Abstract
The regulatory mechanism of recombination is a fundamental problem in genomics, with wide applications in genome-wide association studies, birth-defect diseases, molecular evolution, cancer research, etc. In mammalian genomes, recombination events cluster into short genomic regions called "recombination hotspots". Recently, a 13-mer motif enriched in hotspots is identified as a candidate cis-regulatory element of human recombination hotspots; moreover, a zinc finger protein, PRDM9, binds to this motif and is associated with variation of recombination phenotype in human and mouse genomes, thus is a trans-acting regulator of recombination hotspots. However, this pair of cis and trans-regulators covers only a fraction of hotspots, thus other regulators of recombination hotspots remain to be discovered. In this paper, we propose an approach to predicting additional trans-regulators from DNA-binding proteins by comparing their enrichment of binding sites in hotspots. Applying this approach on newly mapped mouse hotspots genome-wide, we confirmed that PRDM9 is a major trans-regulator of hotspots. In addition, a list of top candidate trans-regulators of mouse hotspots is reported. Using GO analysis we observed that the top genes are enriched with function of histone modification, highlighting the epigenetic regulatory mechanisms of recombination hotspots.
Highlights
Recombination is one of the most fundamental processes in molecular biology, and is under intense research in genomics
PRDM9 is a zinc finger protein that binds to DNA, and its binding site contains a 13-mer motif previously found to be enriched in human hotspots [5]
Using Chip-Seq data, Smagulova et al [8] analyzed the molecular features of mouse recombination hotspots, and observed that a consensus motif enriched in mouse hotspots aligns with the predicted binding site of mouse PRDM9 significantly
Summary
Recombination is one of the most fundamental processes in molecular biology, and is under intense research in genomics. Using an LD-based approach named LDsplit, Zheng et al [6] identified HapMap SNPs (single nucleotide polymorphisms) in human chromosome 6 that are associated with recombination hotspots, and confirmed the sperm typing experimental result on DNA2 hotspot [7]. Using Chip-Seq data, Smagulova et al [8] analyzed the molecular features of mouse recombination hotspots, and observed that a consensus motif enriched in mouse hotspots aligns with the predicted binding site of mouse PRDM9 significantly. These exciting discoveries are promising to integrate previously separate observations into one picture
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