Deletion Mapping of AZF Loci on the Y Chromosome

The idea that azoospermia was linked to the Y chromosome was initially established by the cytogenetic observations of Tiepolo and Zuffardi in 1976 (3), who detected visible deletions of the distal euchromatic region of Yq in 5/1170 infertile males and an additional male of unknown fertility; four of the six were de novo events. The authors, therefore, presciently suggested that factors (in the plural, later designated AZFs for Azoospermia Factors) controlling spermatogenesis were contained within the deleted region. The availability of DNA hybridization probes and subsequently sequence-tagged sites (STSs) detecting Y-specific loci allowed the construction of deletion maps from rearranged chromosomes (4). Deletion mapping provides a clear ordering of loci into deletion intervals when the underlying sequences are

Fig. 1. Distribution of sperm counts in fertile and infertile men. Note the broad ranges and overlap between the two samples. (Modified from data in ref. 42.)

unique, but the results can be misleading when the sequences are present in multiple copies. Some regions of the Y chromosome are entirely multicopy and difficulties in deletion map interpretation underlie some of the problems discussed below. Individuals with cytogeneti-cally normal Ys and idiopathic infertility were characterized using this approach, and microdeletions were identified in a subset of them; however, these did not all overlap (5). An extensive compilation of data from 370 men with azoospermia or oligozoospermia led to a widely held view that three nonoverlapping deletions, designated AZFa, AZFb, and AZFc in the order centromere to Yq telomere, could be defined (6). It was expected that further work would refine the locations of the individual genes within these intervals that were responsible for the spermatogenic failure, using a combination of finer deletion mapping and the subsequent detection of point mutations. Although this expectation has been largely fulfilled for AZFa (see The AZFa Deletion), the AZFb and AZFc intervals have proved more refractory to analysis and the identity of the key genes within them remains unclear.

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