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. 2011 Oct 7;89(4):580-8.
doi: 10.1016/j.ajhg.2011.09.009.

Frequency of Nonallelic Homologous Recombination Is Correlated With Length of Homology: Evidence That Ectopic Synapsis Precedes Ectopic Crossing-Over

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Frequency of Nonallelic Homologous Recombination Is Correlated With Length of Homology: Evidence That Ectopic Synapsis Precedes Ectopic Crossing-Over

Pengfei Liu et al. Am J Hum Genet. .
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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.

Figures

Figure 1
Figure 1
Summary of Rearrangement Results for 131 SMS Deletions (A) A schematic representation of part of the human chromosome 17p (hg18) is illustrated as a horizontal line on the top of the figure with megabase pair genomic coordinates below. The critical region of the SMS deletion where the predominant dosage-sensitive critical gene RAI1 maps is indicated as a black rectangle and a vertical gray shadow. The vertical yellow, blue and orange shadow areas represent LCRs that mediate the CR, UR1, and UR2 SMS deletions. Below, horizontal bars depict the involved genomic intervals for each subject (BAB identification number on the left) from the interpretations of aCGH results: green or white bars represent deletion or normal copy, respectively. The recurrent deletions, flanked by directly oriented LCRs, are most likely produced by NAHR. The simple nonrecurrent or complex deletions have breakpoints not located in LCRs; they were most likely produced by mechanisms other than NAHR, such as NHEJ and/or replicative mechanisms such as FoSTeS or MMBIR. The totals for numbers of subjects with recurrent deletions are shown to the right of the aCGH interpretations. (B) Breakpoint junctions and rearrangement structure in complex deletions BAB1931 and BAB649. The copy-number interpretations from aCGH results for both cases are shown at the top of this panel. For BAB649, the structure of the rearranged product is displayed under the aCGH interpretation. The normal copy segment between the two deletions is inverted. The breakpoint junctions are numbered corresponding to the breakpoint sequences listed below. (C) Junction sequences are aligned to the reference sequence, and the transition between DNA sequences with different colors indicates the breakpoint interval. The black boxes outline microhomologies identified at the breakpoint junctions. The underlined purple sequences are the segments involved in one additional rearrangement step.
Figure 2
Figure 2
The NAHR Frequency Varies as the LCR Length and Is Inversely Influenced by Inter-LCR Distance (A) Identification of the type 2 uncommon recurrent SMS deletion and PTLS duplication. The schematic graph of the newly identified uncommon recurrent type 2 (UR2) deletion (green) and duplication (red) are compared to the common recurrent (CR) and uncommon recurrent type 1 (UR1) rearrangements. The lengths of the flanking LCRs are marked above the LCRs. The inter-LCR distances are listed inside the rearranged bars. One copy of the 24 kb LCRs is expanded to show the exact crossover regions. The black arrow indicates where the crossover occurs in BAB1456. The positions of the 13-mer HR hotspot motif (CCNCCNTNNCCNC) are highlighted as purple vertical bars. (B–C) The natural logarithm of calculated intermolecular NAHR rates in male meiosis as a function of (B) LCR length or (C) LCR length divided by inter-LCR distance. Interchromatidal NAHR (β) is much less frequent than interchromosomal NAHR (γ) in male meiosis. In other words, intermolecular NAHR events (β + γ) occur predominantly by interchromosomal recombinations (γ), and their frequency probably reflects interactions between homologous chromosomes that pair at synapsis. The strongest correlation for the data appears to occur when both LCR length and distance between LCRs are taken into account; i.e., when LCR length divided by inter-LCR distance is the variable. Coordinates for each dot were calculated with data from Tables 2 and 3. (D) Definition of LCR length and distance. The inter-LCR distance is length of the segment in between LCRs plus the length of one LCR.
Figure 3
Figure 3
Ectopic Synapsis Model (A) In meiosis prophase I, a double-strand break (DSB) occurs on one LCR. The yellow and green rectangles indicate paralogous LCRs. (B) The processed double-strand end searches the neighboring regions, making ectopic presynaptic contacts. The presence of gray ellipses indicates establishment of synapsis, which proceeds from subtelomeric regions toward centromeres. (C) Ectopic synapsis is formed after a certain number or density of presynaptic contacts is made. The successful establishment of ectopic synapsis is dependent upon the length of ectopic homology. (D) After ectopic synapsis is set up, crossing-over occurs between nonallelic LCRs. (E) Resolution can lead to NAHR.

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