A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans
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 th...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/65420 |
| _version_ | 1828384553254780928 |
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| author | Pille Hallast Laura Kibena Margus Punab Elena Arciero Siiri Rootsi Marina Grigorova Rodrigo Flores Mark A Jobling Olev Poolamets Kristjan Pomm Paul Korrovits Kristiina Rull Yali Xue Chris Tyler-Smith Maris Laan |
| author_facet | Pille Hallast Laura Kibena Margus Punab Elena Arciero Siiri Rootsi Marina Grigorova Rodrigo Flores Mark A Jobling Olev Poolamets Kristjan Pomm Paul Korrovits Kristiina Rull Yali Xue Chris Tyler-Smith Maris Laan |
| author_sort | Pille Hallast |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T05:05:11Z |
| format | Article |
| id | doaj.art-8edcf883b35d416381d5dc683d243d22 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-12-10T05:05:11Z |
| publishDate | 2021-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-8edcf883b35d416381d5dc683d243d222022-12-22T02:01:16ZengeLife Sciences Publications LtdeLife2050-084X2021-03-011010.7554/eLife.65420A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humansPille Hallast0https://orcid.org/0000-0002-0588-3987Laura Kibena1Margus Punab2Elena Arciero3Siiri Rootsi4Marina Grigorova5Rodrigo Flores6Mark A Jobling7Olev Poolamets8Kristjan Pomm9Paul Korrovits10Kristiina Rull11Yali Xue12Chris Tyler-Smith13Maris Laan14https://orcid.org/0000-0002-8519-243XInstitute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, Cambridge, United KingdomInstitute of Biomedicine and Translational Medicine, University of Tartu, Tartu, EstoniaAndrology Unit, Tartu University Hospital, Tartu, Estonia; Institute of Clinical Medicine, University of Tartu, Tartu, EstoniaWellcome Genome Campus, Wellcome Sanger Institute, Hinxton, Cambridge, United KingdomInstitute of Genomics, Estonian Biocentre, University of Tartu, Tartu, EstoniaInstitute of Biomedicine and Translational Medicine, University of Tartu, Tartu, EstoniaInstitute of Genomics, Estonian Biocentre, University of Tartu, Tartu, EstoniaDepartment of Genetics & Genome Biology, University of Leicester, Leicester, United KingdomAndrology Unit, Tartu University Hospital, Tartu, EstoniaAndrology Unit, Tartu University Hospital, Tartu, EstoniaAndrology Unit, Tartu University Hospital, Tartu, EstoniaInstitute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia; Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; Women’s Clinic, Tartu University Hospital, Tartu, EstoniaWellcome Genome Campus, Wellcome Sanger Institute, Hinxton, Cambridge, United KingdomWellcome Genome Campus, Wellcome Sanger Institute, Hinxton, Cambridge, United KingdomInstitute of Biomedicine and Translational Medicine, University of Tartu, Tartu, EstoniaMale 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.https://elifesciences.org/articles/65420idiopathic male infertilityy-chromosomal azfc regiongr/grb2/b3 deletionscomplex structural rearrangementsy haplogroup r1a1-m458 |
| spellingShingle | Pille Hallast Laura Kibena Margus Punab Elena Arciero Siiri Rootsi Marina Grigorova Rodrigo Flores Mark A Jobling Olev Poolamets Kristjan Pomm Paul Korrovits Kristiina Rull Yali Xue Chris Tyler-Smith Maris Laan A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans eLife idiopathic male infertility y-chromosomal azfc region gr/gr b2/b3 deletions complex structural rearrangements y haplogroup r1a1-m458 |
| title | A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans |
| title_full | A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans |
| title_fullStr | A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans |
| title_full_unstemmed | A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans |
| title_short | A common 1.6 mb Y-chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans |
| title_sort | common 1 6 mb y chromosomal inversion predisposes to subsequent deletions and severe spermatogenic failure in humans |
| topic | idiopathic male infertility y-chromosomal azfc region gr/gr b2/b3 deletions complex structural rearrangements y haplogroup r1a1-m458 |
| url | https://elifesciences.org/articles/65420 |
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