Study On The Role Of The Y Chromosome AZFc Structural Variations On Spermatogenic Failure And Its Mechanism

It is estimated that about 9~15% of couples suffer from infertility and roughly half of these cases are due to the man's problem. Related studies have demonstrated that the sperm quality declined remarkably in half a century. The spermatogenic failure has already become the most common cause for male infertility, from which about 30% are genetic abnormalities caused.Since the concept of Azoospermia Factor (AZF) was proposed by Tiepolo et al. in 1976, Y chromosome microdeletion has become one of the most important genetic factors for spermatogenic failure. The AZF, which located in three different regions of the Y chromosome, termed AZFa, AZFb and AZFc are recurrently deleted in about 10% of cases of abnormospermia. Amony which, the AZFc deletions form the majority of these deletions (80%).Recently, many structural variations, including deletion, inversion, duplication, and etc., have been reported in AZFc. The AZFc deletion patterns include AZFc complete deletion and partial deletion. The complete AZFc deletion is one of the most common causes of spermatogenic failure, while the roles of partial AZFc deletions (gr/gr deletion and b2/b3 deletion) in spermatogenesis are controversial.Several studies have demonstrated that the influence of AZFc partial deletion to spermatogenesis varied across population. Namely the genetic background of Y chromosome affect the distributions of AZFc partial deletion. Therefore, Y haplogrouping is highly recommended for studies on Y-linked disease, such as spermatogenic failure.In this study, in order to investigate the roles of these AZFc structural variations in spermatogenic failure, we performed deletion typing, quantitative analysis of DAZ gene copies, and Y chromosome haplogrouping in seven pedigrees of complete AZFc deletion carriers, 736 infertile and 391 healthy men in Chinese. We found that both the b2/b3 partial deletion and the DAZ3/4+CDY1a deletion pattern were associated with spermatogenic failure.After the detection of deletion patterns of seven pedigrees, we observed that a complete AZFc deletion was derived from partial deletion, suggesting that complete deletions of AZFc can be preceded with partial deletions. We also found that the frequency of complete AZFc deletion in haplogroups (with high frequency of partial deletions) was significantly higher than that in the other haplogroups (with low frequency of partial deletions). Namely, the partial AZFc deletions can increase the risk of complete AZFc deletion. In our following study, we found the predisposition differences of partial deletions (gr/gr and b2/b3) to complete AZFc deletion. Our 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. The relationship between partial AZFc deletions and complete AZFc deletion deserves further examination, especially those with a relatively high frequency of b2/b3 and gr/gr partial deletions.In addition, the duplications of DAZ gene (not only pure partial duplication, but also duplication followed by partial deletion) have also be found . In the process of duplication, the copy numbers of key gene have changed as well. Our results suggested that abnormally high copy numbers of DAZ gene are likely to increase the risk of spermatogenic failure.