Letter to Jmg

Y chromosome microdeletions are the most frequent genetic cause of severe oligozoospermia (,5 million spermatozoa/ml) and azoospermia (absence of spermatozoa in the ejaculate). Microdeletions associated with infertility occur in specific regions of the long arm of the Y chromosome, called azoospermia factor (AZF) regions. 3 In 1996, three types of AZF deletion (AZFa, AZFb, and AZFc) were described by Vogt et al; however, after the complete physical map and sequence of the AZFb and AZFc regions was produced, it became evident that the AZFb and AZFc intervals partially overlap. The Y chromosome is extremely rich in repetitive sequences, organised in amplicons. Ampliconic sequences are characterised by sequence pairs showing nearly complete (.99.9%) nucleotide identity, organised in massive palindromes. These repeated sequences may undergo genetic exchange through gene conversion— that is, non-reciprocal transfer of sequence information occurring between duplicated sequences within the chromosome, a process that could account for the .99.9% nucleotide identity between the arms of a palindrome. Although this mechanism may serve to preserve Y chromosome genes from the gradual accumulation of deleterious mutations and thus prolong their genetic fitness, this peculiar organisation also provides the structural basis for deletions and rearrangements. The classical AZFc deletion, which removes 3.5 Mb between the b2/b4 amplicons, is the most frequent type of deletion. Taking into consideration the Y chromosome structure and the suggested deletion mechanism, a number of other possible partial deletions have been proposed in both the AZFb and AZFc regions. 8 The frequency and the pathological significance of these partial deletions is not yet clear, although recently a partial deletion termed gr/gr has been described specifically in infertile men with varying degrees of spermatogenic failure. 10 This deletion removes half the AZFc gene content, including two copies of the major AZFc candidate gene called DAZ. Another deletion, named b2/b3 or u3-gr/gr or g1/g3, which removes a similar quantity of AZFc genes, seems to have no effect on fertility status in association with a certain Y chromosome background commonly present in northern Eurasian populations (Y haplogroup N). 13 A similar conclusion can also be drawn for the gr/gr deletion found in association with Hgr D2b, which is present in 20% of Japanese men. One of the possible explanations for the heterogeneous phenotype observed in association with complete and partial AZFc deletions is that polymorphisms or mutations are present in the autosomal homologue of DAZ, DAZL. Indeed, the finding that the human DAZ transgene is able to partially rescue the spermatogenic failure of mice homozygous for a null allele of Dazl suggests a possible interplay between DAZL and DAZ in humans. In the case of partial AZFc deletions, we can also speculate that the type and number of missing gene copies or other unknown Y chromosome related factors (for example duplications or beneficial mutations in other parts of the Y chromosome) may also influence the phenotype. The aims of this study were: (a) to establish the clinical significance of partial AZFc deletions (that is, if any of them are specific for spermatogenic failure or can be considered a risk factor); and (b) to gain insight through a combined approach (quantitative and qualitative analysis of DAZ and CDY, definition of Y chromosome haplogroup, and mutational analysis of DAZL in men with partial AZFc deletion) into the molecular basis of the heterogeneous phenotype described in men bearing partial AZFc deletions.