A Large AZFc Deletion Removes DAZ3/DAZ4 and Nearby Genes from Men in Y Haplogroup N

Abstract

Deletion of the entire AZFc locus on the human Y chromosome leads to male infertility. The functional roles of the individual gene families mapped to AZFc are, however, still poorly understood, since the analysis of the region is complicated by its repeated structure. We have therefore used single-nucleotide variants (SNVs) across approximately 3 Mb of the AZFc sequence to identify 17 AZFc haplotypes and have examined them for deletion of individual AZFc gene copies. We found five individuals who lacked SNVs from a large segment of DNA containing the DAZ3/DAZ4 and BPY2.2/BPY2.3 gene doublets in distal AZFc. Southern blot analyses showed that the lack of these SNVs was due to deletion of the underlying DNA segment. Typing 118 binary Y markers showed that all five individuals belonged to Y haplogroup N, and 15 of 15 independently ascertained men in haplogroup N carried a similar deletion. Haplogroup N is known to be common and widespread in Europe and Asia, and there is no indication of reduced fertility in men with this Y chromosome. We therefore conclude that a common variant of the human Y chromosome lacks the DAZ3/DAZ4 and BPY2.2/BPY2.3 doublets in distal AZFc and thus that these genes cannot be required for male fertility; the gene content of the AZFc locus is likely to be genetically redundant. Furthermore, the observed deletions cannot be derived from the GenBank reference sequence by a single recombination event; an origin by homologous recombination from such a sequence organization must be preceded by an inversion event. These data confirm the expectation that the human Y chromosome sequence and gene complement may differ substantially between individuals and more variations are to be expected in different Y chromosomal haplogroups.

Quantitative PCR technique for the identification of microrearrangements of the AZFc region

“…Indeed, "gr-gr" deletion frequency was significantly higher in the infertile group than in the control. Studies have presented "b2-b3" deletion as a polymorphism not associated with a spermatogenesis failure [10]. Only 1 "gr-gr" deletion was found in our fertile population [3.3%], and this finding is in agreement with recent studies.…”

“…The effect of AZFc microrearrangements on male fertility, in particular partial deletions, is still under discussion. Indeed, partial deletions have mainly been detected in infertile men, but several papers indicated that they were also found in fertile control men [5,[10][11][12][26][27][28]. Moreover, differences have been made between the incidence of "gr-gr" deletion and "b2-b3" deletion.…”

“…Recently, partial deletions affecting the AZFc region were identified and involve homologous recombination between "gr-gr" fragments, "b2-b3" fragments (or g1-g3) or "b1-b3" fragments ( Fig. 1) [3,5,10]. Contrary to "complete" AZF deletions, the clinical relevance of partial deletion is still discussed.…”

“…Contrary to "complete" AZF deletions, the clinical relevance of partial deletion is still discussed. Indeed, several studies have shown the existence of partial AZFc deletions responsible for the loss of one cluster of the DAZ genes in fertile men [10][11][12]. In addition to deletion, duplication events and deletion followed by duplication events were identified, but their consequence in male infertility are unknown [3,5,11,[13][14][15].…”

Yq MICRODELETIONS IN IDIOPATHIC MALE INFERTILITY

“…The AZFc region is prone to many smaller subdeletions (eg: gr/ gr, b2/b3) that are thought to be caused by intrachromosomal recombination [28]. The heterogeneities recorded for partial AZFc deletions reflect on two different levels (i) when comparing between different partial patterns (ii) when analysing phenotype diversity associated with single pattern [29,30]. More detailed analysis should be done to diagnose the type of partial deletions according to the ethnic population as in certain populations such sub deletions have been found in.…”