Haplotype blocks

Burke MJ, Preskorn SH (1999) Therapeutic drug monitoring of antidepressants cost implications and relevance to clinical practice. Clin Pharmacokinet 37 147-165 Cardon LR, Abecasis GR (2003) Using haplotype blocks to map hiunan complex trait loci. Trends Genet 19 135-140... 

Cardon LR, Abecasis GR. Using haplotype blocks to map human complex trait loci. Trends Genet 2003 19 135-140. 

Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, Blumenstiel B, Higgins J, DeFelice M, Lochner A, Faggart M, Liu-Cordero SN, Rotimi C, Adeyemo A, Cooper R, Ward R, Lander ES, Daly MJ, Altshuler D. The structure of haplotype blocks in the human genome. Science 2002 296 2225-2229. 

If the human genome is partitioned into haplotype blocks, the definition of LD can be refined. Because a given local haplotype block has multiple variants, the probability that SNPs that are in LD but are not located on the same haplotype block will be in phase (i.e., part of the same local haplotype structure) is a function of increasing distance. For instance, in a hypothetical situation in which two variants or forms are available for every haplotype block, the probability that pairwise SNPs in LD will not be part of the same local haplotype (in phase) is 0.5"+1, where n represents the number of haplotype blocks that separate the two SNPs. For example, if the SNPs are on adjacent blocks (zero block separation), the probability that they will be part of the same local haplotype is 0.5 or 50%. This is the upper limit for SNPs not present on the same haplotype block in this situation. If SNPs are separated by four blocks, the probability that they are part of the same local haplotype falls to 0.03 or 3%, because now there are more blocks and hence more possibilities for variation between the SNPs. 

Wall JD, Pritchard JK. Haplotype blocks and linkage disequilibrium in the human genome. Nat Rev Genet 2003 4 587-597. 

Genome-Wide Association Studies and Haplotype Blocks... 

Haplotype block Hapblock A discrete genome region of high LD and low haplotype diversity, hypothesized to be a region of low recombination flanked by hotspots of high recombination... 

Haplotype tagging SNP HtSNP SNP that can define the haplotype block structure within a genomic region... 

However, Wall and Pritchard s (94) analysis of that same study showed that although recombination hotspots do exist, 50% of the genome cannot be categorized as block-like. Several authors have therefore stressed the importance of a more dense SNP map to better define both the length and integrity of haplotype blocks (hapblocks) in the human genome (94,95). 

Even if the genes influencing a complex disease or trait all fall within haplotype blocks, the haplotype tagging approach will only be effective if the alleles associated with the disease or trait are relatively common. On the contrary, if the alleles associated with a complex disease are very rare (frequency < 1%) such variants are likely to be missed using the LD methods so far described. In fact, if a disease is caused by one or only a few genes with many distinct and individually very rare alleles, linkage analysis can perform better than association-based tests (50). 

Wall JD, Pritchard JK. Assessing the performance of the haplotype block model of linkage disequilibrium. Am J Hum Genet 2003 73 502-515. 

Tishkoff SA, Verrelli BC. Role of evolutionary history on haplotype block structure in the human genome implications for disease mapping. Curr Opin Genet Dev 2003 13 569-575. 

Anderson EC, Slakin M. Population-genetic basis of haplotype blocks in the 5q31 region. Am J Hum Genet 2004 74 40-49. 

In other words, it is believed that a set of haplotype blocks exist, where SNPs within such block boundaries change together, that is, knowing one would reveal the identity of the others. The existence of such boundaries has been the subject of much debate. The haplotype blocks in older populations (e.g., Africans) range from less than 1 Kb to 100 Kb, and in younger populations (e.g., Finns) from more than 50 Kb to more than 1 Mb [7]. The International Haplotype Map project (HapMap) was funded a few years ago and is moving quickly toward completion. The hope is that with the aid of haplotype blocks, one may be able to scale down from analysis of 3 million SNPs to approximately 300,000 SNPs. 

It was mentioned that representative SNPs of haplotype blocks could play a major role in pharmacogenomics by allowing researchers to use a smaller set of SNPs in association and linkage studies. The three popular ways by which haplotype boundaries can be detected are Confidence Intervals [21], Four Gamete Rule [22], and Solid Spine of LD. 

In an attempt to systematically identify the haplotype blocks and assign their corresponding tag SNPs, the International Haplotype Map (HapMap) Project was established in October 2002. This project is a collaboration of scientists from the United States, Canada, China, Japan, the United Kingdom, and Nigeria. Table 13.2 shows the breakdown of the chromosomes and percent coverage on genome for HapMap participants (http //www.hapmap.org). 

Wang, N., J. M. Akey, K. Zhang, R. Chakraborty, and L. Jin. 2002. Distribution of recombination crossovers and the origin of haplotype blocks The interplay of population history, recombination, and mutation. Am J Hum Genet 71 1227-34. 

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