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-- New DNA analysis shows ancient humans interbred with Denisovans - 8/31/12
-- Discovery of Oldest DNA Scrambles Human Origins - 12/04/13
-- Modern Europe's Genetic History Starts in Stone Age - 4/23/13
-- Ancient DNA reveals secrets of human history - 8/09/11
-- Fossil genome reveals ancestral link - 12/22/10
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-- First Aboriginal genome sequenced - 9/22/11

 New DNA analysis shows ancient humans interbred with Denisovans

A new high-coverage DNA sequencing method reconstructs the full genome of Denisovans — relatives to both Neandertals and humans — from genetic fragments in a single finger bone.

31 August 2012    Katherine Harmon

Max Planck Institute for Evolutionary Anthropology

An article from Scientific American.

Tens of thousands of years ago modern humans crossed paths with the group of hominins known as the Neandertals. Researchers now think they also met another, less-known group called the Denisovans. The only trace that we have found, however, is a single finger bone and two teeth, but those fragments have been enough to cradle wisps of Denisovan DNA across thousands of years inside a Siberian cave. Now a team of scientists has been able to reconstruct their entire genome from these meager fragments. The analysis adds new twists to prevailing notions about archaic human history.

"Denisova is a big surprise," says John Hawks, a biological anthropologist at the University of Wisconsin–Madison who was not involved in the new research. On its own, a simple finger bone in a cave would have been assumed to belong to a human, Neandertal or other hominin. But when researchers first sequenced a small section of DNA in 2010—a section that covered about 1.9 percent of the genome—they were able to tell that the specimen was neither. "It was the first time a new group of distinct humans was discovered" via genetic analysis rather than by anatomical description, said Svante Pääbo, a researcher at the Max Planck Institute (M.P.I.) for Evolutionary Anthropology in Germany, in a conference call with reporters.

Now Pääbo and his colleagues have devised a new method of genetic analysis that allowed them to reconstruct the entire Denisovan genome with nearly all of the genome sequenced approximately 30 times over akin to what we can do for modern humans. Within this genome, researchers have found clues into not only this group of mysterious hominins, but also our own evolutionary past. Denisovans appear to have been more closely related to Neandertals than to humans, but the evidence also suggests that Denisovans and humans interbred. The new analysis also suggests new ways that early humans may have spread across the globe. The findings were published online August 30 in Science1.
Who were the Denisovans?

Unfortunately, the Denisovan genome doesn't provide many more clues about what this hominin looked like than a pinky bone does. The researchers will only conclude that Denisovans likely had dark skin. They also note that there are alleles "consistent" with those known to call for brown hair and brown eyes. Other than that, they cannot say.

Yet the new genetic analysis does support the hypothesis that Neandertals and Denisovans were more closely related to one another than either was to modern humans. The analysis suggests that the modern human line diverged from what would become the Denisovan line as long as 700,000 years ago—but possibly as recently as 170,000 years ago.

Denisovans also interbred with ancient modern humans, according to Pääbo and his team. Even though the sole fossil specimen was found in the mountains of Siberia, contemporary humans from Melanesia (a region in the South Pacific) seem to be the most likely to harbor Denisovan DNA. The researchers estimate that some 6 percent of contemporary Papuans' genomes come from Denisovans. Australian aborigines and those from Southeast Asian islands also have traces of Denisovan DNA. This suggests that the two groups might have crossed paths in central Asia and then the modern humans continued on to colonize the islands of Oceania.

Yet contemporary residents of mainland Asia do not seem to posses Denisovian traces in their DNA, a "very curious" fact, Hawks says. "We're looking at a very interesting population scenario"—one that does not jibe entirely with what we thought we knew about how waves modern human populations migrated into and through Asia and out to Oceania's islands. This new genetic evidence might indicate that perhaps an early wave of humans moved through Asia, mixed with Denisovans and then relocated to the islands—to be replaced in Asia by later waves of human migrants from Africa. "It's not totally obvious that that works really well with what we know about the diversity of Asians and Australians," Hawks says. But further genetic analysis and study should help to clarify these early migrations.

Just as with modern Homo sapiens, the genome of a single individual cannot tell us exactly what genes and traits are specific to all Denisovans. Yet, just one genome can reveal the genetic diversity of an entire population. Each of our genomes contains information about generations far beyond those of our parents and grandparents, said David Reich, a researcher at the Massachusetts Institute of Technology–Harvard University Broad Institute and a co-author on the paper. Scientists can compare and contrast the set of genes on each chromosome—passed down from each parent—and extrapolate this process back through the generations. "You contain a multitude of ancestors within you," Reich said, borrowing from Walt Whitman.

The new research reveals that the Denisovans had low genetic diversity—just 26 to 33 percent of the genetic diversity of contemporary European or Asian populations. And for the Denisovans, the population on the whole seems to have been very small for hundreds of thousands of years, with relatively little genetic diversity throughout their history.

Curiously, the researchers noted in their paper, the Denisovan population shows "a drastic decline in size at the time when the modern human population began to expand."

