Early Clues to Yq Complexity

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As attempts to identify AZF genes progressed, it became clear that several lines of evidence could not be incorporated into a simple picture of an intact "normal" Y chromosome with sporadic deletion mutations leading to azoospermia.

Phenotypic Variability

The sperm count associated with any Y-chromosomal genotype is variable. The variation within a single individual has been previously mentioned, so it should not be surprising that considerable variation is also seen in the phenotypes of individuals with deletions that are indistinguishable at the molecular level. Nevertheless, it is striking that men with AZFc deletions, where independent events lead to a common structure (see The AZFc Deletion) and are usually associated with spermatogenic failure, can occasionally conceive children naturally

(6-9). In one family, an AZFc-deleted man fathered four sons, the last at the age of 38, although at the time of analysis when he was aged 63, he was azoospermic (7); the three sons tested were all oligozoospermic. These observations underscore the complexity of the relationship between microdeletions and fertility. Moreover, fertility is a property of couples, not individual males, so there are many additional genetic and environmental factors that can complicate the relationship between low sperm count and fertility.

Polymorphic Deletions and Duplications

Y-chromosomal deletions have also been found in the population as polymorphisms. For example, deletion of the locus 50f2/C within the AZFc region (now known to be part of the single-copy sequence "u3" that is also removed by de novo azoospermia-associated deletions; see Fig. 2) was initially reported in the normal father of a 46,XY female (10), and further investigation showed that both deletion and duplication of this locus were common: 6.4 and 1.4%, respectively, in a worldwide sample (11). Furthermore, different sequences were codeleted or coduplicated with 50f2/C in different individuals, and when the haplotypic background was taken into account, six independent deletion events and four duplications could be identified. Although the spermatogenic status of the men investigated was unknown, one deletion was present at approx 55% in the Finns, and thus was unlikely to be associated with spermatogenic failure.

Surveys of infertile patients and controls (either fertile or normozoospermic individuals) provided further examples of deletions that were not associated with azoospermia, either because they were found only in controls, or were transmitted by the fathers of infertile patients. In one large-scale evaluation using 48 STSs and 920 fertile individuals, 11 men (1.2%) were found to show deletions of single STSs that removed one of four different loci (12). One of these was Amelogenin on Yp, but the other three (sY207, sY269, and sY272) are repeated sequences with copies lying withinAZFb or AZFc, as defined at that time. These four deletions were assumed to represent polymorphisms, but in the same study, deletions of other single STSs (e.g., sY75, sY126) were found only in infertile patients. Are these related to the patient's infertility or not?

Deletion Map Complexities: AZFd

Interpretation of the meaning and order of the intervals defined by deletion mapping proved to be difficult, irrespective of the phenotype associated with any particular deletion. These complexities are illustrated by the proposed designation of a fourth deletion interval, AZFd. This was identified by Kent-First et al. in a study of 514 infertile males (12). Six men who retained DAZ lacked only one STS, sY152, and eight lacked only the adjacent STS, sY153; one of the latter deletions was a de novo event. This was taken as evidence for a distinct deletion interval located between AZFb and AZFc. Yet on the finished sequence (1), all copies of sY152 and sY153 are located within AZFc as defined by the common b2/b4 deletion (Fig. 2). Current European guidelines for molecular diagnosis of Y-chromosomal microdeletions consider that "a putative fourth AZFd region postulated by Kent-First et al. . . . does not exist" (13). The deletion maps and yeast artificial chromosome contigs in many repeated parts of Yq that were available at the time have not been scrutinized in such detail, but may be equally unreliable.

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