Molecular anthropology is the anthropological study of

Paul Plotz sits in his office in the clinical center at the National Institutes of Health (NIH) and recites the opening stanza of Woody Guthrie's song, “So Long, it's Been Good to Know You.” The classic folk song begins: “I've sung this song, but I'll sing it again, of the people I've met and the places I've seen….” Plotz, a researcher at the NIH's National Institute of Arthritis and Musculoskeletal and Skin Diseases, in Bethesda, Maryland, says the words are appropriate for describing the power of studies that use molecular biology to shed light on the history of human migrations. “The people you've met and the places you've seen are in your genome,” he says.

For investigators in the young but flourishing field of anthropological genetics, the human genome offers an ultimately decipherable record of the origins and history of modern humans. By studying the patterns of genetic similarities and differences among human populations, anthropological geneticists can determine the degree of relatedness among different groups and learn about a society's mating structures, historical fluctuations in population size, and the amount of mixing, or admixture, that occurred between populations.

Although much excitement and controversy has swirled around genetic research on the origins of Homo sapiens, genetic anthropologists are also interested in deciphering more recent events in the story of the human race, such as the history and patterns of human migrations. Such questions have traditionally been studied by cultural anthropologists, who use ethnography (the detailed analysis of cultural practices), archaeology, and linguistics to examine the relationships among human populations.

More recently, geneticists have gotten into the act. They began with studies of the so-called classical polymorphisms, examining variation in blood groups, human leukocyte antigen (HLA) types, and other genetic markers among individuals and populations. But it was the molecular biology revolution of the 1980s, including the development of the polymerase chain reaction (PCR), that allowed researchers to study human genetic variation directly at the DNA level rather than at the protein level, throwing open the doors to the new field of anthropological genetics.

Studying genetic polymorphisms at the DNA level provides many advantages for those in search of information on the history of human populations. DNA sequences contain more information than protein sequences, and techniques for studying DNA sequence variation are more reproducible and more easily automated.

In addition, the type and number of DNA polymorphisms available for analysis continues to grow. Commonly studied polymorphic sequences include mitochondrial DNA (mtDNA) and Y chromosome sequences (which tell about maternal and paternal ancestry, respectively); HLA and other genes that code for known polymorphic proteins; and microsatellite DNA—multiple repeats of short nucleotide sequences whose repeat numbers vary from individual to individual. Researchers can analyze these DNA sequences for single nucleotide polymorphisms (SNPs)—that is, replacement, loss, or addition of one nucleotide—and for larger insertions or deletions.

Tracking gene movements along the ancient Silk Road

Geneticist Spencer Wells, who recently completed a postdoctoral fellowship with Luca Cavalli-Sforza at Stanford University, exemplifies the new breed of anthropology researcher whose tools include those of the molecular biology laboratory. Much like traditional anthropologists, genetic anthropologists must sometimes venture into the field. In Wells' case, he and his colleagues spent the summer of 1998 traveling through Eastern Europe and Central Asia along the ancient east-west trade route known as the Silk Road, collecting human blood samples and DNA along the way. Wells, now a research fellow at Oxford University, and research team members Ruslan Ruzibakiev, of the Uzbek Academy of Sciences, and Nathaniel Pearson, a graduate student at the University of Chicago, collaborated with local scientists at each stop along the route. Photographer Mark Read and BBC journalist Darius Bazergan joined the team to help record the journey.

The research team's mission is to explore the relationships among the peoples of the region, which Wells describes as “the melting pot of Asia.” The project's ultimate goal, Wells says, “is to figure out how these people are related to each other, how the groups arose, how they've moved around and interacted.” The answers to such questions as the origins of Indo-European languages, the history of how Turkic groups spread into central Asia, and the degree of admixture that occurred between local populations and invading peoples such as the Mongol armies of Genghis Khan may lie buried in the DNA of the Eurasian people— whose written history, Wells notes, goes back only a few hundred years.

The 1998 trip was the follow-up to a 1996 expedition to Uzbekistan and Kyrgyzstan by Wells, Ruzibakiev, and Read, during which the researchers collected blood samples from members of 13 different linguistic groups. Analysis of DNA polymorphisms from these samples revealed evidence of ancient admixture between groups from western and eastern Asia. “From the preliminary data we obtained, it was quite obvious we needed samples from surrounding areas—the Caucasus, the Middle East, Iran, and also Siberia,” Wells says. Thus, the journey dubbed “EurAsia '98” was born.

