This change in concepts marks the beginning of the end of Mendel’s world,10 which was filled with rare mutations that caused discrete protein effects and gross, visible phenotypic effects. Progress in human genome research transforms genetic variation into a central research theme Major developments in the Human Genome Project have catalyzed

Inhibitors,research,lifescience,medical a dramatic change in picture, transforming the analysis of genetic variation and its implications for disease causation and individually different, drug response into a major research theme. Pharmacogenomics, the vision of a “personalized” medicine and the development of prescriptions with a personal touch, has become the focus of attention and a widely discussed topic.11-14 Such progress was in particular spurred by the development, of cloning and high-throughput sequencing this website technologies,15 the availability of Inhibitors,research,lifescience,medical a draft sequence of the human genome,16,17 and consequently, access to all human genes and their regulators, transcripts, and proteins as the basis for disease gene and drug target, discovery.

With defined reference sequences of genes and genomes, sequence comparisons within and between species became Inhibitors,research,lifescience,medical feasible and, consequently, the identification of differences in DNA sequence, so-called single nucleotide polymorphisms (SNPs).18 For the first, time, human genome variation data Inhibitors,research,lifescience,medical were generated on a large scale, resulting in the establishment, of SNP maps19 and public variation databases. Thus, it was for the first time possible to study the amount, nature, and structure of human genetic variation on a large scale.20-23 For this purpose, different, approaches were taken, ie, completely different, approaches to resolution, which led to completely different pictures of Inhibitors,research,lifescience,medical genetic variation. In the first, series of studies, the structure of genetic variation (specifically the pattern and extent of linkage disequilibrium [LD] between SNPs)

was assessed on a genome-wide scale. Common SNPs, with frequencies of the minor allele >5% to >30%, were randomly generated or extracted from databases at distances of 1.3 to 15 kb, and genotyped in limited numbers of individuals. As a result, SNPs were found to cooccur, ie, exist in blocks of strong Florfenicol LD, within genomic regions that extended up to about 60 to 100 kb in populations of European descent.20-23 These specific combinations of closely linked SNP alleles (haplotypes) were separated by regions of recombination, indicating a haplotype block structure of the human genome.20-23 Because the strong LD between SNPs appeared to result in a striking lack of genetic diversity, only a limited number of haplotypes, two to five per block, were observed, accounting for 75% to 98% of all chromosomes.