Sex-specific differences in human meiotic recombination: A cytogenetic analysis of early meiotic events

Abstract

In humans, a striking 20-30% of all pregnancies are aneuploid and, of these, 95% result from missegregation during maternal meiosis. To date the only molecular mechanism associated with human aneuploidy is errors in recombination. Recombination sites act as anchoring points between homologous chromosomes, and, aberrant recombination (if sites are lost, fail to form, or are sub-optimally placed) can lead to the formation of aneuploid gametes. Although the basics of recombination are consistent across species, distinct differences between males and females within a species, particularly in humans, have been identified. The origins of these sex-differences in recombination are unknown; therefore, our first set of studies investigated human sex-differences throughout the recombination pathway, utilizing genome-wide and chromosome-specific cytological analyses of human spermatocytes and oocytes. We hypothesized that sex-differences in recombination would originate during the recombination pathway. Our analysis of double strand breaks (DSBs) and crossovers (COs), however, suggested that sex-differences are established before the initiation of recombination. Further analysis of chromatin organization led us to hypothesize that levels of chromatin compaction established before meiosis determines variation in recombination between males and females. Studies in multiple species have established that synaptonemal complex initiation sites (SCISs) are associated with subsequent COs. This prompted our second set of studies analyzing human synaptic initiation. Preliminary data suggested extreme sex-differences in the placement of human SCISs and, from these patterns, we hypothesized that no correlation would be found between SCISs and COs. Indeed, no similarities were found between SCIS and CO location in human males or females. In the mouse, however, general similarities in SCIS and CO placement were found in both sexes. Taken together, our studies suggest that, in humans, sex-specific variation in recombination is regulated through mechanisms upstream of the recombination pathway. In addition our data suggest that synaptic initiation has little impact on the placement of downstream recombination sites. From these data we can conclude mammalian recombination cannot be explained by a single paradigm, particularly in light of the unique regulation in human males and females.