At each stop along the route, Wells and his colleagues, with the aid of local collaborators, explained the purpose of their work to volunteers, who donated blood samples for the study. In collaboration with other research groups around the world, Wells plans to analyze the DNA from these samples for polymorphisms in mtDNA, Y chromosome sequences, microsatellites, and HLA genes to find clues to the historical relationships among different groups.

The researchers used linguistics as a guide when choosing their study populations, “in part because ethnic and racial groups have no clear meaning at the genetic level,” Wells explains. Indeed, researchers have found that for the 0.1 percent of the genome that varies between any two individuals, approximately 85 percent of this genetic variation can be found within a single population, whereas only approximately 10–15 percent distinguishes racial and ethnic groups. By contrast, Wells says, “there has been a lot of work done, mostly by Cavalli-Sforza and his colleagues, showing that languages are very good markers for genetic relatedness.” Nevertheless, he notes, “there's been a bit of debate about how you sample these populations: Do you sample purely on the basis of some external criteria, like linguistic or cultural data or history, or do you simply draw a grid and…sample every 500—or 50 or 1000—kilometers across the entire continent of Asia? I think you really need to do both things—especially in areas where nomads live, or in areas where a single linguistic or ethnic group lives.”

Such studies of human genomic diversity can be fraught with cultural and political sensitivities (see BioScience 48: 496). For one thing, Wells says, people have their own myths regarding their origins, passed down through oral history—myths that anthropological genetics may or may not confirm. And although most people were happy to give blood samples once they understood the project's goals, the team did encounter occasional reluctance. For example, Wells says, he was shocked to learn that the Ossetian people of the Republic of Georgia—who speak a different language from the surrounding Georgians and see themselves as a distinct ethnic group— initially feared that the researchers and their Georgian collaborators “might be trying to infect them with something which would destroy their ethnic group and allow the Georgians to come in and take over their land.”

Wells and his team were sensitive to such issues, and “we haven't gone in as conquering imperialist scientists, taken the samples, and left,” he says, emphasizing the ongoing nature of collaborations with scientists in the countries along the route. In addition, many study volunteers expressed interest in finding out what their DNA reveals about their own histories, and Wells hopes to use the local media, some of whom covered the 1998 trip, to spread word of the project's results.

The researchers already have some intriguing results from the samples they collected on their 1996 trip. “We found some very interesting patterns, which…traced the possible origins—certainly the spread—of proto-Indo-European nomads,” Wells says. “We found evidence of what we think are Middle Eastern genes [moving] eastward along the Silk Road into China.” The researchers also studied a Y chromosome marker that is found at a fairly high frequency in Mongolians but is hardly seen at all in central Asians. Wells says this finding suggests that the invading Mongols “probably didn't leave as strong a genetic impression as they did a cultural and historical one” during their conquest of Asia.

Indeed, some human migrations, Wells notes, involve “a small number of people who are moving into a much larger population group,” so that the genetic influence of the immigrants on the extant population is relatively small. Archeologist Colin Renfrew, Wells says, refers to this situation as “the ‘elite dominance model’—you have a people who conquer a region simply because they're technologically advanced, and they don't necessarily inundate it with people.” Another type of migration is the movement of a large group of people from one region to another. “I think the history of human migration is really a combination” of these two types of population movements, Wells says.

Studying migration in the Pacific islands

Evidence for both types of population movements can be found in the results of recent genetic studies of human history in the islands of Pacific Oceania. Archaeologists, anthropologists, and other prehistorians have long been intrigued by the origins of and relationships among the human inhabitants of this far-flung group of islands. In recent years, Erika Hagelberg, a biochemist at the University of Otago, in Dunedin, New Zealand, and other researchers have been using the techniques of genetic anthropology—including the study of ancient DNA—to unravel the complicated history of human migration in these islands.

Anthropological genetic studies are yielding new information on the complex history of human migration among the islands of the Pacific, which are divided into the regions of Melanesia, Micronesia, and Polynesia. Map reproduced from E. Hagelberg, Electrophoresis 18: 1529–1533, Wiley-VCH Publishers, Inc., Weinheim, Germany.

The Pacific islands are divided somewhat arbitrarily into three groups: Melanesia, which consists of Papua New Guinea and many smaller islands; Micronesia, the small islands to the north of Melanesia; and Polynesia, which is a huge triangle with New Zealand, Hawaii, and Easter Island at its corners (see map this page). Although modern-day Polynesians are scattered across a wide area, they speak similar languages, all of which are part of the large Austronesian language family spoken throughout Southeast Asia, New Zealand, coastal Papua New Guinea, parts of island Melanesia, and as far west as Madagascar. Polynesians also share cultural and physical characteristics, bearing a resemblance to Southeast Asians. Papua New Guineans and other Melanesians, by contrast, are diverse in language, culture, and appearance, although many have dark skin and the people of highland New Guinea and some residents of island Melanesia share related Papuan languages.

