Two long homologous retroviral sequence blocks in proximal Yq11 cause AZFa microdeletions as a result of intrachromosomal recombination events

We mapped the breakpoints of the AZoospermia factor a (AZFa) microdeletion located in proximal Yq11 in six men with complete germ cell aplasia, i.e. Sertoli Cell Only syndrome (SCO). The proximal breakpoints were identified in a long retroviral sequence block (HERV15yq1: 9747 nucleotides) at the 5' end of the DYS11 DNA locus in Yq11, interval D3. The distal breakpoints were found in a homologous HERV15 sequence block mapped to the Yq11 interval D6, i.e. in the distal part of the AZFa region (HERV15yq2: 9969 nucleotides). Compared with the HERV15yq1 sequence, HERV15yq2 is marked by a deletion of a HERV15 sequence domain at its 5' end and insertion of an LINE 1 3'-UTR sequence block (L1PA4) of similar length at its 3' end. The deletion of the L1PA4 element was recognized as the molecular origin of the DYS11 12f2 restriction fragment length polymorphism. For all six AZFa patients it was possible to perform PCR experiments bridging both retroviral sequence blocks, which map in a distance of 781.557 kb in proximal Yq11 in fertile men. The AZFa breakpoint-fusion regions were located in their recombined HERV15yq1/HERV15yq2 sequence blocks in either one of two long identical sequence domains (ID1 and ID2). We therefore assume that intrachromosomal recombination events between the two homologous retroviral sequence blocks in proximal Yq11 are probably the causative agents for most of the AZFa microdeletions observed in men with SCO syndrome. A mean value of 792 kb was estimated for their molecular lengths.