Multiple origins and phenotypic implications of an extended human pseudoautosomal region shown by analysis of the UK Biobank

The 2.7-Mb major pseudoautosomal region (PAR1) on the short arms of the human X and Y chromosomes plays a critical role in meiotic sex chromosome segregation and male fertility and has been regarded as evolutionarily stable. However, some European Y chromosomes belonging to Y haplogroups (Y-Hgs) R1b and I2a carry an ∼115-kb extension (ePAR [extended PAR]) arising from X-Y non-allelic homologous recombination (NAHR). To investigate the diversity, history, and dynamics of ePAR formation, we screened for its presence, and that of the predicted reciprocal X chromosome deletion, among ∼218,300 46,XY males of the UK Biobank (UKB), a cohort associated with longitudinal clinical data. The UKB incidence of ePAR is ∼0.77%, and that of the deletion is ∼0.02%. We found that Y-Hg I2a sub-lineages accounted for nearly 90% of ePAR cases but, by Y haplotyping and breakpoint sequencing, determined that, in total, there have been at least 18 independent ePAR origins, associated with nine different Y-Hgs. We found examples of ePAR linked to Y-Hg K among men of self-declared Pakistani ancestry and Y-Hg E1, typical of men with African ancestry, showing that ePAR is not restricted to Europeans. ePAR formation is likely random, with high frequencies in some Y-Hgs arising through drift and male-mediated expansions. Sequencing recombination junction fragments identified likely reciprocal events, and the heterogeneity of ePAR and X-deletion junctions highlighted the recurrent nature of the NAHR events. A phenome-wide association study revealed an association between ePAR and elevated levels of circulating IGF-1 as well as musculoskeletal phenotypes.