Frequency of nonallelic homologous recombination is correlated with length of homology: evidence that ectopic synapsis precedes ectopic crossing-over.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 10/2011; 89(4):580-8. DOI: 10.1016/j.ajhg.2011.09.009
Source: PubMed

ABSTRACT Genomic disorders constitute a class of diseases that are associated with DNA rearrangements resulting from region-specific genome instability, that is, genome architecture incites genome instability. Nonallelic homologous recombination (NAHR) or crossing-over in meiosis between sequences that are not in allelic positions (i.e., paralogous sequences) can result in recurrent deletions or duplications causing genomic disorders. Previous studies of NAHR have focused on description of the phenomenon, but it remains unclear how NAHR occurs during meiosis and what factors determine its frequency. Here we assembled two patient cohorts with reciprocal genomic disorders; deletion associated Smith-Magenis syndrome and duplication associated Potocki-Lupski syndrome. By assessing the full spectrum of rearrangement types from the two cohorts, we find that complex rearrangements (those with more than one breakpoint) are more prevalent in copy-number gains (17.7%) than in copy-number losses (2.3%); an observation that supports a role for replicative mechanisms in complex rearrangement formation. Interestingly, for NAHR-mediated recurrent rearrangements, we show that crossover frequency is positively associated with the flanking low-copy repeat (LCR) length and inversely influenced by the inter-LCR distance. To explain this, we propose that the probability of ectopic chromosome synapsis increases with increased LCR length, and that ectopic synapsis is a necessary precursor to ectopic crossing-over.

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Available from: Pengfei Liu, Dec 14, 2013
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    • "An estimated 10% of all NF1 deletions are atypical [Pasmant et al., 2010; Messiaen et al., 2011]. If all large NF1 deletions are considered, the majority are mediated by NAHR, an important mutational mechanism that is also responsible for many other genomic disorders [Liu et al., 2011, 2012; and references therein]. Current models for meiotic NAHR are based upon the double-strand break (DSB) repair model that includes among its central features the initiation of recombination by a DNA DSB followed by 5 to 3 resection and strand invasion (Fig. 2). "
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    Human Mutation 12/2014; 35(12). DOI:10.1002/humu.22692 · 5.05 Impact Factor
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    • "Based on the short length of uncertainty identified in our patients' breakpoints, when comparing with the reference haploid human genome, 300 bases of 100% identity are not present. Moreover, recent studies suggest that efficiency of NAHR is correlated with LCR length [Cooper et al., 2011; Liu et al., 2011; Dittwald et al., 2013]. However, the homologous regions of the HERV-H elements identified at the breakpoints in our patients totaled only 4.8 kb. "
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    ABSTRACT: We describe the molecular and clinical characterization of nine individuals with recurrent, 3.4-Mb, de novo deletions of 3q13.2-q13.31 detected by chromosomal microarray analysis. All individuals have hypotonia and language and motor delays and also variably express mild to moderate cognitive delays (8/9), abnormal behavior (7/9), and autism spectrum disorders (3/9). Common facial features include down-slanting palpebral fissures with epicanthal folds, a slightly bulbous nose, and relative macrocephaly. Twenty-eight genes map to the deleted region, including four strong candidate genes, DRD3, ZBTB20, GAP43, and BOC, with important roles in neural and/or muscular development. Analysis of the breakpoint regions based on array data revealed directly oriented human endogenous retrovirus (HERV-H) elements ∼5kb in size and of >95% DNA sequence identity flanking the deletion. Subsequent DNA sequencing revealed different deletion breakpoints and suggested non-allelic homologous recombination (NAHR) between HERV-H elements as a mechanism of deletion formation, analogous to HERV-I-flanked and NAHR-mediated AZFa deletions. We propose that similar HERV elements may also mediate other recurrent deletion and duplication events on a genome-wide scale. Observation of rare recurrent chromosomal events such as these deletions helps to further the understanding of mechanisms behind naturally occurring variation in the human genome and its contribution to genetic disease. This article is protected by copyright. All rights reserved.
    Human Mutation 10/2013; 34(10). DOI:10.1002/humu.22384 · 5.05 Impact Factor
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    • "(Liu et al. 2012), were collapsed in previous reports but were separated by our analyses. Moreover, using the less stringent criterion for the length of flanking DP-LCRs copies, we have identified the STS deletions and duplications on Xp22.31 (MIM# 308100) (Hernández-Martín et al. 1999; Liu et al. 2011) that were not included in the analysis by Cooper et al. (2011) and CNVs in Xq28 (El-Hattab et al. 2011) that were not detected by the approach used by Liu et al. (2012). As anticipated, due to the structural differences between the specific inversion haplotypes and the reference haploid genome, we did not detect DP-LCRs mediating two known recurrent CNVs: small CHRNA7 deletion/duplication in 15q13.3 "
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    Genome Research 05/2013; DOI:10.1101/gr.152454.112 · 13.85 Impact Factor
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