A development company controlled by osama bin laden's half brother once advanced the idea that it wanted to build a bridge that would span the Bab el Mandeb, the outlet of the Red Sea to the Indian Ocean. If this ambitious project is ever realized, the throngs of African pilgrims who traverse one of the longest bridges in the world on a journey to Mecca will pass hundreds of feet above the route of the most memorable journey in human history. Fifty or sixty thousand years ago a small band of Africans—a few hundred or even several thousand—may have crossed the strait in tiny boats, never to return. That is just one theory for how modern humans first left Africa. An alternative explanation to a journey over water has these sojourners moving up the coast and through the Sinai Peninsula.

Whether the exit route was over water or land, the reason these travelers left their homeland in eastern Africa is not completely understood. Perhaps the climate changed, or once abundant shellfish stocks vanished. But some things are fairly certain. Those first trekkers out of Africa brought with them the physical and behavioral traits—the large brains and the capacity for language—that characterize fully modern humans. From their bivouac on the Asian continent in what is now Yemen, they appear to have set out on a decamillennial journey that spanned continents and land bridges and reached all the way to Tierra del Fuego, at the bottom of South America.

Scientists, of course, have gained insight into these wanderings because of the fossilized bones or spearheads laboriously uncovered and stored in collections. But ancestral hand-me-downs are often too scant to provide a complete picture of this remote history. In the past 25 years population geneticists have begun to fill in gaps in the paleoanthropological record by fashioning a genetic bread-crumb trail of the earliest migrations by modern humans.

Almost all our DNA—99.9 percent of the three billion “letters,” or nucleotides, that make up the human genome—is the same from person to person. But interwoven in that last 0.1 percent are telltale differences. A comparison among, say, East Africans and Native Americans can yield vital clues to human ancestry and to the inexorable progression of colonizations from continent to continent. Until recent years, DNA passed down only from fathers to sons or from mothers to their children has served as the equivalent of fossilized footprints for geneticists. The newest research lets scientists adjust their focus, widening the field of view beyond a few isolated stretches of DNA to inspect hundreds of thousands of nucleotides scattered throughout the whole genome.

Scanning broadly has produced global migratory maps of unprecedented resolution, some of which have been published only during recent years. The research provides an endorsement of modern human origins in Africa and shows how that continent served as a reservoir of genetic diversity that trickled out to the rest of the world. A genetic family tree that begins with the San people of Africa at its root ends with South American Indians and with Pacific Islanders on its youngest-growing branches.

The study of human genetic variation—a kind of historical Global Positioning System—goes back to World War I, when two physicians working in the Greek city of Thessaloníki found that soldiers garrisoned there had a differing incidence of a given blood group depending on their nationality. Beginning in the 1950s, Luigi Luca Cavalli-Sforza started formalizing the study of genetic differences among populations by examining distinct blood group proteins. Variations in proteins reflect differences in the genes that encode them.

Then, in 1987, Rebecca L. Cann and Allan C. Wilson, then at the University of California, Berkeley, published a groundbreaking paper based on analyzing the DNA of mitochondria, the cell's energy-producing organelles, which are passed down through the maternal line. They reported that humans from different populations all descended from a single female in Africa who lived about 200,000 years ago—a finding that immediately made headlines trumpeting the discovery of the “Mitochondrial Eve.” (Despite the Biblical allusion, this Eve was not the first woman: her lineage, though, is all that has survived.)

All About Eve

The fast, relatively predictable rate of “neutral” mitochondrial mutations—ones that are neither beneficial nor harmful—lets the organelles operate as molecular clocks. Counting the differences in the number of mutations (ticks of the clock) between two groups, or lineages, allows a researcher to construct a genetic tree that tracks back to a common ancestor—Mitochondrial Eve or another woman who founded a new lineage. Comparison of the ages of the lineages from different regions permits the building of a timeline of human migrations.

