The Human Y Chromosome Azfc Structural Changes In Spermatogenesis

The AZFc region on human Y chromosome has been found to be functionallyimportant in spermatogenesis. Many structural variations, including deletion,inversion, duplication, and etc., have also been reported in AZFc. Complete AZFcdeletion is one of the most frequent causes of male infertility, while roles of tworecently identified partial AZFc deletions (gr/gr deletion and b2/b3 deletion) inspermatogenesis are controversial.To further study the roles of these AZFc structural variations in spermatogenicimpairment, we typed these deletions, did quantitative analysis of DAZ gene copies,and performed Y chromosome haplogrouping in seven pedigrees of complete AZFcdeletion carriers, 296 infertile and 280 healthy men in Chinese. Neither gr/gr deletionnor b2/b3 deletion was found to be associated with spermatogenic failure. In fact, oursurvey of 15 populations from 8 ethnic groups suggested partial AZFc deletion isfrequent in Chinese. Combined with previous reports, our data suggested thespermatogenic roles of partial AZFc deletions vary across population.To study the mechanism underlying this phenomenon, we first checked thepossibility of functional difference between DAZ gene copies. The DAZ1/DAZ2deletion was detected as the primary subtype of the gr/gr deletion in this study, thoughthis doublet was considered to be crucial for normal spermatogenesis in Europeans.We also checked the effect of genetic background of Y chromosome and found thefrequencies of AZFc deletions varied greatly in Y haplogroups (hg). In addition, weidentified a new gr/gr-deleted Y haplogroup Q1 and confirmed the reported fixation ofb2/b3 deletion in hg N as well. Therefore, Y haplogrouping is highly recommendedfor studies on Y-linked disease, such as spermatogenic failure.Interestingly, in one of seven pedigrees, we observed that a complete AZFcdeletion was derived from gr/gr deletion, suggesting that complete deletions of AZFccan be preceded with partial deletions. We also showed that the frequency of completeAZFc deletion in hg Q1 and N was significantly higher than that in the otherhaplogroups with less partial deletions. To date, these observations are the firstevidences showing that partial AZFc deletions can increase the risk of complete AZFcdeletion. The susceptibility of partial AZFc deletions to complete AZFc deletiondeserves further examination, especially in the populations or Y haplogroupsabundant in partial AZFc deletions.Duplications of DAZ gene copy have also been observed in this study, and abnormally high copy numbers of DAZ are likely to increase the risk of spermatogenic failure. Since the Dosage Effect Model is challenged by the inconsistent effects of partial AZFc deletions, we propose a new hypothesis on the role of AZFc multi-copy genes in spermatogenesis, Mutation Accumulation Model. This model suggested that mutation accumulation, not dosage reduction, is responsible for the reported association of some AZFc structural variations with spermatogenic failure in some populations. Our new model is able to explain all the previously reported findings in AZFc.