title: ARG-walker: inference of individual specific strengths of meiotic recombination hotspots by population genomics analysis.
abstract: BACKGROUND
  Meiotic recombination hotspots play important roles in various aspects of genomics, but the underlying mechanisms for regulating the locations and strengths of recombination hotspots are not yet fully revealed. Most existing algorithms for estimating recombination rates from sequence polymorphism data can only output average recombination rates of a population, although there is evidence for the heterogeneity in recombination rates among individuals. For genome-wide association studies (GWAS) of recombination hotspots, an efficient algorithm that estimates the individualized strengths of recombination hotspots is highly desirable.
  
  
  RESULTS
  In this work, we propose a novel graph mining algorithm named ARG-walker, based on random walks on ancestral recombination graphs (ARG), to estimate individual-specific recombination hotspot strengths. Extensive simulations demonstrate that ARG-walker is able to distinguish the hot allele of a recombination hotspot from the cold allele. Integrated with output of ARG-walker, we performed GWAS on the phased haplotype data of the 22 autosome chromosomes of the HapMap Asian population samples of Chinese and Japanese (JPT+CHB). Significant cis-regulatory signals have been detected, which is corroborated by the enrichment of the well-known 13-mer motif CCNCCNTNNCCNC of PRDM9 protein. Moreover, two new DNA motifs have been identified in the flanking regions of the significantly associated SNPs (single nucleotide polymorphisms), which are likely to be new cis-regulatory elements of meiotic recombination hotspots of the human genome.
  
  
  CONCLUSIONS
  Our results on both simulated and real data suggest that ARG-walker is a promising new method for estimating the individual recombination variations. In the future, it could be used to uncover the mechanisms of recombination regulation and human diseases related with recombination hotspots.
authors.forename: Hao
authors.initials: H
authors.lastname: Chen
authors.forename: Peng
authors.initials: P
authors.lastname: Yang
authors.forename: Jing
authors.initials: J
authors.lastname: Guo
authors.forename: Chee Keong
authors.initials: CK
authors.lastname: Kwoh
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Przytycka
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
mesh_terms: D000465:Algorithms; D044466:Asian People / Q000235:genetics*; D002681:China; D003198:Computer Simulation; D014644:Genetic Variation; D015894:Genome, Human; D055106:Genome-Wide Association Study / Q000379:methods*; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D059765:Homologous Recombination; D006801:Humans; D007564:Japan; D008540:Meiosis; D056186:Metagenomics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D011495:Histone-Lysine N-Methyltransferase; C544431:PRDM9 protein, human