Since 1987 the data bank on human diversity has broadened to encompass the Y chromosome—the sex chromosome passed down only by males to their sons. The male-transmitted DNA carries many more nucleotides than mitochondrial DNA does (tens of millions, as opposed to just 16,000), enhancing investigators' ability to distinguish one population from another. Analyzing mitochondrial and Y chromosome DNA from human populations has turned up hundreds of genetic markers (DNA sites having identifiable mutations specific to particular lineages).

The route humans took from Africa to the Americas over the course of tens of thousands of years can now be tracked on the map as if the travelers were moving, albeit extremely slowly, on a series of interconnected superhighways. Alphanumeric route signs, such as I-95, can be recast as alphanumeric genetic markers. In the case of the Y chromosome, for instance, cross the Bab el Mandeb on highway (genetic marker) M168, which becomes M89 when heading north through the Arabian Peninsula. Make a right at M9 and set out toward Mesopotamia and beyond. Once reaching an area north of the Hindu Kush, turn left onto M45. In Siberia, go right and follow M242 until it eventually traverses the land bridge to Alaska. Pick up M3 and proceed to South America [see map above].

Mitochondrial DNA and the Y chromosome remain powerful analytical instruments. The National Geographic Society, IBM and the Waitt Family Foundation joined in privately funded research that is primarily devoted to using these tools. With the help of 10 regional academic institutions, the so-called Genographic Project has so far gathered DNA from more than 500,000 people worldwide, including around 75,000 indigenous people. “What we're focusing on are the details of how people made the journeys,” says Spencer Wells, who heads the project. In one report its researchers found that the Khoisan people of southern Africa remained genetically separate from other Africans for 100,000 years. In another study, they demonstrated that some of the gene pool of Lebanese men can be traced to Christian Crusaders and Muslims from the Arabian Peninsula.

Power Tools

Genetic researchers have sampled the DNA of many people living along the migratory routes they have discovered. Yet the seeming certainty of the data sometimes deceives. Scientists who study human origins still would prefer a fossil they can hold in their hands over a genealogical tree. DNA differs from the radioactive isotopes used to date fossils. The rate of mutation can fluctuate from one stretch of DNA to another.

But paleoanthropologists are in a fix. Fossil remains are rare and too often incomplete. The earliest migration from Africa to Australia shows up in mitochondrial and Y genetic material (thanks to Andaman Islanders, among others), yet the physical artifacts are largely missing along the route.

The answer to the absence of stones and bones: more DNA, from wherever. To bolster the case for genetics, researchers have looked to microbes that have hitched a ride on humans, inspecting their genes to look for similar patterns of migration. Freeloaders include bacteria, viruses and even lice. Besides microorganisms, the Human Genome Project and related efforts to look across the expanse of whole genomes have yielded a set of power tools that are helping to compensate for deficiencies in genetic methods. “You can look at so many different places in the genome from many individuals and in many populations to achieve more statistical power in testing different hypotheses,” says Tim Weaver, a professor of anthropology at the University of California, Davis.

For more than a decade researchers have made dramatic discoveries by simultaneously comparing a multitude of variable, or polymorphic, sites interspersed throughout the genome's three billion nucleotides. The first whole-genome studies earlier in the 2000s looked at differences among populations in short repetitive stretches of DNA known as microsatellites. Since then, the scope afforded by whole-genome scans has widened further. In February 2008 two papers, one in Science, the other in Nature, reported the largest surveys to date of human diversity. Both examined more than 500,000 single nucleotide polymorphisms (SNPs)—swaps of one nucleotide for another at a particular spot in the DNA—from the Human Genome Diversity Panel. These cell lines were drawn from more than 1,000 individuals from 52 populations worldwide and are maintained by the Center for the Study of Human Polymorphisms in Paris.

