A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans.
Where this comes from
- Record sourced from PubMed, PMID 33781384.
- Also identified by DOI 10.7554/eLife.65420 and PMC identifier 8009663.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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 <i>Azoospermia Factor c</i> (<i>AZFc</i>) region, combined with gene dosage analysis of the multicopy <i>DAZ, BPY2</i>, and <i>CDY</i>genes 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 <i>r2/r3</i> inversion, destabilizing the <i>AZFc</i> 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<sup>-4</sup>). 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.
Medical subject headings
- Azoospermia
- Chromosome Inversion
- Gene Deletion
- Spermatogenesis