Finally, in contrast to more mutable markers, such as microsatellites 21, SNPs have a low rate of recurrent mutation, making them stable indicators of human history. SNPs are binary, and thus well suited to automated, high-throughput genotyping. SNPs occur (on average) every 1,000–2,000 bases when two human chromosomes are compared 5, 6, 9, 18, 19, 20, and are thus present at sufficient density for comprehensive haplotype analysis. Most human sequence variation is attributable to SNPs, with the rest attributable to insertions or deletions of one or more bases, repeat length polymorphisms and rearrangements. The required density of markers will depend on the complexity of the local haplotype structure, and the distance over which these haplotypes extend, neither of which is yet well defined.Ĭurrent estimates (refs 13, 14, 15, 16, 17) indicate that a very dense marker map (30,000–1,000,000 variants) would be required to perform haplotype-based association studies. Such haplotype-based association studies offer a significant advantage: genomic regions can be tested for association without requiring the discovery of the functional variants. If limited haplotype diversity is general, it should be practical to define common haplotypes using a dense set of polymorphic markers, and to evaluate each haplotype for association with disease. As these common variants are responsible for most heterozygosity in the population, it will be important to assess their potential impact on phenotypic trait variation. Moreover, human genetic diversity appears to be limited not only at the level of individual polymorphisms, but also in the specific combinations of alleles (haplotypes) observed at closely linked sites 8, 11, 12, 13, 14. In the human population most variant sites are rare, but the small number of common polymorphisms explain the bulk of heterozygosity 3 (see also refs 5, 6, 7, 8, 9, 10, 11). One promising approach is systematically to explore the limited set of common gene variants for association with disease 2, 3, 4. If each locus contributes modestly to disease aetiology, more powerful methods will be required. For common diseases, genome-wide linkage studies have had limited success, consistent with a more complex genetic architecture. Genome-wide linkage analysis and positional cloning have identified hundreds of genes for human diseases 1 ( ), but nearly all are rare conditions in which mutation of a single gene is necessary and sufficient to cause disease. A central goal of genetics is to pinpoint the DNA variants that contribute most significantly to population variation in each trait. Inherited differences in DNA sequence contribute to phenotypic variation, influencing an individual's anthropometric characteristics, risk of disease and response to the environment.
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