Haplotype structures

Clark AG, Weiss KM, Nickerson DA, Taylor SL, Buchanan A, Stengard J et al. Haplotype structure and population genetic inferences from nucleotide-sequence variation in human lipoprotein lipase. Am J Hum Genet 1998 63 595— 612. 

This chapter reviews recent progress in irinotecan pharmacogenetics, including novel functional genetic variations and the haplotype structures of UGTlAs, with particular focus on the cumulative data showing the clinical relevance of UGTIAI... 

Haplotype Structures Covering the UGTIA Gene and Ethnic Differences... 

Innocent F, Grimsley C, Das S et al. Haplotype structure of the UDP-glucuronosyltransferase lAl promoter in different ethnic groups. Pharmacogenetics 2002 12 725-733. 

Saeki M, Saito Y, Jinno Ft et al. Haplotype structures of the UGTIA gene complex in a Japanese population. Pharmacogenomics J2006 6 63-75. 

Marsh S, King CR, Porche-Sorbet RM, et al. Population variation in VKORKCI haplotype structure. J Thromb Haemost 2006 4 473-474. 

HAPLOTYPE STRUCTURE IN THE HUMAN GENOME 3.1. Haplotype Classification... 

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. 

Our knowledge about how haplotype analysis may be applied to pharmacogenomics, as well as our understanding of human haplotype structure in general, is in its infancy. In fact, only recently has it been discovered... 

Selection is expected to produce LD non-randomly across the genome, whereas all the other factors should act randomly over the genome. Some regions, such as HLA, show strong evidence of selection and significant LD which spans 3 cM or more. The LD and haplotype structure of the genome is currently being studied by the National Institutes of Health Haplotype Map project (Sec. 4.5). 

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