Mechanisms for recurrent and complex human genomic rearrangements

Abstract

During the last two decades, the importance of human genome copy number variation (CNV) in disease has become widely recognized. However, much is not understood about underlying mechanisms. We show how, although model organism research guides molecular understanding, important insights are gained from study of the wealth of information available in the clinic. We describe progress in explaining nonallelic homologous recombination (NAHR), a major cause of copy number change occurring when control of allelic recombination fails, highlight the growing importance of replicative mechanisms to explain complex events, and describe progress in understanding extreme chromosome reorganization (chromothripsis). Both nonhomologous end-joining and aberrant replication have significant roles in chromothripsis. As we study CNV, the processes underlying human genome evolution are revealed.

Figure 1

NAHR as the mechanism for recurrent genomic rearrangements. (A) Ectopic crossing-over between directly oriented repeats in trans can lead to deletion and reciprocal duplication; whereas ectopic crossing-over between inversely oriented repeats in cis can result in an inversion. (B) NAHR can produce deletion or duplication in three ways, interchromosomal crossover, intrachromosomal (or interchromatidal) crossover, and intrachromatidal crossover. Note that intrachromatidal recombination can only produce deletion, not duplication. NAHR between inverted LCRs on sister chromatids can also result in isochromosome formation. (C) This panel is adapted from Ou et al [12] showing a genome-wide recurrent translocation map mediated by NAHR. In this circularized genome-wide view, LCRs fulfilling the criteria for recurrent translocations are connected by lines. The red line denotes recurrent translocations that are observed and experimentally verified, whereas the grey and green lines (olfactory receptor factor gene families) denote predicted recurrent translocations that could be mediated by paralogous LCRs.

Figure 2

Genome-wide map of computationally predicted NAHR-prone regions and empirically verified NAHR-associated disease regions. LCR pairs fulfilling chosen criteria (> 10 kb in length, > 95% in identity, directly oriented, with intervening sequence between 50 kb and 10 Mb, not spanning the centromere) are considered as potential substrates for NAHR. They are linked by an inverted V-shaped line as illustrated above the chromosome ideograms. Genomic regions flanked by such lines are merged into non-redundant sites, and illustrated as the 89 red bars below the ideograms. Regions of known genomic disorders are shown as green (only deletion associated with disease) or blue (both deletion and duplication associated with disease) bars. a, the 17q21.31 rearrangement occurs on an alternative haplotype [73]. b, the Xp22.31 rearrangement was not predicted by the NAHR map because the flanking LCR substrate is ~ 9 kb in length (< 10 kb) [26,74]. c, the Xq28 rearrangement was not predicted by the NAHR map because the flanking LCR is ~ 9.5 kb in length (< 10 kb) [75]. d, the rearrangement involving AZFa [76] was not predicted by the NAHR map because the deletion is mediated by a pair of HERV repetitive elements.

Figure 3

Triplications and genome-scale complex rearrangements. (A) Two types of structures of triplications; the reference structure is illustrated above the novel structure formed upon triplication below. Red or blue horizontal bars represent regions that are duplicated or triplicated in the novel structure, respectively. Black arrows denote LCRs involved in this process with the orientation indicated by the arrowhead. Note that in type II triplication, the triplicated segment in the middle is inserted in an inverted orientation with respect to the flanking regions. The inversion is indicated by blue dashed lines. (B) Three distinct types of genome-level complex rearrangements. Shown in the figure are three hypothetical array CGH genome-view results representing three types of complex rearrangements. The labels on the X-axis denote chromosome numbers. The numbers on the Y-axis denote the log₂ fluorescence intensity ratio of the hypothetical aCGH results. Red dots represent de novo copy number gains; green dots represent de novo copy number losses. Black dots at zero on the X-axis represent hybridizing oligonucleotide signals with no copy number change.