Insights into non-crossover recombination from long-read sperm sequencing.

ABSTRACT

Meiotic recombination is a fundamental process that generates genetic diversity by creating new combinations of existing alleles. Although human crossovers have been studied at the pedigree, population and single-cell level, the more frequent non-crossover events that lead to gene conversion are harder to study, particularly at the individual level. Here we show that single high-fidelity long sequencing reads from sperm can capture both crossovers and non-crossovers, allowing effectively arbitrary sample sizes for analysis from one male. Using fifteen sperm samples from thirteen donors we demonstrate variation between and within donors for the rates of different types of recombination. Intriguingly, we observe a tendency for non-crossover gene conversions to occur upstream of nearby PRDM9 binding sites, whereas crossover locations have a slight downstream bias. We further provide evidence for two distinct non-crossover processes. One gives rise to the vast majority of non-crossovers with mean conversion tract length under 50bp, which we suggest is an outcome of standard PRDM9-induced meiotic recombination. In contrast ~2% of non-crossovers have much longer mean tract length, and potentially originate from the same process as complex events with more than two haplotype switches, which is not associated with PRDM9 binding sites and is also seen in somatic cells.