Article Text
Abstract
Background: Complete deletion of the complete AZFc interval of the Y chromosome is the most common known genetic cause of human male infertility. Two partial AZFc deletions (gr/gr and b1/b3) that remove some copies of all AZFc genes have recently been identified in infertile and fertile populations, and an association study indicates that the resulting gene dose reduction represents a risk factor for spermatogenic failure.
Methods: To determine the incidence of various partial AZFc deletions and their effect on fertility, we combined quantitative and qualitative analyses of the AZFc interval at the DAZ and CDY1 loci in 300 infertile men and 399 control men.
Results: We detected 34 partial AZFc deletions (32 gr/gr deletions), arising from at least 19 independent deletion events, and found gr/gr deletion in 6% of infertile and 3.5% of control men (p>0.05). Our data provide evidence for two large AZFc inversion polymorphisms, and for relative hot and cold spots of unequal crossing over within the blocks of homology that mediate gr/gr deletion. Using SFVs (sequence family variants), we discriminate DAZ1/2, DAZ3/4, CDY1a (proximal), and CDY1b (distal) and define four types of DAZ-CDY1 gr/gr deletion.
Conclusions: The only deletion type to show an association with infertility was DAZ3/4-CDY1a (p = 0.042), suggesting that most gr/gr deletions are neutral variants. We see a stronger association, however, between loss of the CDY1a SFV and infertility (p = 0.002). Thus, loss of this SFV through deletion or gene conversion could be a major risk factor for male infertility.
- CEPH, Centre d’étude du polymorphisme humain
- FISH, fluorescent in situ hybridisation
- ICSI, intracytoplasmic sperm injection
- SFV, sequence family variant
- AZFc
- gene deletion
- male infertility
- sequence family variant
- Y chromosome
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Footnotes
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This work was supported by funding from the French national medical research body, Inserm. NS was supported by a studentship from the Ministère de l’Education Nationale, de l’Enseignement Supérieur et de la Recherche (MENESR) and a grant from the Fondation Médicale pour la Recherche.
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Conflict of interest: none declared.
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The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint first authors.
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