Abstract
BackgroundAs a fundamental genomic element, meiotic recombination hotspot plays important roles in life sciences. Thus uncovering its regulatory mechanisms has broad impact on biomedical research. Despite the recent identification of the zinc finger protein PRDM9 and its 13-mer binding motif as major regulators for meiotic recombination hotspots, other regulators remain to be discovered. Existing methods for finding DNA sequence motifs of recombination hotspots often rely on the enrichment of co-localizations between hotspots and short DNA patterns, which ignore the cross-individual variation of recombination rates and sequence polymorphisms in the population. Our objective in this paper is to capture signals encoded in genetic variations for the discovery of recombination-associated DNA motifs.ResultsRecently, an algorithm called “LDsplit” has been designed to detect the association between single nucleotide polymorphisms (SNPs) and proximal meiotic recombination hotspots. The association is measured by the difference of population recombination rates at a hotspot between two alleles of a candidate SNP. Here we present an open source software tool of LDsplit, with integrative data visualization for recombination hotspots and their proximal SNPs. Applying LDsplit on SNPs inside an established 7-mer motif bound by PRDM9 we observed that SNP alleles preserving the original motif tend to have higher recombination rates than the opposite alleles that disrupt the motif. Running on SNP windows around hotspots each containing an occurrence of the 7-mer motif, LDsplit is able to guide the established motif finding algorithm of MEME to recover the 7-mer motif. In contrast, without LDsplit the 7-mer motif could not be identified.ConclusionsLDsplit is a software tool for the discovery of cis-regulatory DNA sequence motifs stimulating meiotic recombination hotspots by screening and narrowing down to hotspot associated SNPs. It is the first computational method that utilizes the genetic variation of recombination hotspots among individuals, opening a new avenue for motif finding. Tested on an established motif and simulated datasets, LDsplit shows promise to discover novel DNA motifs for meiotic recombination hotspots.
Highlights
As a fundamental genomic element, meiotic recombination hotspot plays important roles in life sciences
As a case study to demonstrate the usefulness of LDsplit software for the discovery of cis-regulatory motifs of meiotic recombination hotspots, we will analyze the 7mer motif of CCTCCCT, which has been established as the core binding motif of PRDM9
Running LDsplit, we confirm that, when the 7-mer motif containing a Single nucleotide polymorphism (SNP) is disrupted by one allele of the SNP, its proximal hotspot would have lower intensity estimated from Linkage disequilibrium (LD) patterns
Summary
As a fundamental genomic element, meiotic recombination hotspot plays important roles in life sciences. Despite the recent identification of the zinc finger protein PRDM9 and its 13-mer binding motif as major regulators for meiotic recombination hotspots, other regulators remain to be discovered. It is desirable to understand how the locations and intensities of recombination hotspots are regulated. For the regulatory mechanisms of recombination hotspots, striking progress has been made recently, thanks to the high-throughput genomic technology and bioinformatics techniques. Three groups reported the discovery of PRDM9 protein as a trans-acting regulator of the locations and intensities of meiotic recombination hotspots in human and mouse [5,6,7]. The discovery of PRDM9 protein and its binding motifs was a major breakthrough in the understanding of the regulation of meiotic recombination hotspots. Follow-up investigation of the functions of PRDM9, e.g. its detailed mechanism to mediate the location and intensity of meiotic recombination, is under intense research [9,13,14]
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