Cytological Studies of Human Meiosis: Sex-Specific Differences in Recombination Originate at, or Prior to, Establishment of Double-Strand Breaks

Abstract

Meiotic recombination is sexually dimorphic in most mammalian species, including humans, but the basis for the male:female differences remains unclear. In the present study, we used cytological methodology to directly compare recombination levels between human males and females, and to examine possible sex-specific differences in upstream events of double-strand break (DSB) formation and synaptic initiation. Specifically, we utilized the DNA mismatch repair protein MLH1 as a marker of recombination events, the RecA homologue RAD51 as a surrogate for DSBs, and the synaptonemal complex proteins SYCP3 and/or SYCP1 to examine synapsis between homologs. Consistent with linkage studies, genome-wide recombination levels were higher in females than in males, and the placement of exchanges varied between the sexes. Subsequent analyses of DSBs and synaptic initiation sites indicated similar male:female differences, providing strong evidence that sex-specific differences in recombination rates are established at or before the formation of meiotic DSBs. We then asked whether these differences might be linked to variation in the organization of the meiotic axis and/or axis-associated DNA and, indeed, we observed striking male:female differences in synaptonemal complex (SC) length and DNA loop size. Taken together, our observations suggest that sex specific differences in recombination in humans may derive from chromatin differences established prior to the onset of the recombination pathway.

Meiotic Recombination: The Essence of Heredity

“…Several studies have established that the metric of crossover interference is the physical lengths of prophase chromosomes (as opposed to genetic distance or genomic distance, i.e., bps of DNA) (Martini et al 2006;Drouaud et al 2007;Petkov et al 2007;Zhang et al 2014b). Thus, crossover rates for the same chromosomes vary coordinately with changes in axis lengths, which reflect differences in chromatin packaging with respect to the size and density of chromatin loops (Lynn et al 2002;Hillers and Villeneuve 2003;Kleckner et al 2003;Tease and Hulten 2004;Qiao et al 2012b;Gruhn et al 2013;Baier et al 2014). For example, in humans, variation in the lengths of prophase chromosomes account for long-known differences in recombination rates between males and females.…”

“…For example, in humans, variation in the lengths of prophase chromosomes account for long-known differences in recombination rates between males and females. Oocyte prophase chromosomes are about twice as long as their spermatocyte counterparts, have shorter, denser chromatin loops, and experience 60% more crossovers (Gruhn et al 2013). However, interference distances (expressed as mm of synaptonemal complex) are comparable between the sexes (Petkov et al 2007).…”

“…Moreover, in budding yeast, there appears to be a 1:1 correlation between designated crossover sites (marked by crossover-specific markers) and initiation sites for polymerization of synaptonamal complex (Fung et al 2004;Henderson and Keeney 2004). In other organisms, these sites are also correlated, but synaptonemal complex-initiation sites outnumber crossover sites (Zickler et al 1992;Zickler and Kleckner 1999;Brown et al 2005;Gruhn et al 2013;Zhang et al 2014a).…”

Evidence for Paternal Age-Related Alterations in Meiotic Chromosome Dynamics in the Mouse

“…We further analyzed MLH1 placement on chromosomes 1 and 11 in B6 males and found no differences between age groups ( Figure S2). Because recombination has been positively correlated with SC length (Lynn et al 2002;Gruhn et al 2014), we measured total autosomal SC lengths in pachytene spermatocytes to determine if the age-related increase in recombination was accompanied by a corresponding increase in SC length (Table 1). Mean SC length, like recombination, exhibited an age-dependent increase on two of the three genetic backgrounds.…”

“…Age-dependent differences in recombination occur downstream of double-strand breaks Sex and strain-specific differences in recombination have been correlated with differences in RAD51 foci (Barlow et al 1997;Lenzi et al 2005;Oliver-Bonet et al 2005;Gruhn et al 2014). To determine if age-dependent differences in recombination are similarly correlated, we analyzed RAD51 foci in zygotene-stage cells (Table 3).…”