Why were modern humans so successful whereas Denisovans (and Neandertals) went extinct? Pääbo and his co-authors could not resist looking into the genetic factors that might be at work. Some of the key differences, they note, center around brain development and synaptic connectivity. "It makes sense that what pops up is connectivity in the brain," Pääbo noted. Neandertals had a similar brain size–to-body ratio as we do, so rather than cranial capacity, it might have been underlying neurological differences that could explain why we flourished while they died out, he said.

More from Scientific American.

Hawks counters that it might be a little early to begin drawing conclusions about human brain evolution from genetic comparisons with archaic relatives. Decoding the genetic map of the brain and cognition from a genome is still a long way off, he notes—unraveling skin color is still difficult enough given our current technologies and knowledge.
New sequencing for old DNA

The Denisovan results rely on a new method of genetic analysis developed by paper co-author Matthias Meyer, also of M.P.I. The procedure allows the researchers to sequence the full genome by using single strands of genetic material rather than the typical double strands required. The technique, which they are calling a single-stranded library preparation, involves stripping the genetic material down to individual strands to copy and avoids a purification step, which can lose precious genetic material.

The finger bone—just one distal phalanx—is so small that it does not contain enough usable carbon for dating, the researchers note. But by counting the number of genetic mutations in a genome and comparing them with other living relatives, such as modern humans and chimpanzees, given assumed rates of mutations since breaking with a last common ancestor, "for the first time you can try to estimate this number into a date and provide molecular dating of the fossil," Meyer said. With the new resolution, the researchers estimate the age of the bone to 74,000 to 82,000 years ago. But that is a wide window, and previous archaeological estimates for the bone are a bit younger, ranging from 30,000 to 50,000 years old. These genetic estimations are also still in limbo because of ongoing debate about the average rate of genetic mutations over time, which could skew the age. "Nevertheless," the researchers noted in their paper, "the results suggest that in the future it will be possible to determine dates of fossils based on genome sequences."

This new sequencing approach can be used for any DNA that is too fragmented to be read well through more traditional methods. Meyer noted that it could come in handy for analysis of both ancient DNA and contemporary forensic evidence, which also often contains only fragments of genetic material.

Hawks is excited about the new sequencing technology. It is also helpful to have a technology developed specifically for the evolutionary field, he notes. "We're always using the new techniques from other fields, and this is a case where the new technique is developed just for this."

Hawks himself has heard from the researchers that have worked with the Denisovan samples that "the Denisovan pinky is just extraordinary" in terms of the amount of DNA preserved in it. Most bone fragments would be expected to contain less than 5 percent of the individual's endogenous DNA, but this fortuitous finger had a surprising 70 percent, the researchers noted in the study. And many Neandertal fragments have been preserved in vastly different states—many are far worse off than this Denisovan finger bone.

The new sequencing approach could also improve our understanding of known specimens and the evolutionary landscape as a whole. "It's going to increase the yield from other fossils," Hawks notes. Many of the Neandertal specimens, for example, have only a small fraction of their genome sequenced. "If we can go from 2 percent to the whole genome, that opens up a lot more," Hawks says. "Going back further in time will be exciting," he notes, and this new technique should allow us to do that. "There's a huge race on—it's exciting."

The Denisovans might be the first non-Neandertal archaic human to be sequenced, but they are likely not going to be the last. The researchers behind this new study are already at work using the new single-strand sequencing technique to reexamine older specimens. (Meyer said they were working on reassessing old samples but would not specify which specimens they were studying—the mysterious "hobbit" H. floresiensis would be a worthy candidate.) Pääbo suggests Asia as a particularly promising location to look for other Denisovan-like groups. "I would be surprised if there were not other groups to be found there in the future," he said.

Taking this technique to specimens from Africa is also likely to yield some exciting results, Hawks says. Africa, with its rich human evolutionary history, holds the greatest genetic diversity. The genomes of contemporary pygmy and hunter–gatherer tribes in Africa, for example, have roughly as many differences as do those of European modern humans and Neandertals. So "any ancient specimen that we find in Africa might be as different from us as Neandertals," Hawks says. "Anything we find from the right place might be another Denisovan."


This article was originally published by Scientific American on 30 August 2012.


Meyer, M. et al. Science. doi:10.1126/science.1224344 (2012).


 Discovery of Oldest DNA Scrambles Human Origins

December 4, 2013    By Karl Gruber    for National Geographic

New tests on human bones hidden in a Spanish cave for some 400,000 years set a new record for the oldest human DNA sequence ever decoded—and may scramble the scientific picture of our early relatives.

Analysis of the bones challenges conventional thinking about the geographical spread of our ancient cousins, the early human species called Neanderthals and Denisovans. Until now, these sister families of early humans were thought to have resided in prehistoric Europe and Siberia, respectively. (See also: "The New Age of Exploration.")

But paleontologists write in a new study that the bones of what they thought were European Neanderthals appear genetically closer to the Siberian Denisovans, as shown by maternally inherited "mitochondrial" DNA found in a fossil thighbone uncovered at Spain's Sima de los Huesos cave.

