Deletion of azoospermia factor a (AZFa) region of human Y chromosome caused by recombination between HERV15 proviruses

Deletion of any of three regions of the human Y chromosome results in sperm atogenic failure and infertility, Vile previously sequenced one of these re gions, azoospermia factor a (AZFa) and found that it spanned similar to 800 kb. By sequence-tagged site (STS) content mapping, we roughly defined dele tion breakpoints in two unrelated, azoospermic men with AZFa deletions. The positions of proximal and distal breakpoints were similar in the two men. Hypothesizing that the deletions might have been generated by homologous re combination, we searched electronically for DNA sequence similarities betwe en the proximal and distal breakpoint regions. These comparisons revealed t he most striking sequence similarities anywhere along or near the AZFa regi on. In the proximal breakpoint region, we identified a 10 kb provirus of th e recently defined HERV15 class of endogenous retroviruses. In the distal b reakpoint region, we found a second HERV15 provirus, 94% identical in DNA s equence to the first and in the same orientation. (A partial LINE insertion in this distal provirus proved to be the basis of the previously described DYS11/ p12f polymorphism.) The AZFa deletions in the two men differed slig htly, but all breakpoints fell within the HERV15 proviruses. Indeed, sequen cing of deletion junctions from the two men revealed that homologous recomb ination had occurred within large domains of absolute sequence identity bet ween the proximal and distal proviruses. When combined with published STS m apping data for other AZFa-deleted men, our findings suggest that recombina tion between these two HERV15 proviruses could account for most AZFa deleti ons.