Abstract
The azoopsermia factor c (AZFc) region of human Y-chromosome is an essential genomic segment for spermatogenesis with frequent non-allele homologous recombination (NAHR). Recent case-control studies on the association of the NAHR-based AZFc structural mutations with spermatogenic failure produced inconsistent results. To more precisely evaluate their spermatogenesis effects, we investigated the correlation between the subdivided AZFc mutations and sperm production in 3,439 Han Chinese males. Our results showed that both partial AZFc deletion-only and primary duplication mutation presented a significant risk for decreased sperm production. Restoration of the reduced dosage of the AZFc content to the normal level had a milder effect, whereas an overdose of the AZFc content arising from multiple duplications of a partial AZFc-deleted structure produced a more serious consequence compared to the partial deletion-only mutation. Additionally, the AZFc-mutated structures with excessive NAHR-substrate showed a notably negative effect on spermatogenesis. These results suggest that the recurrent NAHR-based AZFc mutations may be associated with decreased spermatogenesis efficiency in present population. More significantly, our finding implies that the overdose of AZFc NAHR-substrate may produce an additional risk for the massive AZFbc deletions during the multi-stage division process of germ cells and thus impair the global spermatogenesis efficiency in the carriers.
Highlights
Frequent non-allele homologous recombination (NAHR)[2,3]
Among the 3 AZF regions, the Azoospermia factor c (AZFc) region possesses the highest mutation rate resulting in a wide variety of NAHR-based structural deletions and duplications[3]
With the accumulation of data regarding the correlation of AZFc mutations to the spermatogenic phenotype, two issues have been clarified: the b2/b4 deletion, that is found exclusively in infertile males, is the known most common molecular cause for severe spermatogenic failure, and partial AZFc deletions confer a significant risk for impaired spermatogenesis[1,19,21,22]
Summary
Frequent non-allele homologous recombination (NAHR)[2,3]. Recent population-based association studies suggest that several recurring partial AZFc deletions (b1/b3, b2/b3, and gr/gr deletions with or without secondary duplication) and primary AZFc duplications (without deletion and duplication only) may impair spermatogenesis[1,4,5,6,7,8,9,10,11,12], further supporting the theory that structural mutations in the AZFc region play a significant role in modulating spermatogenic output. A detailed subtyping of AZFc structural mutations was performed using a complete experimental procedure including AZFc-STS (sequence tagged sites) detection, AZFc gene copy analysis, and dosage analysis of deleted in azoospermia (DAZ), chromodomain protein, Y chromosome, 1 (CDY1) and basic protein, Y chromosome, 2 (BPY2). These analyses were performed in males with AZFc deletions and primary duplications who were screened from among 3,439 unrelated Han Chinese males, including 891 patients with idiopathic azoospermia, 1,366 patients with idiopathic oligozoospermia, and 1,182 controls with normozoospermia. The correlations between the subdivided AZFc structural mutations and sperm production, including sperm concentration and total motile sperm count (TMC) were investigated to evaluate their influence on spermatogenesis efficiency
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