Abstract
The human X and Y chromosomes are heteromorphic but share a region of homology at the tips of their short arms, pseudoautosomal region 1 (PAR1), that supports obligate crossover in male meiosis. Although the boundary between pseudoautosomal and sex-specific DNA has traditionally been regarded as conserved among primates, it was recently discovered that the boundary position varies among human males, due to a translocation of ~110 kb from the X to the Y chromosome that creates an extended PAR1 (ePAR). This event has occurred at least twice in human evolution. So far, only limited evidence has been presented to suggest this extension is recombinationally active. Here, we sought direct proof by examining thousands of gametes from each of two ePAR-carrying men, for two subregions chosen on the basis of previously published male X-chromosomal meiotic double-strand break (DSB) maps. Crossover activity comparable to that seen at autosomal hotspots was observed between the X and the ePAR borne on the Y chromosome both at a distal and a proximal site within the 110-kb extension. Other hallmarks of classic recombination hotspots included evidence of transmission distortion and GC-biased gene conversion. We observed good correspondence between the male DSB clusters and historical recombination activity of this region in the X chromosomes of females, as ascertained from linkage disequilibrium analysis; this suggests that this region is similarly primed for crossover in both male and female germlines, although sex-specific differences may also exist. Extensive resequencing and inference of ePAR haplotypes, placed in the framework of the Y phylogeny as ascertained by both Y microsatellites and single nucleotide polymorphisms, allowed us to estimate a minimum rate of crossover over the entire ePAR region of 6-fold greater than genome average, comparable with pedigree estimates of PAR1 activity generally. We conclude ePAR very likely contributes to the critical crossover function of PAR1.
Highlights
The major pseudoautosomal region (PAR1), located at the tips of the short arms of the human sex chromosomes, is a region of interchromosomal homology [1, 2]
Direct evidence of pseudoautosomal region plasticity came from a chance discovery during an aCGH screen for copy number variation (CNV) in ~4,300 patients with developmental disorders, which showed that a small subset of men carry an extended pseudoautosomal region 1 (PAR1): this demonstrates that the PAR1 boundary is not static, but polymorphic in modern humans [11]
The extended PAR1 (ePAR) has been found in two Y-chromosome haplogroups, I2a and R1b, that are frequent in Europe [20, 21] so we focused on North European semen donors in our collection
Summary
The major pseudoautosomal region (PAR1), located at the tips of the short arms of the human sex chromosomes, is a region of interchromosomal homology [1, 2]. Despite this, there is evidence that its boundary, PAB1, has shifted distally in the past, as the proximal 240 bp of sex-specific DNA shows 77% sequence similarity between the human X and Y [8,10]. Direct evidence of pseudoautosomal region plasticity came from a chance discovery during an aCGH (array comparative genomic hybridization) screen for copy number variation (CNV) in ~4,300 patients with developmental disorders, which showed that a small subset of men carry an extended PAR1 (ePAR): this demonstrates that the PAR1 boundary is not static, but polymorphic in modern humans [11]
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