The two research teams analyzed the wealth of data in various ways. They compared SNPs directly among distinct populations. They also looked at haplotypes, blocks of DNA containing numerous SNPs that are inherited intact through many generations. The group that wrote the Nature paper also explored a new technique for surveying human variation by comparing repetitions or deletions of DNA stretches of up to a million nucleotides long (copy number variations) throughout a person's genome, consistent with the larger trend to mine the genome for ever more markers of variation. “Any one piece of the genome will have a history that doesn't necessarily reflect the ancestry of the genome as a whole,” says Noah A. Rosenberg, now at Stanford University and one of the authors of the Nature paper. But looking at many areas at once, he explains, can overcome that problem: “With thousands of markers, it's possible to determine the overall story of human migrations.”

Looking at hundreds of thousands of SNPs allowed the researchers to resolve the identities of individual populations—and to see how genetically close relations spread far and wide. Native South American ancestry was tracked back to Siberians and some other Asians. The Han people, China's principal ethnic group, has distinct northern and southern populations. Bedouins are related to groups from Europe and Pakistan as well as the Middle East.

The findings, which jibed with previous research from anthropology, archaeology, linguistics and biology (including previous mitochondrial and Y DNA studies), also provided a broader statistical foundation for the out of Africa hypothesis, supporting the idea that a small population of humans moved out of the continent, then grew in size in a new home until another subgroup of “founders” broke off and moved away—a process that repeated itself until the entire world was settled. These wayfarers edged out archaic human populations—Homo neanderthalensis and Homo erectus. The new DNA work indicates that each time a smaller group split off, it carried only a subset of the genetic diversity originally present in the African population. So as distance (and time) removed from Africa lengthens, diversity diminishes, providing a means to follow population movements. Native Americans, sojourners on the last major continental migrations, have much less variety in their genomes than Africans do.

Many scientists believe that the weight of evidence, now backed by large statistical analyses such as the ones in Science and Nature, gives the out of Africa proponents a clear edge in a long-running debate over human origins. The multiregional hypothesis—a competitor to the out of Africa one—argues that populations that descended from archaics, such as H. erectus, evolved over the past 1.8 million years in Africa, Europe and Asia and gradually emerged as Homo sapiens. Occasional interbreeding ensured that the groups did not split off into separate species.

Few scientists still hold a banner for a strict interpretation of multiregionalism. But modified versions still circulate, mostly as attempts to pinpoint whether H. sapiens bear genetic signatures of our encounters with hominid cousins. Vinayak Eswaran of the Indian Institute of Technology, aided by Henry C. Harpending and Alan R. Rogers of the University of Utah, has come up with a set of simulations that suggest that after humans migrated out of Africa they interbred extensively with archaic species such as H. erectus. Eswaran's model suggests that as much as 80 percent of the modern human genome may have been subject to the effects of this kind of interbreeding.

The genetic imprint is not as visible as might be expected if interbreeding occurred, but Harpending offers an explanation. A set of beneficial genes carried by African emigrants, perhaps ones that assisted in childbearing, brought a selective advantage that eventually blotted out the signature of some archaic genes. “The result is that the population seems more closely related to the [African] source population of the favored genes than it really is,” he says.

Are We Part Neandertal?

Those simulations are no longer figments of a computer model. Some fossilized skeletal remains of H. sapiens have features that are reminiscent of earlier hominids, and the genetic record of contemporary humans has also provided increasing fuel for discussion.

Continued advances in gene-sequencing techniques have meant that the Max Planck Institute for Evolutionary Anthropology in Leipzig has succeeded in sequencing the genomes of Neandertals and another recently discovered extinct hominid, the Denisovans. It turns out that H. sapiens, except in Africa, did engage in interhominid trysts. Representatives of our species outside of that continent have 2.5 percent Neandertal DNA, and some of those in Oceania bear a 5 percent genetic imprint from Denisovans as well as a complement of Neandertal DNA. Moreover, 1 percent of the DNA of Southeast Asians comes from Denisovans.

