The Genom of Homo sapiens.pdf

DNA Sequence Variation of Homo sapiensD.R. BENTLEYThe Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, United KingdomThe finished genome sequence of Homo sapiens(Rogers, this volume) provides a starting point for the studyof sequence variation in the human population. Every variantthat is discovered can be mapped back to the humangenome and correlated with genes, regulatory elements,and other functionally important sequences. As we gain abetter understanding of the biological information encodedby the human genome sequence, we should aim to definethe sequence variants that have biochemical and phenotypicconsequences.The genome sequence enables us to develop targetedstrategies to search for disease-related sequence variants.This requires a better understanding of the patterns of variationand of the genetic variants that can be used as referencemarkers throughout the genome. Genome sequenceinformation will also underpin future surveys of somaticvariation and cancer. Studying the DNA sequence variationof Homo sapiens will enable us to understand our originsand evolution and will help characterize the genetic basis ofour individuality—for example, in our susceptibility or resistanceto disease, and our variable response to drugs, toxins,and other environmental factors.THE ORIGIN OF SEQUENCE VARIATIONModern humans are believed to have migrated east outof Africa 50,000–60,000 years ago (Jobling et al. 2004)and subsequently spread across the world, replacing earlierHomo species. This pattern was originally deducedlargely from archaeological and anthropological evidence(Stringer 2002) but received substantial reinforcementfrom DNA sequence information. For example, geneticvariability is generally higher in Africa than on other continents,and phylogenetic reconstructions of non-recombiningregions usually place the root in Africa (Cavalli-Sforza and Feldman 2003; Pääbo 2003). A subset of thegenetic variants in Africa at the time were therefore presentin the migrant founders of all later subsequentgroups, while many variants remained only within populationsubgroups in Africa. More recent migrations betweendifferent parts of the globe have since contributedto admixture between multiple subgroups, and in the lastfew hundred years, this process has increased substantially.Sequence variation arises as a result of new mutationand recombination (see Fig. 1). Based on observed variationand simulations, the average human mutation ratehas been estimated to be 1–2 bases in 100 million per generation(Drake et al. 1998; Giannelli et al. 1999; Reich etal. 2002) which corresponds to around 30–60 new mutationsper gamete. For variants that are neutral (not underselection), the allele frequency in the population will beaffected by random drift. Many new mutations will disappearwithin a few generations; a few may become com-Figure 1. Origin of sequence variation. Sequence variation arises by mutation (colored bases) and by recombination (dotted lines).These processes give rise to individual haplotypes (listed on the right) that coexist in the population.Cold Spring Harbor Symposia on Quantitative Biology, Volume LXVIII. © 2003 Cold Spring Harbor Laboratory Press 0-87969-709-1/04. 55