Divergent outcomes of intrachromosomal recombination on the human Y chromosome: male infertility and recurrent polymorphism

The Y chromosome provides a unique opportunity to study mutational processe s within the human genome, decoupled from the confounding effects of interc hromosomal recombination. It has been suggested that the increased density of certain dispersed repeats on the Y could account for the high frequency of causative microdeletions relative to single nucleotide mutations in infe rtile males. Previously we localised breakpoints of an AZFa microdeletion c lose to two highly homologous complete human endogenous retroviral sequence s (HERV), separated by 700 kb. Here we show, by sequencing across the break point, that the microdeletion occurs in register within a highly homologous segment between the HERVs. Furthermore, we show that recurrent double cros sovers have occurred between the HERVs, resulting in the loss of a 1.5 kb i nsertion from one HERV, an event underlying the first ever Y chromosomal po lymorphism described, the 12f2 deletion. This event produces a substantiall y longer segment of absolute homology and as such may result in increased p redisposition to further intrachromosomal recombination. Intrachromosomal c rosstalk between these two HERV sequences can thus result in either homogen ising sequence conversion or a microdeletion causing male infertility. This represents a major subclass of AZFa deletions.