Multiple origins and phenotypic implications of an extended human pseudoautosomal region shown by analysis of the UK Biobank
Issued Date
2025-01-01
Resource Type
ISSN
00029297
eISSN
15376605
Scopus ID
2-s2.0-105000077036
Pubmed ID
39983723
Journal Title
American Journal of Human Genetics
Rights Holder(s)
SCOPUS
Bibliographic Citation
American Journal of Human Genetics (2025)
Suggested Citation
Poriswanish N., Eales J., Xu X., Scannali D., Neumann R., Wetton J.H., Tomaszewski M., Jobling M.A., May C.A. Multiple origins and phenotypic implications of an extended human pseudoautosomal region shown by analysis of the UK Biobank. American Journal of Human Genetics (2025). doi:10.1016/j.ajhg.2025.01.026 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/108535
Title
Multiple origins and phenotypic implications of an extended human pseudoautosomal region shown by analysis of the UK Biobank
Corresponding Author(s)
Other Contributor(s)
Abstract
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.