Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes

Abstract

Four unrelated families with the same unbalanced translocation der(4)t(4;11)(p16.2;p15.4) were analyzed. Both of the breakpoint regions in 4p16.2 and 11p15.4 were narrowed to large~359-kb and~215-kb low-copy repeat (LCR) clusters, respectively, by aCGH and SNP array analyses. DNA sequencing enabled mapping the breakpoints of one translocation to 24 bp within interchromosomal paralogous LCRs of~130 kb in length and 94.7% DNA sequence identity located in olfactory receptor gene clusters, indicating nonallelic homologous recombination (NAHR) as the mechanism for translocation formation. To investigate the potential involvement of interchromosomal LCRs in recurrent chromosomal translocation formation, we performed computational genome-wide analyses and identified 1143 interchromosomal LCR substrate pairs, >5 kb in size and sharing >94% sequence identity that can potentially mediate chromosomal translocations. Additional evidence for interchromosomal NAHR mediated translocation formation was provided by sequencing the breakpoints of another recurrent translocation, der(8)t(8;12)(p23.1;p13.31). The NAHR sites were mapped within 55 bp in~7.8-kb paralogous subunits of 95.3% sequence identity located in the~579-kb (chr 8) and~287-kb (chr 12) LCR clusters. We demonstrate that NAHR mediates recurrent constitutional translocations t(4;11) and t(8;12) and potentially many other interchromosomal translocations throughout the human genome.

Mouse model implicates GNB3 duplication in a childhood obesity syndrome

“…Although the der(8)t(8;12) unbalanced translocation has been previously reported in three children with ID (27,42,43), our finding connects this genomic rearrangement with ID, seizures, macrocephaly, eczema, and obesity in multiple individuals and suggests that, like other recurrent CNVs (44), the der(8)t(8;12) translocation constitutes a unique genomic syndrome. As is the case for the recurrent translocation between chromosomes 4 and 8, all of the de novo der(8)t(8;12) translocations are maternally derived.…”

“…S2 and S3). Recurrent translocations between paralogous segments of the genome are consistent with rearrangement by nonallelic homologous recombination (NAHR) (25)(26)(27)(28)(29)(30).…”

NAHR-mediated copy-number variants in a clinical population: Mechanistic insights into both genomic disorders and Mendelizing traits

“…Recent evidence suggests a greater than twofold genome-wide enrichment for CNVs between DP-LCRs (Li et al 2012). NAHR events in trans between LCRs on nonhomologous chromosomes can cause recurrent constitutional translocations (Giglio et al 2002;Ou et al 2011). For LCRs in inverted orientation, Dittwald et al (2013) showed that 12.0% of the human genome is potentially susceptible to NAHR-mediated inversions between inverse paralogous LCRs, with 942 genes (99 of which are on the X chromosome) predicted to be disrupted secondary to such an inversion.…”

Read Clouds Uncover Variation in Complex Regions of the Human Genome

“…High-identity segmental duplications are highly variable between individuals, and copy number variants (CNVs) within these regions are strongly correlated with increased sequence identity (Redon et al 2006). Nonallelic homologous recombination between LCRs as well as Alu repetitive elements can result in a variety of balanced and unbalanced structural alteration events (Redon et al 2006;Sasaki et al 2010;Ou et al 2011). These regions are enriched for transcript content, and a subset of these regions consists of multicopy genes also known to vary widely in copy number between populations and individuals (Sudmant et al 2010).…”