Translocation and gross deletion breakpoints in human inherited disease and cancer I: Nucleotide composition and recombination-associated motifs

Abstract

Translocations and gross deletions are important causes of both cancer and inherited disease. Such gene rearrangements are nonrandomly distributed in the human genome as a consequence of selection for growth advantage and/or the inherent potential of some DNA sequences to be frequently involved in breakage and recombination. Using the Gross Rearrangement Breakpoint Database [GRaBD; www.uwcm.ac.uk/uwcm/mg/grabd/grabd.html] (containing 397 germ-line and somatic DNA breakpoint junction sequences derived from 219 different rearrangements underlying human inherited disease and cancer), we have analyzed the sequence context of translocation and deletion breakpoints in a search for general characteristics that might have rendered these sequences prone to rearrangement. The oligonucleotide composition of breakpoint junctions and a set of reference sequences, matched for length and genomic location, were compared with respect to their nucleotide composition. Deletion breakpoints were found to be AT-rich whereas by comparison, translocation breakpoints were GC-rich. Alternating purine-pyrimidine sequences were found to be significantly over-represented in the vicinity of deletion breakpoints while polypyrimidine tracts were over-represented at translocation breakpoints. A number of recombination-associated motifs were found to be over-represented at translocation breakpoints (including DNA polymerase pause sites/frameshift hotspots, immunoglobulin heavy chain class switch sites, heptamer/nonamer V(D)J recombination signal sequences, translin binding sites, and the chi element) but, with the exception of the translin-binding site and immunoglobulin heavy chain class switch sites, none of these motifs were over-represented at deletion breakpoints. Alu sequences were found to span both breakpoints in seven cases of gross deletion that may thus be inferred to have arisen by homologous recombination. Our results are therefore consistent with a role for homologous unequal recombination in deletion mutagenesis and a role for nonhomologous recombination in the generation of translocations.

RAR-related orphan receptor A isoform 1 (RORa1) is disrupted by a balanced translocation t(4;15)(q22.3;q21.3) associated with severe obesity

“…This confirms previous analysis of translocation breakpoints of which some have shown both GC-rich regions and polypyrimidine and polypurine tracts. 20,21 From our findings we suggest that the sequence similarities (80%) between the two chromosomes flanking the breakpoints as well as the surrounding polypurine and polypyrimidine tracts are predisposing factors for the reciprocal translocation. Recombination-associated sequence motifs have been shown to be over-represented at translocation breakpoints, including DNA polymerase core elements (frameshift hotspots) and heptamer recombination signals.…”

Fusion tyrosine kinases: a result and cause of genomic instability

“…Moreover, translocation breakpoints are GC-rich (Abeysinghe et al, 2003) and oxidative damage is predominantly detected in GC-rich sequences (Akman et al, 2000). Thus, it is tempting to speculate that clustered oxidative damage may generate multiple DNA lesions in a short DNA fragment, which pose a serious obstacle for replication forks and may result in a DSB.…”

Retrosequence formation restructures the yeast genome

“…Multiple studies have identified associations between retrotransposons and chromosome rearrangements, including studies in mammalian cells revealing that retrotransposons are often found at breakpoint junctions of translocations and deletions present in tumor cells or cells derived from individuals with inherited disorders (Abeysinghe et al 2003;Florl and Schulz 2003). In Figure 2, respectively.…”