Somewhere in Africa, between 60,000 and 100,000 years ago, a small population of humans got it into their newly rounded skulls to set out across the continent and take up residence in the northeast corner, possibly in the Nile Valley. According to this scenario, popularly known as the out-of-Africa hypothesis, members of this founding population swept north into the Middle East and Europe, east into Asia, and south into Australia, replacing the Neanderthals and other hominids.
But the initial urge to move—the founding impulse—may have been one that occurred primarily among the males of the species. A new study by Alon Keinan, David Reich, and colleagues in the January issue of Nature Genetics suggests that the original out-of-Africa population included significantly more males than females and might have been fed by successive waves of mostly male migrants.
Genetic FootprintsThe researchers came to this proposal by comparing the amount of genetic drift occurring on the X and other chromosomes of three different groups of modern humans. First described in the 1920s by the great geneticist Sewall Wright, genetic drift occurs when variants change in frequency not by natural selection but instead by chance, through the shuffling of genes during meiosis or other random events associated with reproduction.
In a population with equal numbers of males and females, there are three X chromosomes for every four of each autosome, since males carry only one X. Knowing that, and that genetic drift operates more strongly the smaller the sample, the researchers calculated that the ratio of drift on the X versus nonsex chromosomes should be the inverse of the 3/4 ratio, namely 4/3. But when they calculated the amount of genetic drift occurring between the presumably more conserved West African population (used as a surrogate for the original Africans) and the European populations—using a database of more than 130,000 noncoding single nucleotide polymorphisms (SNPs) scattered over the genome—they found a surprising discrepancy: the ratio was significantly higher, suggesting greater X-related drift among the Europeans.
“You see that the X chromosome has drifted much more than you would expect,” said Reich, HMS associate professor of genetics. The ratio was even higher when they compared the West African population with East Asians. Intriguingly, when they compared East Asian with Northern European populations, they found the expected 4/3 ratio.
What this means, said the researchers, is that the period of intense X chromosome drift, and presumably of male dominated population structure, occurred during a well-defined slice of human prehistory, after the split from the ancestral African population but before the dispersal of migrants into Asia and Europe. “So it’s localized to a fairly short period of time, probably no more than a few tens of thousands of years,” said Reich.
He and Keinan tested several scenarios to see which might have produced the period of intense X chromosome drift. “We think the most parsimonious model is multiple waves of mostly male migrations into a population that already formed,” said Keinan, HMS research fellow in genetics.
“I see no problem,” said Ofer Bar-Yosef, the George Grant Maccurdy and Janet G. B. Maccurdy professor of prehistoric archaeology at Harvard University. “From my viewpoint, their conclusions are absolutely logical that the males would be at the front of the wave of migrations and the females would come later.”
The Telltale X This is not the first time Reich has gained insight from the X chromosome. In 2006, he and colleagues discovered that the X chromosomes of humans and chimps were more similar than their autosomes, a finding that led them to suggest that members of the ancestral population of humans and chimps might have initially diverged and then undergone a subsequent period of hybridization before fully separating into different species.Keinan set his sights on a later turning point in the human evolutionary saga, the origins of modern humans, and particularly the out-of-Africa hypothesis. Though it is supported by the fossil record, the hypothesis grows out of genetic analyses, specifically comparisons of the mitochondrial DNA and Y chromosomes of living human populations. Keinan wanted to broaden the dataset to the autosomes and seized upon the vast database of SNPs known as the HapMap. But there was a problem. The HapMap SNPs were a motley and biased group, “ascertained at different times, in different groups, by different researchers, for different purposes,” Keinan said.
Sorting through the HapMap and other databases, he and colleagues collected a subset of more than 130,000 SNPs. Using a statistic known as the Q value, they compared the ratio of genetic drift occurring on the X chromosome and autosomes, expecting to find a value of 4/3. When they compared the West African with the Northern European and East Asian samples, the Q value was significantly higher, suggesting fewer X chromosomes and, presumably, fewer females among the non-African ancestral population. “I was very surprised,” said Keinan.
He and his colleagues needed more proof. It turns out, genetic drift leaves a characteristic mark on the allele frequencies within an individual population. Rare variants tend to occur at even lower frequencies than they do in larger populations; conversely, common SNPs occur at unusually high frequencies. Keinan and colleagues decided to look at the distribution of gene frequencies within each of their three groups and found, once again, that genetic drift had left an even deeper imprint on the X chromosomes than on the autosomes in the North European and East Asian samples.
They performed a third analysis in conjunction with National Institutes of Health researcher James Mullikin. Drawing on a public DNA database, they aligned DNA sequences of individuals from each of their three groups, assessing the differences among them. Genetic drift tends to reduce genetic diversity, randomly dropping alleles from a population while bolstering others. The amount of diversity on the X chromosome should have been 3/4 of that found on the autosomes if there had been equal numbers of males and females in the ancestral population. But again, the Northern Europeans and East Asians, when compared with West Africans, deviated from expectation: the ratios were lower than 3/4, meaning that their X chromosomes had lost disproportionately more alleles due to genetic drift since the split from the West Africans.
Intriguingly, researchers at the University of Arizona, conducting a similar sequence-based study, found an opposite conclusion. They determined that the ratio of diversity was 4/3, but they used only the single analysis. “My belief is our research is likely to be correct just because our first two lines of evidence also support it,” said Reich.
The analysis by Reich, Keinan, and colleagues tells a compelling but still mysterious tale. What might have motivated the males to venture into new territories? “I don’t really know. Today males have migrated long distances for military purposes and also looking for new resources,” said Reich.
Africa may be a huge continent, but only a small portion was hospitable to early humans, said Bar-Yosef. “All the north is the Sahara desert. And the tropical rainforest is not a place for a normal human being. Then you have the Kalahari. The area where a hominid could survive in Africa was a very small fraction of the continent,” he said.
Students may contact David Reich at reich@genetics.med.harvard.edu for more information.
Conflict Disclosure: The authors report no conflicts of interest.
Funding Sources: The National Institutes of Health and the Burroughs Wellcome Fund
