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

Abstract

Male infertility is a prevalent condition, concerning 5-10% of men. So far, only some recurrent genetic factors have been described as confident 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 and Y-haplogroup determination. In analysing 2,324 Estonian men, we uncovered a novel structural variant as a high-penetrant risk factor to male infertility. The Y lineage R1a1-M458, reported at >20% frequency in several European populations, carries a fixed ∼1.6 Mb long r2/r3 inversion destabilizing the AZFc region and predisposing to recurrent microdeletions. Such complex rearrangements were significantly enriched among severe oligozoospermia cases. The carrier vs non-carrier risk to spermatogenic failure was increased 8.6-fold (p = 6.0 × 10−4). The finding contributes to improved molecular diagnostics and clinical management of infertility. Carrier identification in young age will facilitate timely counselling and reproductive decision-making.

Expanding the conservation genomics toolbox: Incorporating structural variants to enhance genomic studies for species of conservation concern

“…In contrast, in some cases where a particular SV is associated with a trait, the SV may not be the causal variant, but rather increase the likelihood of de novo causal mutations nearby. This is the case for a relatively common 1.3 Mb inversion on the human Y‐chromosome where microdeletions accrue at inversion breakpoints, which can result in profound impacts on male fertility (Hallast et al, 2021). There is also growing evidence that SVs can further impact the gene regulatory landscape by altering the formation of topologically associating domains (TADs), genomic regions that physically interact with themselves more frequently than with regions elsewhere (Sadowski et al, 2019; Shanta et al, 2020).…”