The physical differences among peoples of the Pacific are thought to be due to the lengthy interval between the arrival of different population groups into the region. Australia and Papua New Guinea were settled by small groups of hunter-gatherers as many as 60,000 years ago, and humans arrived from the west to parts of island Melanesia at least 33,000 years ago. But archaeological evidence suggests that humans did not arrive in the central Pacific region of Fiji, Tonga, and Samoa until much more recently—approximately 3500 years ago—and the farthest reaches of Polynesia were settled only in the past 1500 years or so.

The origins and migration history of Pacific populations, and the biological and linguistic relationships among them, have been the subject of a great deal of study and debate. One theory on the settlement history of the Pacific, known as the “express train to Polynesia model,” is supported by many scholars on the basis of linguistic and archaeological evidence and data from studies of modern mtDNA. This model holds that the first settlers of Polynesia were Austronesian-speaking agricultural people from island Southeast Asia who sailed many thousands of kilometers into the central Pacific just several thousand years ago. Along with Austronesian languages, the theory says, the proto-Polynesian settlers brought with them a culture known as Lapita, noted for its distinctive pottery, domesticated animals, and navigational skills, and believed to have its cultural and linguistic origins in agricultural societies that developed in southern China approximately 8000 years ago.

In the early 1990s, Hagelberg was working in the laboratory of John Clegg, at the University of Oxford's Institute of Molecular Medicine, when she became interested in learning about the history of human migration patterns in the Pacific using DNA recovered from ancient human bones—a task that was greatly facilitated by the development of PCR techniques. Hagelberg hoped that such studies would help resolve conflicting evidence on the origins of different Pacific populations and the settlement history of the Pacific derived from genetic studies of modern-day Pacific islanders. Although studies of ancient DNA can be constrained by the often limited number of human remains available and pose special technical challenges because of the risk that ancient tissue samples may be contaminated with modern DNA, such studies can nevertheless yield information about events in human history that analysis of modern DNA may not readily provide.

Hagelberg examined mtDNA polymorphisms in samples from skeletons that were between 300 and 2700 years old from several Pacific island archaeological sites and compared her findings to data from analyses of mtDNA from modern-day Pacific islanders. She chose to study mtDNA because, at 1000–10,000 copies per cell, “you stand a much better chance of retrieving a piece of mtDNA than a single-copy [nuclear] gene”—an important consideration when working with ancient and often degraded tissues. And mtDNA has a relatively rapid mutation rate, making it useful for studying evolutionary events over recent timescales.

The results of Hagelberg's work with Clegg and other colleagues on ancient mtDNA, along with data from Hagelberg's more recent studies of modern DNA, suggest that the “express train to Polynesia” model for the settlement of Pacific Oceania may be “an oversimplified explanation of Pacific prehistory,” she says. Although Hagelberg agrees that there was a rapid and recent expansion of people into Polynesia, the analyses of ancient DNA suggest that the first people to expand into the islands of the western and central Pacific, perhaps as far as Fiji, were not Polynesians but rather were related to modern-day Melanesians. She believes that more recent Polynesian arrivals from Southeast Asia then displaced some of the earlier settlers of island Melanesia and the central Pacific. Furthermore, Hagelberg says, her analysis of mtDNA from skeletal remains associated with Lapita archaeological sites in the Pacific supports a still-controversial theory, also supported by some anthropological evidence, that the Lapita culture may have its origins in Melanesia rather than among the proto-Polynesian people from Southeast Asia.

Hagelberg notes that her views on the “express train” model and the origins of the Lapita culture go against the prevailing tide, particularly among geneticists. But she hopes to formulate a new model for the settlement history of the Pacific and do further research to prove or disprove her model.

Hagelberg's recent genetic studies of modern-day people add new information to the complex picture of the history of human migration in the Pacific. Along with colleagues from Germany, Hagelberg examined mtDNA, HLA, and Y chromosome polymorphisms in approximately 300 individuals from eight geographic locations in Asia and the Pacific. The researchers' objective was to determine whether there is a straightforward relationship between the spread of Austronesian languages and of genes among peoples of the Pacific, thereby gaining further insight into the nature and timing of the proto-Polynesian expansion into this region.

