are interested in identifying the cis and trans features that recruit XND-1 to the autosomes and how this localization influences X versus autosome crossover regulation.  

This project has also raised questions about how the sex chromosomes differ from the autosomes in the germ line, a feature that appears conserved between nematodes and humans. Since nondisjunction of the sex chromosomes is a major cause of human infertility, these studies have immediate potential to identify conserved pathways required for sex chromosome segregation.

The formation of crossovers during meiosis ensures their proper segregation at the first meiotic division. Therefore multiple checkpoints are active in the germline to guarantee the correct execution of the early meiotic events. We have identified the activation of a novel meiotic checkpoint in the germlines of xnd-1 and him-5 animals. This checkpoint is responding the lack of DSBs on the X chromosome as it is rescued by formation of exogenous breaks. We believe this checkpoint is monitoring the formation of DSBs on every chromosome. Current projects are aimed at understanding the features that activate this checkpoint and signaling cascade that ensues.