Y chromosome microdeletions and haplotypes

The human Y chromosome contains a number of genes and gene families that are necessary for spermatogenesis. Many of these genes are embedded in repetitive elements that are subject to deletion events. Deletions of azoospermia factor (AZF) regions AZFa, AZFb, and AZFc are found in approx 10-15% of men with either unexplained severe oligozoospermia or azoospermia. These deletions fall on different Y chromosome backgrounds and there is no evidence for a link between a Y-chromosome lineage and the presence or absence of an AZF deletion. Several partial AZFc deletions,have been described. One of these, which removes around half of all the genes within the AZFc region, appears to be present as in inconsequential polymorphism in populations of northern Eurasia. A second deletion, termed gr/gr, results in the absence of several AZFc genes and has been suggested to be a genetic risk factor for spermatogenic failure. However, the link between the gr/gr deletion and infertility is more complex. First, the gr/gr deletion is actually not a single type of deletion but a combination of deletions that vary in size and complexity and result in the absence of different members of the deleted azoospermia (DAZ) gene family as well as other AZFc genes, such as CDY1. Second, there are regional or ethnic differences in the frequency of gr/gr deletions. In some Y-chromosome lineages, these deletion appear to be fixed and may have little influence on spermatogenesis. Third, these observations have influenced a number of association. studies aimed to determine the relationship between the gr/gr deletion and male infertility. Consequently, some studies suggest that the gr/gr deletion confers a strong genetic susceptibility to reduced sperm counts, whereas others suggest that the genetic susceptibility may not exist or be limited to specific Y-chromosome haplotypes. Clearly there is need for additional studies that combine an analysis of a series of markers in the AZFc region together with the haplotype of the Y chromosome in well-defined case and control populations. Many of the genes in the AZFc region present in multiple copies and gr/gr deletions can be associated with reciprocal duplication events. Therefore, there is a need to determine gene dosage if the relationship between gr/gr deletions and infertility is to be completely understood.