The relatively recent influx of Austronesian-speaking seafarers from Southeast Asia into the Pacific is thought to have displaced Papuan speakers from some parts of coastal Papua New Guinea and many island areas of Melanesia. But although the people living in these areas today speak Austronesian languages, they are “Melanesian” in appearance. Hagelberg's results, which show a variable distribution pattern for DNA polymorphisms thought of as typically “Polynesian” or “Melanesian” among Austronesian-speaking people from different locations, indicate that there is no simple correlation between the spread of language and genes across the Pacific. The Tolai people of the Melanesian island of New Britain, for example, have a relatively low frequency of the mtDNA polymorphisms that are characteristic of Polynesians, and their most common HLA type is one that is typical of many Melanesians. The Tolai are Melanesian in appearance, yet the Tolai language is Austronesian.

The results of these studies, Hagel-berg says, indicate that people can acquire a new language without acquiring the genes of the newcomers. Languages can be acquired by people for many reasons, and she and her colleagues hypothesize that some Papuan people in island Melanesia adopted Austronesian languages to facilitate trade with their new island neighbors. The expansion of the Austronesians into the Pacific may have had a greater genetic impact in some regions than others—depending, for instance, on how technologically developed the earlier settlers were and on their population size. Thus, as Wells found in Eurasia, multiple factors determine the degree of genetic mixing between immigrants and resident peoples. For example, Hagelberg says, some islands in Melanesia may have been more sparsely populated or more accessible, and thus more likely to become dominated by the genes— and culture—of the Austronesian-speaking newcomers.

Hagelberg and her colleagues also found a high frequency and homogeneity of typically Polynesian mtDNA sequences among people from island Melanesia and coastal New Guinea, leading the researchers to suspect a relatively recent (within the last few hundred years) major back-migration of people from Polynesia to islands farther west in the Pacific—the direction, Hagelberg notes, of the prevailing ocean currents. The genetic evidence of back-migration, she says, is consistent with some archaeological evidence. Indeed, gaining greater understanding of the complex pattern of genes and languages among Pacific islanders, Hagelberg says, will require going full circle to link the genetic data with information from more traditional anthropological approaches such as archaeology, ethnography, and linguistics.

Rare disease gene reveals African-American roots

Examining genetic data in the context of information from other fields enabled NIH's Plotz—a rheumatologist who studies rare muscle diseases—to discover the genome's potential to provide new insights into the history of human migration. In this case, Plotz used genetics to trace a different type of migration: the forced migration of Africans to America during the Atlantic slave trade.

Whereas much genetic anthropology research is based on the study of so-called “neutral polymorphisms”— that is, DNA sequence variations that have no apparent effect on pheno-type—Plotz and his colleagues used a specific mutation that is associated with a disease to trace the African origins of African-Americans. Although this type of marker is used less often, it is nonetheless valuable. Indeed, Plotz points out that “disease mutations are entrenched polymorphic markers…. There is a dichotomous terminology in which people say ‘mutation’ and ‘polymorphism’ to mean two different things, whereas they're really the same thing.”

Researchers used a rare disease-causing mutation to trace the likely African origins of African-Americans with the disease, known as Pompe Syndrome, or acid maltase deficiency (AMD). Present-day African carriers of AMD come from the four areas of Africa identified on the map and are affiliated with four different tribes (shown in parentheses). The mutation was probably carried to the Americas by the Ashanti people, although it most likely arose among the Hausa people at least 1000 years ago and spread to the other tribes. Map: Paul Plotz, as adapted from the US Geological Survey.

The primary focus of Plotz's research is a group of inflammatory muscle diseases known as myositis. But he became interested in a rare recessively inherited disorder known as Pompe Syndrome, or acid maltase deficiency (AMD), when Cornelius Boerkoel, a former student in his laboratory, diagnosed the disorder in a patient whom doctors had thought had myositis. In its mildest form, AMD—which causes glycogen to accumulate in lysosomes in skeletal and heart muscle—first shows up in adults as progressive muscle weakness, “looking for all the world like myositis,” Plotz says. In its most severe form, AMD causes fatal heart failure in the first year of life.

Working in Plotz's lab, Jeffrey Becker, Nina Raben, and Elizabeth Adams began identifying the various disease-causing mutations in the acid maltase gene in patients with AMD. Through a fortuitous series of coincidences, the researchers discovered the same mutation—dubbed R854X—in an African-American infant with AMD and in three African infants with the disease who were born in Washington, DC, within a single year while their parents were working there temporarily.

At that point, Plotz says, “we got our hands on [samples from] every known African-American case [of AMD].” Among the 12 additional African-American patients studied, seven had the R854X mutation— which converts an arginine codon in the acid maltase gene to a stop codon— as did a fourth African AMD patient. Intrigued by these findings, Plotz wondered whether there was a connection between the African-Americans with R854X and the Africans who had the same mutation. Were they descended from a common ancestor? Or had the mutation simply arisen several times independently?

