A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans

Pille Hallast, Laura Kibena, Margus Punab, Elena Arciero, Siiri Rootsi, Marina Grigorova, Rodrigo Flores, Mark A. Jobling, Olev Poolamets, Kristjan Pomm, Paul Korrovits, Kristiina Rull, Yali Xue, Chris Tyler-Smith, Maris Laan, George H. Perry

Research output: Contribution to journalArticlepeer-review

Abstract

Male infertility is a prevalent condition, affecting 5-10% of men. So far, few genetic factors have been described as contributors to spermatogenic failure. Here, we report the first re-sequencing study of the Y-chromosomal Azoospermia Factor c (AZFc) region, combined with gene dosage analysis of the multicopy DAZ, BPY2, and CDYgenes and Y-haplogroup determination. In analysing 2324 Estonian men, we uncovered a novel structural variant as a high-penetrance risk factor for male infertility. The Y lineage R1a1-M458, reported at >20% frequency in several European populations, carries a fixed ~1.6 Mb r2/r3 inversion, destabilizing the AZFc region and predisposing to large recurrent microdeletions. Such complex rearrangements were significantly enriched among severe oligozoospermia cases. The carrier vs non-carrier risk for spermatogenic failure was increased 8.6-fold (p=6.0×10-4). This finding contributes to improved molecular diagnostics and clinical management of infertility. Carrier identification at young age will facilitate timely counselling and reproductive decision-making.

Original languageEnglish (US)
Article numbere65420
JournaleLife
Volume10
DOIs
StatePublished - Mar 2021

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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