Gene conversion between the X chromosome and the male-specific region of the Y chromosome at a translocation hotspot

Abstract

Outside the pseudoautosomal regions, the mammalian sex chromosomes are thought to have been genetically isolated for up to 350 million years. However, in humans pathogenic XY translocations occur in XY-homologous (gametologous) regions, causing sex-reversal and infertility. Gene conversion might accompany recombination intermediates that resolve without translocation and persist in the population. We resequenced X and Y copies of a translocation hotspot adjacent to the PRKX and PRKY genes and found evidence of historical exchange between the male-specific region of the human Y and the X in patchy flanking gene-conversion tracts on both chromosomes. The rate of X-to-Y conversion (per base per generation) is four to five orders of magnitude more rapid than the rate of Y-chromosomal base-substitution mutation, and given assumptions about the recombination history of the X locus, tract lengths have an overall average length of approximately 100 bp. Sequence exchange outside the pseudoautosomal regions could play a role in protecting the Y-linked copies of gametologous genes from degeneration.

Figure 1

XY Translocations between PRKX and PRKY, the PRKY Gene Region, and Gametologous Sequence Variants and Conversions around Translocation Hotspot A (A) Idiograms of the sex chromosomes (not to scale) showing the pseudoautosomal regions (PAR1, PAR2), the SRY gene, and the PRKX and PRKY gene pair. (B) The PRKY gene region, showing positions of exons and HSA. Exon numbering is based on PRKX, so exon 6 is absent. Gene orientation varies as a result of a polymorphic Yp inversion, and the orientation shown is that permissive for XY translocation (opposite to the Y reference sequence⁷). There is no reason to expect orientation to influence the probability of conversion. (C) Sequence states of GSVs in the Y- and X-chromosomal reference sequences of an ∼1.9 kb region encompassing HSA. The positions of 66 surveyed gametologous sequence variants (GSVs) are indicated by circles (see key below figure), and some are numbered sequentially. Y- and X-specific primers (arrows) cover the proximal- and distal-most four GSVs. (D) Sequence states of GSVs in Y-chromosomal copies of part of the region. Names of DNA samples and their Y-chromosomal haplogroups are given to the left. Samples with the prefix “YCC” are from the Y Chromosome Consortium, and haplogroup information is as described. Other human samples of known haplogroup are from collections of the authors. Below is shown the shorter region surveyed in the Y chromosome of sample YCC4. (E) Sequence states of GSVs in X-chromosomal copies; DNA sample names and their populations of origin are given to the left. Haplotypes (ht) are numbered to the right.

Figure 2

Phylogenetic Network of HSA Sequences in Humans and Great Apes Phylogenetic split network (based on alignment shown in Figure S2) showing the relationships between HSA segments, produced with SplitsTree4 via the “NeighborNet” method and the “uncorrectedP” distance. Lengths of edges represent the proportion of sites at which sequences differ, as indicated by the scale-bar. The reticulated structure indicates a history of gene conversion. Abbreviations are as follows: Hu, human; Ch, chimpanzee; and Go, gorilla.