A recurrent translocation is mediated by homologous recombination between HERV-H elements

Array CGH resolved the breakpoints of the 6.97-Megabase (Mb) loss of 18q and the 7.30-Mb gain of 4q. Sequencing across the translocation breakpoints revealed that both translocations occurred between 92%-identical human endogenous retrovirus (HERV) elements in the same orientation on chromosomes 4 and 18. In addition, we find sequence variation in the chromosome 4 HERV that makes one allele more like the chromosome 18 HERV.Homologous recombination between HERVs on the same chromosome is known to cause chromosome deletions, but this is the first report of interchromosomal HERV-HERV recombination leading to a translocation. It is possible that normal sequence variation in substrates of non-allelic homologous recombination (NAHR) affects the alignment of recombining segments and influences the propensity to chromosome rearrangement.Chromosome rearrangements play a major role in intellectual disability, birth defects, and autism [1-3], and many heterogeneous mechanisms have been implicated in the formation of chromosome rearrangements. Analyses of breakpoint junctions from a host of chromosome rearrangements have revealed signatures of homologous recombination (HR), nonhomologous end-joining (NHEJ), microhomology-mediated end joining (MMEJ), and break-induced replication (BIR) [4-6].Recurrent chromosome abnormalities give us a unique opportunity to unravel specific factors involved in rearrangement, as their frequency and shared breakpoints indicate a rearrangement-prone genomic architecture. Deletions and duplications mediated by non-allelic homologous recombination (NAHR) are the most common class of recurrent constitutional chromosome rearrangements and are responsible for several genetic syndromes [7-9]. Such rearrangements are relatively easy to identify by paralogous genomic segments that are highly identical and typically hundreds of kilobases in size flanking breakpoint junctions [9-11]. Analysis of translocation breakpoints has shown that some recurrent translo