To find out, the researchers analyzed polymorphisms in the DNA sequences flanking the R854X mutation in the acid maltase gene in each patient. The idea was to determine whether the rest of the acid maltase gene had the same polymorphisms in all Africans and African-Americans with the disease (which would indicate a common ancestor) or whether the rest of the AMD gene was different (which would indicate that the mutation arose several times).

Indeed, the researchers found that “in every case that we were able to test…the Africans and the African-Americans had the same polymorphisms, and therefore we could be reasonably sure that this was a mutation that had arisen once on this polymorphic background,” Plotz says. In other words, all of the patients with R854X were likely to have a common ancestor. The researchers also learned of a Pakistani patient with the R854X mutation who had the same set of polymorphisms on the acid maltase allele. “There was a known slave trade from Africa to South Asia,” Plotz says, “so we knew that this was a mutation that must have arisen in Africa and moved out in both directions.”

Plotz recognized that these genetic data might be used to trace the relationships between African-Americans and their African ancestors, but he needed more information. At a party, a friend suggested that Plotz talk to John Vlach, a professor of American studies and anthropology at George Washington University, in Washington, DC, and an expert on the history of the African slave trade. Thus began a collaboration between Plotz and Vlach, who, Plotz says, “educated me about the fact that nobody among African-Americans, with very rare exceptions…, truly knows which tribe and which country they come from.”

“Most migrations,” Plotz says, “have a story behind them,” and most immigrants know at least something about their family histories— perhaps the village they came from, or the boat they traveled on. By contrast, “African-Americans don't know that,” Plotz emphasizes. “They were enslaved, their ties were completely ruptured, and the information was lost.” Learning this “made me realize that this genetic information was probably a way in which the migration, which it really was, of Africans to the Americas could be reconstructed,” he says.

Plotz had had the foresight to ask the parents of the four young Africans with AMD about their tribal affiliations. He determined that the African carriers of the R854X mutation that was passed down to the infants with AMD were from four tribes: the Gueré, from the Ivory Coast, and the Ashanti, from present-day Ghana, both of which lie near the west coast of Africa; the Hausa, from an inland region of western Africa in what is now northern Nigeria; and the Ovambo, from southwestern Africa (see map page 102).

Using this information and his knowledge of African history, Vlach concluded by a process of elimination that it was the Ashanti people who were the most likely to have carried the mutation across the Atlantic to the Americas. “While individual Gueré, Hausa, or Ovambo might have been brought to the United States sometime between 1536 and 1861, among the peoples that we currently know to be carriers of the trait for acid maltase deficiency, only the Ashanti appear to have been regularly included in the slave cargoes arriving on our shores,” Vlach said in a recent presentation he gave with Plotz at NIH.

But how did the mutation spread among the four African tribes, given the large distances and sometimes rugged territories that separated them? These four African groups actually have a long-standing history of interaction through trade and other contacts, as the researchers noted in a recent article in the American Journal of Human Genetics (62: 991–994). The Hausa, whose homeland is in northern Nigeria, are widely dispersed throughout western Africa and had been well known as traders across this region since as early as 1100. Their trading brought them into contact with both the Gueré and the Ashanti. And the Ovambo are descended from people who originally lived in an area adjacent to the Hausa homelands and gradually migrated southward until they reached their current location in southwestern Africa over 1000 years ago.

Considering this historical information together with the DNA data, Vlach proposed that the R854X mutation arose among the Hausa at least 1000 years ago, before the Ovambo's ancestors migrated south, and was spread to the other groups during the Hausa's travels. Thus, the researchers wrote, although the African-American patients with AMD are likely to have descended from the Ashanti, who were brought to America from the Guinea Coast, “their genetic makeup suggests that they have Hausa roots.”

The genome as biography

The molecular genetic approach to anthropology clearly has its limitations and uncertainties. Nevertheless, research such as that being done by Wells, Hagleberg, Plotz, and their colleagues demonstrates the human genome's great potential to reveal aspects of human history that cannot be determined solely by other means. “The genome is the history of the human race,” Plotz says. “If we understood every gene and where it came from, we would know where humans come from [and] exactly how we descended…. And for any individual human being, [the genome] is a biography—where you've been and who you've been with is in your chromosomes.”

This concept of the genome as biography, Plotz believes, “touches something that is very important to a lot of people.” The desire to know about one's history and roots, whether through oral histories passed from generation to generation, the study of ancient potsherds, or modern molecular biology techniques, will no doubt continue to intrigue and engage researchers—and individuals—for generations to come.

© 1999 American Institute of Biological Sciences.

© 1999 American Institute of Biological Sciences.

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