Analysis of Meiotic Recombination in the Human Pseudoautosomal Regions

Meiotic recombination in humans is essential for the faithful segregation of chromosomes during meiosis and is key in generating genetic diversity. Inferring past events from contemporary SNP haplotypes and studying de novo events in sperm DNA has shown that recombination occurs within 1-2 kb wide ‘hot spots’ in the human genome. In terms of male recombination, the pseudoautosomal regions (PARs) are especially interesting. PAR1 undergoes obligatory crossover in male meiosis and therefore constitutes a male-specific recombination ‘hot’ domain (rate approximately 20-fold above the genome average). It is thus ideally suited to sperm DNA studies. PAR2 is not essential in male meiosis, but nonetheless recombines at a rate >6-times the genome average. Despite this, relatively little is known about the fine-scale distribution of recombination in either pseudoautosomal region. To address this, linkage disequilibrium analysis and high-resolution sperm typing was used in this work, in order to identify and characterise a collection of PAR hot spots. This survey led to the identification of five active PAR hot spots, thereby providing relatively easy access to crossovers and noncrossovers. A second hot spot was identified in the SHOX region, providing information on hot spot spacing in PAR1 and facilitating important comparisons with autosomes. The first PAR1 double hot spot, a potential resource for investigating crossover interference, was also identified. Data from the two PAR2 hot spots (SPRY3 and PAR2A) provided direct evidence of hot spot activation by trans-acting PRDM9, with different protein variants activating either hot spot. The strongest meiotic drive observed at any human hot spot was also identified at SPRY3, providing insights into likely mechanisms of hot spot evolution. Finally, an extensive survey at SPRY3 provided unprecedented insights into the relative frequencies of crossovers and noncrossovers at hot spots and highlighted the presence of a second pathway of noncrossover-formation in humans.