Correlation between frequency of non-allelic homologous recombination and homology properties: evidence from homology-mediated CNV mutations in the human genome

Abstract

Non-allelic homologous recombination (NAHR) is one of the key mechanisms of DNA rearrangement. NAHR occurring between direct homologous repeats can generate genomic copy number variation (CNV) and make significant contributions to both genome evolution and human diseases such as cancer. Intriguingly, previous observations on the rare CNVs at certain genomic disorder loci suggested that NAHR frequency could be dependent on homology properties. However, such a correlation remains unclear at the other NAHR-mediated CNV loci, especially the common CNVs in human populations. Different from the rare CNVs associated with genomic disorders, it is challenging to identify de novo NAHR events at common CNV loci. Therefore, our previously proposed statistic M was employed in estimating relative mutation rate for the NAHR-mediated CNVs in human populations. By utilizing generalized regression neural network and principal component analysis in studying 4330 CNVs ascertained in 3 HapMap populations, we identified the CNVs mediated by NAHR between paired segmental duplications (SDs) and further revealed the correlations between SD properties and NAHR probability. SD length and inter-SD distance were shown to make major contributions to the occurrence of NAHR, whereas chromosomal position and sequence similarity of paired SDs are also involved in NAHR. An integrated effect of SD properties on NAHR frequency was revealed for the common CNVs in human populations. These observations can be well explained by ectopic synapsis in NAHR together with our proposed model of chromosomal compression/extension/looping (CCEL) for homology mis-pairing. Our findings showed the important roles of SDs in NAHR and human genomic evolution.

Contrasting mechanisms of de novo copy number mutagenesis suggest the existence of different classes of environmental copy number mutagens

“…This vulnerability is further exacerbated when the DP‐LCRs contain binding sequences for the PRDM9 histone methyltransferase, which modifies the local chromatin structure, recruiting SPO11 and thus creating meiotic recombination hotspots [Dittwald et al, ; Pratto et al, ]. In addition to the local genomic architecture (i.e., number, distance, and size of DP‐LCRs), evidence from classic studies in yeast and recent analyses of large human CNV databases strongly suggest that inaccurate meiotic chromosome synapsis and/or defective meiotic checkpoints facilitate NAHR between DP‐LCRs, thus leading to recurrent CNV formation [Petes and Hill ; Haber et al, ; Goldman and Lichten ; Grushcow et al, ; Thompson and Stahl ; Goldman and Lichten ; Liu et al, ; Dittwald et al, ; Shinohara and Shinohara ; Peng et al, ].…”

An exploratory study of predisposing genetic factors for DiGeorge/velocardiofacial syndrome

“…Different authors have reported a correlation between the alignment length and the sequence identity between paired LCRs and NAHR frequency356, thus supporting the idea that CNVs at LCRs might change NAHR susceptibility. Moreover, according to the ectopic synapsis model15, variations in the length of the LCRs might originate ectopic presynaptic contacts between near homologous segments that would act as a precursor to NAHR.…”

Consideration of the haplotype diversity at nonallelic homologous recombination hotspots improves the precision of rearrangement breakpoint identification

“…The precise assignment of SERs is therefore of critical importance if we are to confidently assess the relevance of specific DNA sequence features within recombination hotspots to the regulation of NAHR frequency. These sequence features may include the distance between the recombining paralogs, the extent of DNA sequence identity between the paralogs, GC content, and the frequency of the PRDM9‐binding motifs within NAHR hotspots (Dittwald et al., ; Guo et al., ; Myers et al., ; Peng et al., ; Pratto et al., ). PRDM9 is a meiosis‐specific histone methyltransferase with a zinc‐finger protein domain that binds to the sequence motif 5′‐CCNCCNTNNCCNC‐3′ thereby regulating the genome‐wide positioning of AHR hotspots in humans via sequence‐specific DNA binding of its zinc finger array (Baudat et al., ; Berg et al., ; Myers et al., ; Parvanov, Petkov, & Paigen, ).…”