Genomic rearrangements in inherited disease and cancer involve gross alterations of chromosomes or large chromosomal regions and can take the form of deletions, duplications, insertions, inversions or translocations. The characterization of a considerable number of rearrangement breakpoints has now been accomplished at the nucleotide sequence level, thereby providing an invaluable resource for the detailed study of the mutational mechanisms which underlie genomic recombination events. A better understanding of these mutational mechanisms is vital for improving the design of mutation detection strategies. At least five categories of mutational mechanism are known to give rise to genomic rearrangements: (i) homologous recombination including non-allelic homologous recombination (NAHR), gene conversion, single strand annealing (SSA) and break-induced replication (BIR), (ii) non-homologous end joining (NHEJ), (iii) microhomology-mediated replication-dependent recombination (MMRDR), (iv) long interspersed element-1 (LINE-1 or L1)-mediated retrotransposition and (v) telomere healing. Focussing on the first three of these general mechanisms, we compare and contrast their hallmark characteristics, and discuss the role of various local DNA sequence features (e.g. recombination-promoting motifs, repetitive sequences and sequences capable of non-B DNA formation) in mediating the recombination events that underlie gross genomic rearrangements. Finally, we explore how studies both at the level of the gene (using the neurofibromatosis type-1 gene as an example) and the whole genome (using data derived from cancer genome sequencing studies) are shaping our understanding of the impact of genomic rearrangements as a cause of human genetic disease.
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