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

Author:

Hallast Pille12ORCID,Kibena Laura1,Punab Margus34,Arciero Elena2,Rootsi Siiri5,Grigorova Marina1,Flores Rodrigo5,Jobling Mark A6,Poolamets Olev3,Pomm Kristjan3,Korrovits Paul3,Rull Kristiina147,Xue Yali2,Tyler-Smith Chris2,Laan Maris1ORCID

Affiliation:

1. Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia

2. Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, Cambridge, United Kingdom

3. Andrology Unit, Tartu University Hospital, Tartu, Estonia

4. Institute of Clinical Medicine, University of Tartu, Tartu, Estonia

5. Institute of Genomics, Estonian Biocentre, University of Tartu, Tartu, Estonia

6. Department of Genetics & Genome Biology, University of Leicester, Leicester, United Kingdom

7. Women’s Clinic, Tartu University Hospital, Tartu, Estonia

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.

Funder

Estonian Research Council

Wellcome Trust

European Regional Development Fund

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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