The DNA replication FoSTeS mechanism can cause human genomic, genic, and exon shuffling rearrangements. F. Zhang1, M. Khajavi1, J. R. Lupski1,2,3 1) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030; 2) Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030; 3) Texas Childrens Hospital, Houston, TX 77030.

   We recently proposed a DNA replication based mechanism of Fork Stalling and Template Switching (FoSTeS) to explain the complex rearrangements associated with Pelizaeus-Merzbacher disease (PMD), an X-linked dysmyelinating central nervous system disorder. The hallmarks of FoSTeS are complex rearrangements that result from template driven juxtaposition of sequences from different genomic locations with DNA sequence microhomology at the join point(s). Here we provide further evidence for human genomic rearrangements generated by FoSTeS and the involvement of autosomal loci in which such rearrangements convey genomic disorders including Potocki-Lupski syndrome (PTLS) and Charcot-Marie-Tooth disease type 1A (CMT1A). We now show by oligonucleotide array CGH and breakpoint sequencing that 8/14 nonrecurrent PTLS associated duplications are complex and occur by FoSTeS. Furthermore, we show that >99% of CMT1A duplications/HNPP deletions occur by NAHR, but the majority of nonrecurrent rearrangements (6/7) appear to occur by FoSTeS. Our data suggest FoSTeS may be a major mechanism for generating structural variation of the human genome. Furthermore, we show that this mechanism can also apply to both genic and single exon rearrangements indicating a link to gene evolution and potentially the mechanism for the long postulated exon shuffling.