Inverted low-copy repeats and genome instability--a genome-wide analysis

Abstract

Inverse paralogous low-copy repeats (IP-LCRs) can cause genome instability by nonallelic homologous recombination (NAHR)-mediated balanced inversions. When disrupting a dosage-sensitive gene(s), balanced inversions can lead to abnormal phenotypes. We delineated the genome-wide distribution of IP-LCRs >1 kB in size with >95% sequence identity and mapped the genes, potentially intersected by an inversion, that overlap at least one of the IP-LCRs. Remarkably, our results show that 12.0% of the human genome is potentially susceptible to such inversions and 942 genes, 99 of which are on the X chromosome, are predicted to be disrupted secondary to such an inversion! In addition, IP-LCRs larger than 800 bp with at least 98% sequence identity (duplication/triplication facilitating IP-LCRs, DTIP-LCRs) were recently implicated in the formation of complex genomic rearrangements with a duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) structure by a replication-based mechanism involving a template switch between such inverted repeats. We identified 1,551 DTIP-LCRs that could facilitate DUP-TRP/INV-DUP formation. Remarkably, 1,445 disease-associated genes are at risk of undergoing copy-number gain as they map to genomic intervals susceptible to the formation of DUP-TRP/INV-DUP complex rearrangements. We implicate inverted LCRs as a human genome architectural feature that could potentially be responsible for genomic instability associated with many human disease traits.

Figure 1

Ideogram of the human chromosomes showing distribution of known benign inversions (DGV) potentially mediated by IP-LCRs (above chromosomes) and genomic regions flanked by IP-LCR (and potentially susceptible to genomic instability via NAHR inversions), DTIP-LCRs with 1 MB flanking segments and regions occupied by IP-LCRs and DTIP-LCRs (below chromosomes). The blue track depicts 47 inversions found in the DGV database with both breakpoints mapping within IP-LCRs. In violet are genomic regions flanked by 1,337 IP-LCRs greater than 1-kB in size of 95% sequence identity and in red IP-LCRs. The black track (below IP-LCRs) highlights predicted DTIP-LCRs genomic regions and the yellow track shows DTIP-LCRs with 1 MB flanking regions.

Figure 2

A: Chromosome percent coverage of genomic regions flanked by 1,337 IP-LCRs greater than 1-kB in size of 95% sequence identity and mapping <10 MB apart from each other (violet) and DTIP-LCRs with 1 MB flanking regions (yellow), representing potential genome instability regions. B: Chromosome percent coverage, of IP-LCRs (red) and DTIP-LCRs (black). Note that ~43% of chromosome 17 is flanked by IP-LCRs (A) and chromosome Y is the most IP-LCR rich (>11.1%) (B).

Figure 3

Distributions of estimated lengths of LCR-mediated NAHR rearrangements. The length was calculated as a sum of a unique distance between LCRs pairs plus the size of a shorter LCR element. A: Blue bars depict the frequencies of distances between paralogous elements in the set of IP-LCRs satisfying the defined criteria, that is, fraction matching >95% and maximal distance <10 MB. Yellow bars refer to he distribution of distances in the subset of IP-LCRs intersecting human genes. B: Distributions of directly oriented paralogous LCRs (fraction matching >95%, distance between LCRs <10 MB, LCR size >1 kB) intersecting with both breakpoints of known pathogenic deletions and reciprocal duplications. Note that, in contrast to directly oriented LCRs, the majority of IP-LCRs inversions are between paralogous elements mapping <1.5 MB from each other.

Figure 4

Circos plots showing the location of IP-LCRs (fraction matching above 95%) and intersected genes. Each blue line inside the circle connects chromosomal locations of the IP-LCR paralogous genomic segments. Light–dark scale of this blue color refers to the ascending fraction matching (from 95% to 100%) between repeats. Genes that intersect with at least one IP-LCR are depicted outside the circles. (A) genome-wide and (B) X chromosome IP-LCR architecture across the entire genome shown with dosage-sensitive genes (red), known disease-causing genes (violet), and genes belonging to both classes (green). Each plot was made using the Circos tool [Krzywinski et al., 2009].