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

Elife. 2021 Mar 30:10:e65420. doi: 10.7554/eLife.65420.


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.

Keywords: b2/b3 deletions; complex structural rearrangements; daz, bpy2, cdy1 dosage; evolutionary biology; genetics; genomics; gr/gr; human; idiopathic male infertility; variants; y haplogroup r1a1-m458; y-chromosomal azfc region.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Azoospermia / epidemiology
  • Azoospermia / genetics*
  • Chromosome Inversion / genetics*
  • Estonia
  • Gene Deletion*
  • Humans
  • Male
  • Middle Aged
  • Spermatogenesis / genetics*
  • Young Adult