The Effect of Single-Nucleotide Polymorphism Marker Selection on Patterns of Haplotype Blocks and Haplotype Frequency Estimates

The definition of haplotype blocks of single-nucleotide polymorphisms (SNPs) has been proposed so that the haplotypes can be used as markers in association studies and to efficiently describe human genetic variation. The International Haplotype Map (HapMap) project to construct a comprehensive catalog of haplotypic variation in humans is underway. However, a number of factors have already been shown to influence the definition of blocks, including the population studied and the sample SNP density. Here, we examine the effect that marker selection has on the definition of blocks and the pattern of haplotypes by using comparable but complementary SNP sets and a number of block definition methods in various genomic regions and populations that were provided by the Encyclopedia of DNA Elements (ENCODE) project. We find that the chosen SNP set has a profound effect on the block-covered sequence and block borders, even at high marker densities. Our results question the very concept of discrete haplotype blocks and the possibility of generalizing block findings from the HapMap project. We comparatively apply the block-free tagging-SNP approach and discuss both the haplotype approach and the tagging-SNP approach as means to efficiently catalog genetic variation.