The importance of maintaining the stability of the genome is revealed by the numerous genetic diseases caused by inherited and de novo
mutations ranging from base changes to genome rearrangements1, 2
. In addition, many cancers are associated with ongoing genome instability and the continued accumulation of mutations and genome rearrangements3-7
. Despite the problems introduced by genome instability, the human genome contains many features prone to be unstable, including microsatellite repeats, minisatellite repeats, triplet repeats, short separated repeats, mirror repeats, inverted repeats, and dispersed repetitive elements such as retroviral elements, SINEs, LINEs, segmental duplications and regions of copy number variation (CNVs)8, 9
. Dispersed repetitive elements can underlie chromosomal rearrangements through non-allelic homologous recombination (HR) between elements at non-homologous chromosomal locations. The Alu elements, for example, cause HR-mediated deletions, duplications, and chromosomal translocations implicated in over 15 inherited diseases as well as rearrangements leading to cancer10
. Similarly, more than 20 human diseases are caused by rearrangements mediated by non-allelic HR between segmental duplications11
. Given the large numbers of repeated regions in the genome, it is surprising that the genome is as stable as it is.
Some types of “at-risk” sequences have been characterized in Saccharomyces cerevisiae9
. Engineered duplications are targets of ectopic recombination, leading to both gene conversion and chromosomal rearrangements12
. Similarly, Ty transposons, which are dispersed, repeated sequences, can recombine to produce genome rearrangements13
, and inverted copies of Ty transposons can cause DSBs during replication resulting in genome rearrangements14
. Consistent with this, “at-risk” sequences appear to be selected against15
; however, the human genome still retains many such sequences. While “at-risk” sequences can induce genome instability, little is known about how such genome rearrangements are prevented and whether there are specific pathways that prevent such sequences from causing genome rearrangements.
We have described assays for measuring the rate of accumulating gross chromosomal rearrangements (GCRs)16
. This assay system detects GCRs that occur in natural DNA sequences and does not depend on the introduction of artificial DNA sequences or the artificial induction of DSBs. Here, we applied this system to compare the rates and properties of GCRs in a chromosomal region devoid of “at-risk” sequences with that of a region of the genome containing a sequence homeologous to ectopic regions of the the genome reminiscent of segmental duplications.