Genetic Diversity on the Human X Chromosome Does Not Support a Strict Pseudoautosomal Boundary

Abstract

Unlike the autosomes, recombination between the X chromosome and the Y chromosome is often thought to be constrained to two small pseudoautosomal regions (PARs) at the tips of each sex chromosome. PAR1 spans the first 2.7 Mb of the proximal arm of the human sex chromosomes, whereas the much smaller PAR2 encompasses the distal 320 kb of the long arm of each sex chromosome. In addition to PAR1 and PAR2, there is a human-specific X-transposed region that was duplicated from the X to the Y chromosome. The X-transposed region is often not excluded from X-specific analyses, unlike the PARs, because it is not thought to routinely recombine. Genetic diversity is expected to be higher in recombining regions than in nonrecombining regions because recombination reduces the effect of linked selection. In this study, we investigated patterns of genetic diversity in noncoding regions across the entire X chromosome of a global sample of 26 unrelated genetic females. We found that genetic diversity in PAR1 is significantly greater than in the nonrecombining regions (nonPARs). However, rather than an abrupt drop in diversity at the pseudoautosomal boundary, there is a gradual reduction in diversity from the recombining through the nonrecombining regions, suggesting that recombination between the human sex chromosomes spans across the currently defined pseudoautosomal boundary. A consequence of recombination spanning this boundary potentially includes increasing the rate of sex-linked disorders (e.g., de la Chapelle) and sex chromosome aneuploidies. In contrast, diversity in PAR2 is not significantly elevated compared to the nonPARs, suggesting that recombination is not obligatory in PAR2. Finally, diversity in the X-transposed region is higher than in the surrounding nonPARs, providing evidence that recombination may occur with some frequency between the X and Y chromosomes in the X-transposed region.

Keywords: X-transposed region (XTR); genetics of sex; nucleotide diversity; pseudoautosomal region (PAR); recombination; sex chromosome evolution.

Figure 1

Diversity along the human X chromosome. Genetic diversity (measured by π) is shown in 100 kb overlapping windows across the human X chromosome that includes PAR1 (shown in red), the nonPARs (shown in black), the X-transposed region (XTR) (shown in blue), and PAR2 (shown in red) for (A) human diversity uncorrected for divergence and then human diversity corrected for variable mutation rate using (B) human-chimpanzee divergence, (C) human-macaque divergence, (D) human-dog divergence, and (E) human-mouse divergence. The light-gray-shaded areas are the low-diversity regions, and the dark-gray-shaded areas are the ampliconic regions that were filtered out.

Figure 2

Negative correlation between diversity and distance from Xp, crossing the pseudoautosomal boundary. Diversity in 100 kb nonoverlapping windows along the pseudoautosomal boundary is plotted across the first 6 Mb of the human X chromosome, spanning the annotated pseudoautosomal boundary at 2.7 Mb. A series of linear regressions was run, including 30 windows, sliding by one window across the PARs to the nonPARs. Each 100 kb window is colored red if it is included in a regression in which distance from Xp and diversity are significantly negatively correlated; otherwise, the windows are colored black. For the entire region together, diversity is significantly negatively correlated with distance from Xp (P = 3.281 × 10⁻¹⁰; r = −0.7321563) and spans the pseudoautosomal boundary.

Figure 3

Diversity along the X chromosome split by region. Genetic diversity (measured by π) is shown in box plots depicting the average diversity with error bars for the nonPARs, PAR1, XTR, and PAR2. The P-values from a permutation test with 10,000 replicates comparing the diversity of each region to the diversity of the nonPARs are shown.