Chromosome breakage in the Prader-Willi and Angelman syndromes involves recombination between large, transcribed repeats at proximal and distal breakpoints.

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are distinct neurobehavioral disorders that most often arise from a 4-Mb deletion of chromosome 15q11-q13 during paternal or maternal gametogenesis, respectively.
At a de novo frequency of approximately. 67-1/10, 000 births, these deletions represent a common structural chromosome change in the human genome.
To elucidate the mechanism underlying these events, we characterized the regions that contain two proximal breakpoint clusters and a distal cluster.
Novel DNA sequences potentially associated with the breakpoints were positionally cloned from YACs within or near these regions.
Analyses of rodent-human somatic-cell hybrids, YAC contigs, and FISH of normal or rearranged chromosomes 15 identified duplicated sequences (the END repeats) at or near the breakpoints.
The END-repeat units are derived from large genomic duplications of a novel gene (HERC2), many copies of which are transcriptionally active in germline tissues.
One of five PWS/AS patients analyzed to date has an identifiable, rearranged HERC2 transcript derived from the deletion event.
We postulate that the END repeats flanking 15q11-q13 mediate homologous recombination resulting in deletion.
Furthermore, we propose that active transcription of these repeats in male and female germ cells may facilitate the homologous recombination process.