The actual sequencing effort turned into a gargantuan project. Handling or even breathing on a sample can be an impediment to working with ancient DNA: some anthropologists wrap themselves in the clean-room “bunny suits” used in microchip factories when they head to the field on a dig. In the laboratory at Max Planck, researchers place tags made up of four nucleotides of synthetic DNA at the beginning of each strand of Neandertal genetic material. Once each strand exits the sequencing machine, it goes through a molecular identity check.

How Have We Adapted?

As researchers continue sequencing DNA from shards of old bone to explore whether humans mated with other species of the genus Homo, other investigators are applying genome-wide analyses of DNA to see which genetically controlled traits changed through genetic drift (random mutations) and natural selection as migrants adapted to their new homes.

A second study in February 2008 in Nature showed the consequences of the declining genetic diversity as humans left Africa. The project compared 40,000 SNPs from a group of 20 European-Americans and 15 African-Americans. It found that the European-Americans had a higher proportion of harmful genetic changes, ones potentially related to disease, than the African-Americans did, although the authors refrained from speculation about any specific health effects. The research shows what lead scientist Carlos D. Bustamante called a “population genetic echo” of Europe's founding. The low genetic diversity of Europe's small initial population allowed a set of harmful mutations to disperse widely and new harmful ones to emerge when the numbers of people began to grow. Natural selection has not yet had time to remove deleterious changes.

Genome-wide research is also starting to furnish a panoramic picture of how natural selection helped migrants adapt to new environs. A spate of recent studies have looked for genetic alterations that have occurred since humans left Africa or took up agriculture and that appear to have been useful for surviving in novel circumstances. Genetic prospectors mined the International HapMap, a catalogue of haplotypes and the 3.9 million SNPs contained therein from North Americans with ancestry in northwestern Europe and from individuals sampled in Nigeria, China and Japan.

One study, co-authored by Harpending, showed that the rate of change of DNA, and thus the pace of evolution, has accelerated over the past 40,000 years. Another by Pardis C. Sabeti of the Broad Institute in Cambridge, Mass., and her colleagues indicated that hundreds of regions of the genome are still undergoing selection, including areas that govern resistance to disease, development of skin color, and hair follicles, which regulate sweat. Such findings imply that human populations are continuing to adapt to regional differences in sun exposure, foods and pathogens they encountered when they left their ancestral African home. And Africans have evolved as their environs changed.

One study led by Lluis Quintana-Murci of the Pasteur Institute in Paris showed that 580 genes, including ones that play a role in diabetes, obesity and hypertension, are undergoing selection differently among the HapMap populations, perhaps explaining geographical differences in disease patterns and providing clues to new targets for developing drugs.

Consideration of the processes underlying human diversity of course moves beyond the dimensions of hair follicles and the ability to digest milk. Scientific debate over what constitutes race and ethnicity can quickly enter the picture. What does it mean if a gene variant related to cognition is found more in Europeans than in Africans? Better public understanding of genetics—that a single gene does not act like a light switch that toggles between intelligence and doltishness—may quell misguided speculations.

Genetic literacy will let a term like “Asian” or “Chinese” be replaced by more subtle classifications based on the differences in ancestral genetic makeup found in recent genome-wide scans, such as the distinction between China's Han groups. “There is no race,” Quintana-Murci says. “What we see [from the standpoint of genetics] is geographical gradients. There are no sharp differences between Europeans and Asians. From Ireland to Japan, there is no sharp boundary where something has changed completely.”

The journey through evolutionary history set in place by comparative genomics is still starting. In the meantime, the hunger for more data and more powerful computers and algorithms knows no limits. Amassing larger databases—an international consortium announced in January 2008 is proceeding with the sequencing of 1,000 genomes from various regional populations—will let researchers run ever more realistic simulations of alternative models of human evolution and weigh the probabilities of each one, yielding the best picture yet of who we are and where we came from.