Microdeletions in the azoospermia factor (AZF) regions on the long arm of the human Y chromosome are known to be associated with spermatogenic failure. Although AZFc is recurrently deleted in azoospermic or oligozoospermic males, no definitive conclusion has been reached for the contribution of different partial AZFc deletions to spermatogenic failure. To further investigate the roles of partial deletions in spermatogenic failure and the relationship between the complete and partial AZFc deletions, we performed deletion typing and Y chromosome haplogrouping in 756 idiopathic infertile Han-Chinese and 391 healthy Han-Chinese. We found that both the b2/b3 partial deletion and the DAZ3/4+CDY1a deletion pattern were associated with spermatogenic failure. We also confirmed that two previously reported fixations, the b2/b3 deletion in haplogroup N1 and the gr/gr deletion in haplogroup Q1. Remarkably, the frequency of the complete AZFc deletion in haplogroup N1 was significantly higher than that in the haplogroup Q1. These results suggest that the b2/b3 partial deletion was associated with a higher risk of complete AZFc deletion compared with the gr/gr partial deletion. Compared with the gr/gr deletion, the b2/b3 deletion presents a shorter distance among recombination targets and longer recombination substrates, which may be responsible for the increased incidence of subsequent recombination events that can lead to the complete AZFc deletion in this Chinese study population. The susceptibility of the b2/b3 partial deletion to the complete AZFc deletion deserves further investigation in larger and diverse populations, especially those with a relatively high frequency of b2/b3 and gr/gr partial deletions.

BackgroundThe mismatch repair (MMR) pathway plays an important role in the maintenance of the genome integrity, meiotic recombination and gametogenesis. This study investigated whether genetic variations in MMR genes are associated with an increased risk of sperm DNA damage and male infertility.MethodsWe selected and genotyped 21 tagging single nucleotide polymorphisms (SNPs) in five MMR genes (MLH1, MLH3, PMS2, MSH4 and MSH5) using the SNPstream 12-plex platform in a case-control study of 1,292 idiopathic infertility patients and 480 fertile controls in a Chinese population. Sperm DNA damage levels were detected with the Tdt-mediated dUTP nick end labelling (TUNEL) assay in 450 cases. Fluorescence resonance energy transfer (FRET) and co-immunoprecipitation techniques were employed to determine the effects of functional variants.ResultsOne intronic SNP in MLH1 (rs4647269) and two non-synonymous SNPs in PMS2 (rs1059060, Ser775Asn) and MSH5 (rs2075789, Pro29Ser) seem to be risk factors for the development of azoospermia or oligozoospermia. Meanwhile, we also identified a possible contribution of PMS2 rs1059060 to the risk of male infertility with normal sperm count. Among patients with normal sperm count, MLH1 rs4647269 and PMS2 rs1059060 were associated with increased sperm DNA damage. Functional analysis revealed that the PMS2 rs1059060 can affect the interactions between MLH1 and PMS2.ConclusionsOur results provide evidence supporting the involvement of genetic polymorphisms in MMR genes in the aetiology of male infertility.

No abstract