The Human Genome Project and Molecular Anthropology Mark Stoneking 1

Downloaded from genome.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press PERSPECTIVE The Human Genome Project and Molecular Anthropology Mark Stoneking 1 Department of Anthropology, Pennsylvania State University, University Park, Pennsylvania 1 6802 It has been -10 years since the idea of determining MtDNA Genome Project was completed in 1981 the complete nucleotide sequence of the human ge- with the publication of the complete sequence of nome was first proposed as a "big-science" project the human mtDNA genome (Anderson et al. 1981). to the scientific community at the 1986 meeting at In considering what the HGP might mean for mo- Cold Spring Harbor Laboratory on the molecular bi- lecular anthropologists, then, it is instructive to ology of Homo sapiens (Bodmer 1986). The ensuing consider what the availability of a complete human decade has seen the realization of this goal as a wor- mtDNA sequence has meant for studies of human thy endeavor, and an enormous amount of progress mtDNA variation and evolution. has been made in developing new technologies and in determining a physical map of the genome. It appears as if the Human Genome Project (HGP) is Human DNA Variation and Evolution: Lessons from now in the home stretch, with the consensus mtDNA emerging that everything is in place to determine The complete human mtDNA sequence has greatly the sequence itself (Marshall and Pennisi 1996). Al- facilitated the analysis and interpretation of human though the HGP was initially promoted on the basis mtDNA variation and evolution. During the pre- of what the resulting knowledge would contribute PCR era of molecular anthropology, the complete to efforts to alleviate human misery caused (or con- human mtDNA sequence made possible detailed, tributed to) by our genes, the purpose of this paper high-resolution restriction site maps by the se- is to preview what a complete human DNA sequence-comparison mapping method (Cann et al. quence might mean for molecular anthropology. 1984). By comparing the DNA fragments generated Molecular anthropology is defined here as the by a particular restriction enzyme for a particular use of molecular genetic techniques to address ques- DNA sample to the DNA fragment that would be tions that anthropologists are interested in concern- predicted from the complete sequence, any differ- ing human evolution and diversity. Molecular an- ences could be localized quickly to a particular lo- thropology encompasses the analysis and interpre- cation in the mtDNA genome, and frequently the tation of the following: (1) patterns of molecular exact nucleotide substitution responsible for the genetic variation in various contemporary human polymorphism could be inferred. A recent African populations; (2) patterns of molecular genetic varia- origin of the human mtDNA ancestor was first pro- tion in nonhuman primate populations; (3) com- posed from such high-resolution restriction site parisons of human and nonhuman primate genes; studies (Cann et al. 1987), and restriction site analy- and (4) the retrieval of genetic information directly sis continues to be useful in tracing the evolutionary from ancient specimens. The purpose of this article history of particular human populations (Stoneking is not to review the present state of molecular an- et al. 1990; Wallace and Torroni 1992; Torroni et al. thropology, as that has been ably done in several 1993; Chen et al. 1995). recent edited volumes (Boyce and Mascie-Taylor With the advent of PCR, the availability of a 1996; Chadwick and Cardew 1996; Jackson et al. complete mtDNA sequence has meant that it is a 1996). Rather, what follows is a speculative preview trivial matter to design primers for amplifying and of what the HGP might contribute to molecular an- either sequencing or otherwise analyzing variation thropology. in any segment of mtDNA that might be of interest Mitochondrial DNA (mtDNA) has been used ex- (Schurr et al. 1990; Stoneking et al. 1991; Vigilant et tensively by molecular anthropologists, and the al. 1991), up to and including the entire mtDNA genome (Cheng et al. 1994; Horai et al. 1995). This has not only greatly facilitated the analysis of 1E-MAIL [email protected]; FAX (814) 863-1474. mtDNA variation within and among human popu- 7:87-91 9 by Cold Spring Harbor Laboratory Press ISSN 1054-9803/97 $5.00 GENOME RESEARCHJ 87 Downloaded from genome.