Fine-scale detection of population-specific linkage disequilibrium using haplotype entropy in the human genome

To find population-specific LD within small regions, we have devised an entropy-based method that utilizes differences in haplotype frequency between populations. The method has the advantages of incorporating multilocus association, conciliation with low allele frequencies, and independence from allele polarity, which are ideal for short haplotype analysis. The comparison of HapMap SNPs data from African and Caucasian populations with a median resolution size of ~23 kb gave us novel candidates as well as known selection targets. Enrichment analysis for the yielded genes showed associations with diverse diseases such as cardiovascular, immunological, neurological, and skeletal and muscular diseases. A possible scenario for a selective force is discussed. In addition, we have developed a web interface (ENIGMA, available at http://gibk21.bse.kyutech.ac.jp/ENIGMA/index.html webcite), which allows researchers to query their regions of interest for population-specific LD.The haplotype entropy method is powerful for detecting population-specific LD embedded in short regions and should contribute to further studies aiming to decipher the evolutionary histories of modern humans.Modern humans emerged in Africa approximately 200,000 years ago and over the last 100,000 years dispersed around the world adapting to different environments [1]. The evolutionary histories during this period are reflected in the human genome by "selective sweeps" wherein beneficial alleles keep the genetic patterns of the surrounding sites [1,2]. The recent availability of high density maps of single nucleotide polymorphisms (SNPs) has provided us with a unique opportunity to uncover such selection traits.Classically, statistical measurements such as r2 and D' that test linkage disequilibrium (LD) at the resolution of two SNPs have been used to detect regions that have undergone recent selection [2]. However, their pairwise fashion cannot capture multilocus associations and so their testing power is