eLife (Mar 2021)

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

DOI
https://doi.org/10.7554/eLife.65420
Journal volume & issue
Vol. 10

Abstract

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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.

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