The t(4;8) is mediated by homologous recombination between olfactory receptor gene clusters, but other 4p16 translocations occur at random.

Summary: The t(4;8) is mediated by homologous recombination between olfactory receptor gene clusters, but other 4p16 translocations occur at random: The t(4;8)(p16;p23) is the second most common constitutional chromosomal translocation and is caused by an ectopic meiotic recombination between the olfactory receptor gene clusters (ORGC), located on chromosome 4p and 8p. Given that ORGCs are scattered across the genome and make-up about 0.1% of the human genome we reasoned that translocations between 4p16 and other chromosomes might be mediated by ectopic recombination between different ORGC. In 13 patients, we mapped the breakpoints of either a balanced or unbalanced translocation between chromosome 4p16 and different chromosomes. For all four t(4;8) cases, the breakpoints fall within the 4p and 8pter ORGC, confirming that non-allelic homologous recombination (NAHR) between the ORGC is the main mechanism of the t(4;8) formation. For the nine other translocations, the breakpoints on chromosome 4 mapped to different loci, one of them within the ORGC and in two flanking the ORGC. In these three cases, the translocation breakpoint at the reciprocal chromosome did not contain ORGC sequences. We conclude that only the t(4;8) is mediated by NAHR between ORGC. Key-words: Translocation - Chromosome 4 - Wolf-Hirschhorn syndrome - Olfactory receptor gene cluster - Telomere capture - Non-allelic homologous recombination INTRODUCTION Recurrent non-Robertsonian constitutional translocations in man are very rare. The t(11;22)(q23;q11.2) translocation is the most common reciprocal translocation. The breakpoint of the t(11;22) translocation has been identified within palindromic AT-rich repeats on chromosomes 11 and 22, suggesting that hairpin/cruciform structures mediate double-strand breaks leading to the translocation (13). The t(4;8)(p16;p23) translocation is the second most frequent translocation (10). The t(4;8) rearrangement is mediated by non allelic homologous recombination (NAHR). Two pairs of the olfactory receptor gene clusters (ORGC) are located close to each other, on both 4p16 and 8p23. The breakpoints of the t(4;8) at both 4p16 and 8p23 are located within these highly homologous ORGC. Giglio et al. also showed that an inversion polymorphism between the ORGC present at 4p16 in 12.5% of the population and at 8p23 in 26% of the population causes predisposition for the t(4;8) in inversion heterozygotes (10). The olfactory receptor (OR) genes constitute the largest gene family of the human genome and reside in gene clusters. The olfactory subgenome may include more than 0.1% of the human genome (11), and is responsible for the olfactory sense. The evolution of OR genes was found to be profoundly influenced by the all-pervasive interspersed repetitive elements in their surroundings. These repeats can cause tandem gene duplications, mobilize genes to more remote locations (11) and even become part of their exon structure (24). The ORGC regions at 4p and 8p contain the 7E subfamily OR genes: they are composed of blocks of more than 95% identical sequences, each spanning ~400 kb and consisting of genes and pseudogenes. Gene conversion among 7E OR genes and sequence exchange between paralogous regions support the idea that highly similar 7E OR gene sequences at distant loci may predispose to chromosome breakage and rearrangement (29). Although the t(4;8) is likely to be the second most common recurrent reciprocal translocation (10, 20, 28), numerous case reports describe unbalanced translocations of 4p16 with other chromosomes (4, 6, 8, 16, 18, 26). However, the exact position of the breakpoints on chromosome 4 and the partner chromosomes has never been studied. There is also a small number of reports on ring chromosomes 4, reviewed by Baici et al. (1) and Laleye et al. (14). Ring chromosomes are thought to be the result of breakage in both arms of a chromosome with fusion of the points of fracture. …