The AZFc region of the Y chromosome: at the crossroads between genetic diversity and male infertility

Abstract

BACKGROUNDThe three azoospermia factor (AZF) regions of the Y chromosome represent genomic niches for spermatogenesis genes. Yet, the most distal region, AZFc, is a major generator of large-scale variation in the human genome. Determining to what extent this variability affects spermatogenesis is a highly contentious topic in human reproduction.METHODSIn this review, an extensive characterization of the molecular mechanisms responsible for AZFc genotypical variation is undertaken. Such data are complemented with the assessment of the clinical consequences for male fertility imputable to the different AZFc variants. For this, a critical re-evaluation of 23 association studies was performed in order to extract unifying conclusions by curtailing methodological heterogeneities.RESULTSIntrachromosomal homologous recombination mechanisms, either crossover or non-crossover based, are the main drivers for AZFc genetic diversity. In particular, rearrangements affecting gene dosage are the most likely to introduce phenotypical disruptions in the spermatogenic profile. In the specific cases of partial AZFc deletions, both the actual existence and the severity of the spermatogenic defect are dependent on the evolutionary background of the Y chromosome.CONCLUSIONSAZFc is one of the most genetically dynamic regions in the human genome. This property may serve as counter against the genetic degeneracy associated with the lack of a meiotic partner. However, such strategy comes at a price: some rearrangements represent a risk factor or a de-facto causative agent of spermatogenic disruption. Interestingly, this precarious balance is modulated, among other yet unknown factors, by the evolutionary history of the Y chromosome.

Susceptibility of gr/gr rearrangements to azoospermia or oligozoospermia is dependent on DAZ and CDY1 gene copy deletions

“…In accordance with previous studies [13,[20][21][22], the gr/gr deletions were found to be most prevalent whereas the b1/b3 and b2/b3 deletions were of rare occurrence in the Indian population. Amongst these, the frequency of gr/gr but not b1/b3 and b2/b3 deletions was significantly higher in men with azoospermia or oligozoospermia as compared to fertile controls, none of the individuals had b2/b4 deletions.…”

“…The OR for gr/gr deletions is 2.8 and 5.7 for b1/b3 deletion in infertile men. This OR is higher as compared to those reported in meta-analyses and large p<0.05 is considered as statistically significant Pregnancy rate (%) 59 (25.7) 3 (30) n are the number of men assessed in each group population-based studies [20,21,25,26] suggesting that both gr/gr and b1/b3 deletions are strong predisposing factors for male infertility in Indian population. Although gr/gr and b1/b3 deletions seem to be a risk factor for male infertility, there are normozoospermic fertile men with AZFc subdeletions, moreover b2/b3 deletions which remove almost identical amount of genetic material (and the same genes) do not predispose an individual to male infertility.…”

“…While in some studies the frequency of AZFc subdeletions (mainly the gr/gr) is higher in infertile men as compared to fertile controls [5,11,[20][21][22]; others have failed to confirm this association [23,24]. Based on four meta-analysis studies and a large population study involving >20,000 individuals it appears that the gr/gr deletion is a risk factor for male infertility [13,20,21,25,26]; the odds ratio is estimated to be 1.4-2.4 [5,20,21,25,26].…”

“…It has been observed that the Europeans and the Han Chinese have a strong association of gr/gr deletions with male infertility [11,22,27]; the American and African men with gr/gr deletions do not seem to be susceptible to azoospermia or oligozoospermia [20,21,[28][29][30]. In the Asian population, the gr/gr deletions are not associated with male infertility in the Malaysian and Japanese men; a significant association has been observed in the Korean and Chinese men [20,21,27,[31][32][33]. In the context of Indian population, the association of AZFc subdeletions and male infertility is unclear.…”

Efficient combined FISH and PRINS technique for detection of DAZ microdeletion in human sperm

“…About 15-20 % of azoospermia and 7-10 % of oligozoospermia patients have microdeletion in AZFc region [10]. There is a variety of genes in this region from which DAZ (Deleted in Azoospermia) gene is the most susceptible candidate for deletion in oligozoospermia and azoospermia males [11]. Since the development of assisted reproduction technology, intracytoplasmic sperm injection (ICSI) now offers an effective therapeutic option for these men and is believed to allow transmission of genetically determined infertility to the male offspring [12].…”