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press STONEKING lations, but it has also made it much easier to deter- coming possible. And there is plenty of precedence mine mtDNA sequences from other species for evo- for this in the mtDNA field; it is well known that lutionary comparisons (Ruvolo et al. 1991; Horai et different mtDNA regions evolve at different rates, al. 1992; Morin et al. 1994). Thus, the HGP will aid and hence are not equally suitable for all studies. For similarly in analyzing human variation and evolu- analyzing variation within human populations, the tion by making it just as simple to design the prim- hypervariable segments of the noncoding mtDNA ers to amplify any stretch of nuclear DNA that is of control region provide the most information, interest. whereas for reconstructing primate evolution, more slowly evolving regions such as the mitochondrial rRNA genes are more appropriate--the control re- Selection of Appropriate Polymorphisms gion evolves too rapidly to be informative over mil- lions of years of evolutionary history, whereas the The HGP will permit a more rational approach to rRNA genes evolve too slowly to reveal how varia- selecting appropriate regions of nuclear DNA to ana- tion is apportioned within and between human lyze, depending on what question is being ad- populations. dressed. Historically, the selection of polymor- It is thus expected that HGP will permit molecu- phisms for studies of human nuclear genetic diver- lar anthropologists to select regions of the genome sity and evolution has been based largely on what is with evolutionary properties that can be utilized to available and what is popular, whereas the discov- the greatest advantage. This has already begun to ery of such markers has largely been driven by hu- some extent. For example, one type of polymor- man disease concerns. For example, the first poly- phism that is proving to be extremely useful for re- morphism was the ABO blood groups, which were constructing human evolution are Alu insertion discovered at the beginning of this century by Land- polymorphisms, where the polymorphism consists steiner in his efforts to understand and prevent of the presence or absence of an Alu element at a blood transfusion reactions, and were subsequently particular chromosomal location (Batzer et al. used by the Hirszfields in their pioneering studies of 1991). Because the insertion of an Alu element at a human genetic diversity (Mourant 1983). As an particular locus is a unique event, and because Alu aside, for those who would question the value of elements are rarely deleted (and even then, the de- human diversity studies, it is worth pointing out letion is never exact, but leaves behind a footprint), that the inheritance of the ABO blood groups was the presence of an Alu element marks a chromo- not worked out by family studies but, rather, by an somal region as being identical by descent for which elegant application of population genetic theory by the ancestral state is known; these properties have Bernstein that made use of the data collected by the been used to demonstrate that Alu insertion poly- Hirszfields (Crow 1993). morphisms indicate a recent African origin of mod- Subsequent polymorphisms involving gene ern humans (Batzer et al. 1994). Similarly, when one products in the blood that were initially discovered considers why mtDNA has proven to be so useful in by the medical genetic community [such as human reconstructing human evolution and population leukocyte antigen (HLA), immunoglobulin types, history, it is because not only is mtDNA highly vari- and isozymes] we later used in human diversity able, but the lack of recombination provides a studies without much consideration given to the framework for interpreting the high levels of vari- suitability of these polymorphisms for the ques- ability. This suggests that the most informative tions that were addressed. This trend continued nuclear DNA regions for reconstructing human evo- with the discovery of DNA polymorphisms, includ- lution would have these same properties, and two ing restriction fragment-length polymorphisms recent studies have focused on analyzing haplo- (RFLPs), variable number of tandem repeat (VNTR) types that consist of highly variable nuclear DNA polymorphisms, and short tandem repeat (STR) regions that are closely linked to (Tishkoff et al. polymorphisms, although in some cases these poly- 1996) or encompass (Armour et al. 1996) more morphisms have provided useful information (Bow- slowly evolving polymorphisms. The more slowly cock et al. 1994; Mountain and Cavalli-Sforza 1994; evolving polymorphisms enable much more de- Goldstein et al. 1995). tailed insight into the highly variable polymor- However, as our knowledge of properties of the phisms, and both studies provide strong support for human genome and the various types of polymor- a recent African origin of modern humans. phisms grows, a more rational selection of markers, Another fruitful source of markers for molecular appropriate to the questions being addressed, is be- anthropologists will arise out of the disease gene 88 J GENOME RESEARCH Downloaded from genome.cshlp.org on October 7, 2021 - Published by Cold Spring Harbor Laboratory Press HGP AND MOLECULAR ANTHROPOLOGY studies that will be facilitated by the HGP. As men- The "'New" Molecular Anthropology tioned previously, the HGP is usually promoted by the scientific community in terms of how it will These technological advances will, in turn, permit advance our knowledge of genes that contribute to molecular anthropologists to consider novel kinds abnormal (disease) variation in humans.

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