Mechanisms for human genomic rearrangements

Abstract

Genomic rearrangements describe gross DNA changes of the size ranging from a couple of hundred base pairs, the size of an average exon, to megabases (Mb). When greater than 3 to 5 Mb, such changes are usually visible microscopically by chromosome studies. Human diseases that result from genomic rearrangements have been called genomic disorders. Three major mechanisms have been proposed for genomic rearrangements in the human genome. Non-allelic homologous recombination (NAHR) is mostly mediated by low-copy repeats (LCRs) with recombination hotspots, gene conversion and apparent minimal efficient processing segments. NAHR accounts for most of the recurrent rearrangements: those that share a common size, show clustering of breakpoints, and recur in multiple individuals. Non-recurrent rearrangements are of different sizes in each patient, but may share a smallest region of overlap whose change in copy number may result in shared clinical features among different patients. LCRs do not mediate, but may stimulate nonrecurrent events. Some rare NAHRs can also be mediated by highly homologous repetitive sequences (for example, Alu, LINE); these NAHRs account for some of the non-recurrent rearrangements. Other non-recurrent rearrangements can be explained by non-homologous endjoining (NHEJ) and the Fork Stalling and Template Switching (FoSTeS) models. These mechanisms occur both in germ cells, where the rearrangements can be associated with genomic disorders, and in somatic cells in which such genomic rearrangements can cause disorders such as cancer. NAHR, NHEJ and FoSTeS probably account for the majority of genomic rearrangements in our genome and the frequency distribution of the three at a given locus may partially reflect the genomic architecture in proximity to that locus. We provide a review of the current understanding of these three models.

Breakpoint determination of X;autosome balanced translocations in four patients with premature ovarian failure

“…23 In conclusion, we could determine four t(X;autosome) breakpoints at the nucleotide level. We found that only one X-linked gene, COL4A6, was disrupted, resulting in functionally null status.…”

Genomic segmental duplications on the basis of the t(9;22) rearrangement in chronic myeloid leukemia

“…SDs cover about 10% of the human genome and are involved in numerous genomic diseases or cancer (Bailey and Eichler, 2006;Sharp et al, 2006;Gibcus et al, 2007;Darai-Ramqvist et al, 2008;Gu et al, 2008;Mefford and Eichler, 2009). In this paper, the involvement of SDs was proposed to explain the recurrent t(9;22) translocation in CML and the genomic deletions that could accompany the rearrangement.…”

“…During the last few years, genome analyses have revealed the crucial role of segmental duplications (SDs) in triggering constitutional and also tumor chromosomal abnormalities (Sharp et al, 2006;Gibcus et al, 2007;Darai-Ramqvist et al, 2008;Gu et al, 2008;Mefford and Eichler, 2009). Several rearrangements have been described so far to explain the occurrence of genomic disorders: recurrent, sharing a common size and showing clustering of breakpoints inside the SDs, and nonrecurrent rearrangements, involving regions of different sizes and showing breakpoints scattering in large regions (Gu et al, 2008).…”

“…Several rearrangements have been described so far to explain the occurrence of genomic disorders: recurrent, sharing a common size and showing clustering of breakpoints inside the SDs, and nonrecurrent rearrangements, involving regions of different sizes and showing breakpoints scattering in large regions (Gu et al, 2008). Most of the recurrent rearrangements result from a nonallelic homologous recombination between closely located SDs (Gu et al, 2008).…”

“…Several rearrangements have been described so far to explain the occurrence of genomic disorders: recurrent, sharing a common size and showing clustering of breakpoints inside the SDs, and nonrecurrent rearrangements, involving regions of different sizes and showing breakpoints scattering in large regions (Gu et al, 2008). Most of the recurrent rearrangements result from a nonallelic homologous recombination between closely located SDs (Gu et al, 2008). Although a great deal of information has accumulated on the mechanisms underlying constitutional DNA rearrangements associated with inherited disorders, limited knowledge is yet available on the molecular processes resulting in chromosomal, somatic rearrangements in tumors.…”