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

Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Genome Research (Impact Factor: 14.63). 01/2011; 21(1):33-46. DOI: 10.1101/gr.111609.110
Source: PubMed


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. Furthermore, we provide a computationally determined genome-wide "recurrent translocation map."

Download full-text


Available from: Sau Wai Cheung
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We delineated and analyzed directly oriented paralogous low-copy repeats (DP-LCRs) in the most recent version of the human haploid reference genome. The computationally defined DP-LCRs were cross-referenced with our Chromosomal Microarray Analysis (CMA) database of 25,144 patients subjected to genome-wide assays. This computationally guided approach to the empirically-derived large dataset allowed us to investigate genomic rearrangement relative frequencies and identify new loci for recurrent nonallelic homologous recombination (NAHR)-mediated copy-number variants (CNVs). The most commonly observed recurrent CNVs were NPHP1 duplications (233), CHRNA7 duplications (175), and 22q11.21 deletions (DiGeorge/Velocardiofacial syndrome, 166). In the ~ 25% of CMA cases for which parental studies were available, we identified 190 de novo recurrent CNVs. In this group, the most frequently observed events were deletions of 22q11.21 (48), 16p11.2 (autism, 34), and 7q11.23 (Williams-Beuren syndrome, 11). Several features of DP-LCRs, including length, distance between NAHR substrate elements, DNA sequence identity (fraction matching), GC content, and concentration of the homologous recombination (HR) hot spot motif 5'-CCNCCNTNNCCNC-3' correlate with the frequencies of the recurrent CNVs events. Four novel adjacent DP-LCR-flanked and NAHR-prone regions, involving 2q12.2q13 were elucidated in association with novel genomic disorders. Our study quantitates genome architectural features responsible for NAHR mediated genomic instability and further elucidates the role of NAHR in human disease.
    Full-text · Article · May 2013 · Genome Research
  • Source
    • "This is not necessarily unusual to humans, as cattle reciprocal translocations have been estimated to occur at a rate of 1.4 per 1000 animals [85]. These high rates of translocations are thought to be mediated via NAHR using duplicated or repetitive segments located in different chromosomes, that is interchromosomal low-copy repeats (LCRs) [86]. Ou et al. [86] characterized several hundred interchromosomal LCRs in the human genome, ranging in size from 5kb to over 50kb, all of which they suggest can act as the substrates for reciprocal translocations. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Duplication of genetic material is clearly a major route to genetic change, with consequences for both evolution and disease. A variety of forms and mechanisms of duplication are recognised, operating across the scales of a few base pairs upto entire genomes. With the ever-increasing amounts of gene and genome sequence data that are becoming available, our understanding of the extent of duplication is greatly improving, both in terms of the scales of duplication events as well as their rates of occurrence. An accurate understanding of these processes is vital if we are to properly understand important events in evolution as well as mechanisms operating at the level of genome organisation. Here we will focus on duplication in animal genomes and how the duplicated sequences are distributed, with the aim of maintaining a focus on principles of evolution and organisation that are most directly applicable to the shaping of our own genome.
    Full-text · Article · Aug 2012
  • Source
    • "Nonetheless, a comparison of phenotypes between vertebrates and non-vertebrate may provide vital information about the relative contributions of immune dysfunction to the ASD or SCZ phenotype. A similar logic has been used to explore novel cell-death pathways, where regulated cell death processes are examined in species lacking classical caspase enzymes (Degterev & Yuan, 2008; Guisti et al., 2010; Smirlis & Soteriadou, 2011). A thorough, systematic analysis of differences in key disease networks is also required to gain the best insights into the strengths and weaknesses of each specific model organism. "

    Full-text · Chapter · Apr 2012
Show more