The application of molecular genetic approaches to the study of human evolution L. Luca Cavalli-Sforza 1 & Marcus W. Feldman 2 doi:10.1038/ng1113 The past decade of advances in molecular genetic technology has heralded a new era for all evolutionary stud- ies, but especially the science of human evolution. Data on various kinds of DNA variation in human popula- tions have rapidly accumulated. There is increasing recognition of the importance of this variation for medicine and developmental biology and for understanding the history of our species. Haploid markers from mitochon- drial DNA and the Y chromosome have proven invaluable for generating a standard model for evolution of modern humans. Conclusions from earlier research on protein polymorphisms have been generally supported by more sophisticated DNA analysis. Co-evolution of genes with language and some slowly evolving cultural traits, together with the genetic evolution of commensals and parasites that have accompanied modern humans in their expansion from Africa to the other continents, supports and supplements the standard model of genetic evolution. The advances in our understanding of the evolutionary history of humans attests to the advantages of multidisciplinary research. review 266 nature genetics supplement • volume 33 • march 2003 1 Department of Genetics, Stanford Medical School, Stanford University, Stanford, California 94305-5120, USA. 2 Department of Biological Sciences, Stanford University, Stanford, California 94305-5020, USA. Correspondence should be addressed to M.W.F. (e-mail: marc@charles.stanford.edu). Reconstructing human evolution requires both historical and statistical research. Although conclusions are not experimentally verifiable because the process cannot be repeated, various disci- plines such as physical and social anthropology, archaeology, demography and linguistics provide complementary approaches to researching questions of human evolution. The existence of molecular genetic variation among human populations was first demonstrated by Hirszfeld and Hirszfeld 1 in a classic study pub- lished in 1919 of the first human gene to be describedABO, which determines ABO blood groups. The subsequent identifica- tion of blood group protein markers, such as MNS and Rh expanded the repertoire of polymorphic markers that could be analyzed using antibodies. R.A. Fisher showed that evolution could be reconstructed by analyzing the multilocus genotypes on a chromosome observed in populations and their inheritance within families 2 . The term ‘haplotype’ for the multilocus combi- nation of alleles on a chromosome was introduced by Ceppellini et al. 3 during early research on the major histocompatibility complex. Immunological methods remained the only satisfac- tory technique for detecting genetic variation until Pauling et al. 4 introduced electrophoresis to separate different mutants of hemoglobin, a technique that was rapidly adapted to analyze variation in other blood proteins . It was soon obvious that genetic variation was not rare but, on the contrary, that almost every protein had genetic vari- ants 5,6 . These variants became useful markers for population studies. The first book of allele frequencies in populations, published in 1954, was limited almost completely to serological variation 7 , and books listing genetic variation increased rapidly in size and number 8–10 . In 1980, a method for studying varia- tion in DNA 11 identified mutants of restriction sites by using radioisotopes and generated several new markers. But it was only with the development of PCR in 1986 that the study of more general DNA variation became possible. The develop- ment of automated DNA sequencing in the early 1990s paved the way for the application of systematic study of genome varia- tion to human evolutionary biology. Data from protein markers (sometimes called ‘classical’ mark- ers) are still more abundant than are data from DNA, although this situation is rapidly changing. For example, Rosenberg et al. 12 studied 377 autosomal microsatellite polymorphisms in 1,065 individuals from 52 populations producing a total of 4,199 dif- ferent alleles, about half of which were found in all principal con- tinental regions. Another study 13 of 3,899 single-nucleotide polymorphisms (SNPs) in 313 genes sampled in 82 Americans self-identified as African American, Asian, European or Hispanic Latino found that only 21% of the sites were polymorphic in all four groupsa fraction that would be expected to increase with more sampled individuals. It is interesting to note, however, that so far no conclusions derived from the earlier studies of classical polymorphisms 14 have been found to be in disagreement with those obtained with DNA markers. Nonetheless, molecular genetic markers have provided previously unavailable resolution into questions of human evolution, migration and the historical © 2003 Nature Publishing Group http://www.nature.com/naturegenetics