A major recombination hotspot in the XqYq pseudoautosomal region gives new insight into processing of human gene conversion events

Shriparna Sarbajna,Rita Neumann,María Soler Artigas,Alec J Jeffreys,Celia A May,Matthew Denniff,Amelia Veselis

doi:10.1093/hmg/dds019

Abstract

Recombination plays a fundamental role in meiosis. Non-exchange gene conversion (non-crossover, NCO) may facilitate homologue pairing, while reciprocal crossover (CO) physically connects homologues so they orientate appropriately on the meiotic spindle. In males, X-Y homologous pairing and exchange occurs within the two pseudoautosomal regions (PARs) together comprising <5% of the human sex chromosomes. Successful meiosis depends on an obligatory CO within PAR1, while the nature and role of exchange within PAR2 is unclear. Here, we describe the identification and characterization of a typical ~1 kb wide recombination hotspot within PAR2. We find that both COs and NCOs are strongly modulated in trans by the presumed chromatin remodelling protein PRDM9, and in cis by a single nucleotide polymorphism (SNP) located at the hotspot centre that appears to influence recombination initiation and which causes biased gene conversion in SNP heterozygotes. This, the largest survey to date of human NCOs reveals for the first time substantial inter-individual variation in the NCO:CO ratio. Although the extent of biased transmission at the central marker in COs is similar across men, it is highly variable among NCO recombinants. This suggests that cis-effects are mediated not only through recombination initiation frequencies varying between haplotypes but also through subsequent processing, with the potential to significantly intensify meiotic drive of hotspot-suppressing alleles. The NCO:CO ratio and extent of transmission distortion among NCOs appear to be inter-related, suggesting the existence of two NCO pathways in humans.

Highlights

Our understanding of the fundamental process of meiotic recombination in humans has greatly advanced through complementary genome-wide analyses and focused fine-scale sperm DNA approaches
European population diversity data together with high-resolution mapping of familial recombinants showed that most crossover events (COs) events in PAR2 co-localize to an interval encompassing the promoter region of the most proximal gene, SPRY3
The tight clustering of both types of event is similar to that seen at autosomal hotspots[1,48,52] and at a hotspot characterized in PAR153

Summary

Introduction

Our understanding of the fundamental process of meiotic recombination in humans has greatly advanced through complementary genome-wide analyses and focused fine-scale sperm DNA approaches. Most crossover events (COs) in our genome cluster into narrow hotspots 1-2 kb in width[1,2], and many of these hotspots contain degenerate GCrich sequence motifs which appear to influence the initiation of recombination[3]. PRDM9 contains a zinc-finger (ZnF) domain, encoded by a variable minisatellite that is capable of binding hotspot sequences, plus a SET domain implicated in histone methylation and perhaps activation of hotspots via chromatin remodelling. Sperm DNA typing has revealed cis-acting effects within hotspots that down-regulate CO activity[12,13], and has been used to explore a second class of meiotic recombination event, highly localised non-reciprocal gene conversions or noncrossovers (NCOs) between homologues[14]

Methods

Results

Conclusion