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

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

doi:10.7554/elife.65420

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.

Highlights

The diagnosis of male factor infertility due to abnormal semen parameters concerns ~10% of men (Jungwirth et al, 2012; Datta et al, 2016)
A statistically significant excess of gr/gr deletions was detected in idiopathic male infertility patients (2.7%; n = 32/ 1190) compared to reference cases (1.2%; n = 14/1134) (Fisher’s exact test, p=0.016; odds ratio [OR] = 2.2 [95% confidence interval (CI) 1.2–4.2]) (Figure 1D, Supplementary file 2)
We conducted a comprehensive investigation of partial deletion subtypes of the Y-chromosomal Azoospermia Factor c (AZFc) region in 2324 Estonian men, approximately half with idiopathic spermatogenic impairment (n = 1190) in comparison to the reference group (n = 1134)

Summary

Introduction

The diagnosis of male factor infertility due to abnormal semen parameters concerns ~10% of men (Jungwirth et al, 2012; Datta et al, 2016). The most widely considered genetic factors are karyotype abnormalities (up to 17% of patients) and recurrent de novo microdeletions of the Y-chromosomal Azoospermia Factor a (AZFa) (~0.8 Mb), AZFb (~6.2 Mb), and AZFc (~3.5 Mb) regions (2–10%) (Punab et al, 2017; Olesen et al, 2017; Tuttelmann et al, 2011). For more than 15 years, testing for AZF deletions has been strongly recommended in the diagnostic workup for infertility patients with sperm concentration of

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Conclusion