The relatively simple relationship observed for AZFa and AZFc between a deletion interval mapped using STSs and a single common deletion structure does not hold true for AZFb. There are at least two recurrent deletions that remove the AZFb interval defined by STS mapping, as well as additional nonrecurrent deletions (30). All of these deletions also remove part of the AZFc region, suggesting that the AZFb interval is not a discrete block as was originally supposed (6). NAHR is again the most likely mechanism underlying the recurrent deletions, although the lack of homology at the breakpoints of a nonrecurrent deletion indicates a low background level of nonhomologous recombination.
As with AZFc, the direct repeats responsible for both of the recurrent deletions lie within different palindromes in distal Yq. The 6.2-Mb recurrent deletion that removes only a small portion of the AZFc locus in addition to the AZFb region occurs between approx 100-kb direct repeats that reside in the proximal copies of palindromes P1 and P5 (30) (see Fig. 3). The 7.7-Mb recurrent deletion that removes a much greater proportion of the AZFc region occurs between the corresponding repeats in the distal copies of palindromes P1 and P5 (Fig. 3). There is evidence that within the approx 100-kb repeats lies a 933-bp hotspot in which the deletion breakpoints are preferentially located, although more AZFb-deleted chromosomes need to be characterized at the sequence level for unambiguous identification of hotspot activity.
Twenty-one protein-coding genes and 11 non-coding transcripts are removed by the proximal P1/P5 deletion, which represents all the family members of 15 different genes (20,30). In the larger distal P1/P5 deletion, an additional four protein-coding genes and six non-coding transcripts are deleted, with the result that 19 gene families are lost in their entirety.
When overlapping deletions elsewhere in the genome result in similar phenotypes, it is usual to assume that the critical genes underlying the phenotype map to the region of overlap. This viewpoint has not been adopted for the overlapping AZFb/AZFc deletions causing male infertility on Yq, probably for historical reasons. The overlap of the deletions contains only members of gene families and not entire families. Is loss of these members primarily responsible for the phenotype, with modifications by flanking genes, or do similar phenotypes arise from the loss of genes in the nonoverlapping regions?
Further AZFb Complexity: 50f2/E Duplications
Perhaps unsurprisingly in view of the AZFc complexity, there are hints of a greater variety of AZFb rearrangements. One case of a duplication involving both 50f2/C (Fig. 2) and a second locus approx 1.4 Mb proximal, 50f2/E, was detected in a population screen of 595 normal individuals (11), and may represent an example of one of the predicted P1/P5 duplications (31). It seems likely that systematic searches would reveal a wealth of further inversions, duplications, and deletions.
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