"The fact that they show a mitochondrial genome sequence similar to that of Denisovans is irritating," says Matthias Meyer of Germany's Max Planck Institute for Evolutionary Anthropology in Leipzig, lead author of the study, published Wednesday in Nature.

"Our results suggest that the evolutionary history of Neanderthals and Denisovans may be very complicated and possibly involved mixing between different archaic human groups," he said.

Neanderthals and Denisovans arose hundreds of thousands of years before modern-looking humans spread worldwide from Africa more than 60,000 years ago. The small traces of their genes now found in modern humans are signs of interbreeding among ancient human groups.

Previously, the oldest human DNA sequenced came from bones that were less than 120,000 years old.

Meyer said stable temperatures in the cave helped preserve the mitochondrial DNA, and credited recent advances in gene-sequencing technology for establishing the basis for the new milestone.

Mixed Up or Mixing It Up?

For humanity's tangled past, the new mitochondrial DNA results raise an unexpected question: How does a Spanish early human species end up with Siberian DNA?

The authors propose several possible scenarios. For instance, Sima hominins could simply be close relatives of the Denisovans. But that would mean they lived right alongside Neanderthals without having close genetic ties to them.

The Sima hominins could also be a completely independent group that mingled with Denisovans, passing on their mitochondrial DNA, but it would be hard to explain why they also have Neanderthal features.

Another possibility, suggested by anthropologist Chris Stringer of the Natural History Museum in London, is that mitochondrial DNA from the Sima people reached the Denisovans thanks to interspecies sexual adventures among early humans, which introduced the DNA to both the Sima and Denisovans.

In the end, the identity of these ancient people remains a mystery, and further work is needed to clarify their identity. "The current genetic data [mitochondrial DNA] is too limited to conclude much about their population history," Meyer says.

As with the Denisovans, only the decoding of the full genetic map or genome, and not just the mitochondrial DNA, will provide convincing evidence of Sima family history, Meyer says.

New Piece of the Puzzle

In recent years, paleogeneticists have released surprising reports about such early human species, notably the interspecies breeding that likely occurred among Neanderthals, Denisovans, and modern humans.

Uncovered only in 2010, Denisovans are known solely from a pinkie and a tooth found in 30,000- to 50,000-year-old rock layers in Siberia's Denisova cave. DNA from those Siberian bones first established their owners as genetically distinct from Neanderthals and modern people.

(Read "The Case of the Missing Ancestor" in National Geographic magazine.)

"The fact that the Sima de los Huesos [mitochondrial DNA] shares a common ancestor with Denisovan rather than Neanderthal [mitochondrial DNA] is unexpected in light of the fact that the Sima de los Huesos fossils carry Neanderthal-derived features," says the study.

But paleoanthropologist John Hawks of the University of Wisconsin, Madison, who was not part of the study, says "there's not really anything very surprising" about the Spanish bones' bearing mitochondrial DNA that is not an earlier version of Neanderthal genes.

Ancient mitochondrial DNA from many other species—"bison, mammoths, cave bears, and others"—doesn't resemble that of more recent species, he notes.

Hawks is more cautious than the study authors about regarding the Spanish genes and younger Denisovan ones as being closely related: "The difference between Sima and Denisova [gene] sequences is about as large as the difference between Neanderthal and living human sequences.

"It would not be fair to say that Denisova and Sima represent a single population, any more than that Neandertals and living people do."

One reason for caution is that mitochondrial DNA results in the past have pointed scholars in errant directions; for example, some early studies suggested that humans and Neanderthals did not share any common ancestry.

Mitochondrial DNA is a small part of the human genome that is generally transmitted only through the female line, from mothers to offspring. This has important implications for the study of past events.

For instance, ancient interspecies breeding events might not be picked up by mitochondrial DNA.

But mitochondrial DNA can be transferred between species when interspecies mingling events occur. Such scenarios have been observed for other groups, such as polar and brown bears, where it has been found that interspecies breeding led to mixed-up mitochondrial genomes.

The Mountain of Bones

The Atapuerca Mountains, where the human bones were found, is a world-famous archaeological site located in northern Spain; a group of caves there contain some of Western Europe's oldest known human remains.

The most famous of these caves, Sima de los Huesos, has been studied since 1997 and hosts more than 6,000 ancient bone samples belonging to 28 ancient humans that lived roughly 400,000 years ago. The exact origin of the bone pile is unclear.

"Could a natural catastrophe or carnivore activities explain the accumulation of so many bodies?" asks anthropologist Juan-Luis Arsuaga, a co-author of the study and lead excavator at the cave for the past 30 years. "Or were there hominins that accumulated the corpses of their relatives and friends in such a dark and remote place: a pit in a cave?

"I would like to live to know the answer."

The bones of the Sima people share the features of Neanderthals, notably their thick-browed skulls, as well as the features of a much older group of human ancestors called Homo heidelbergensis, which lived about 600,000 years ago.

That species is also considered an ancestor of modern humans, Denisovans, and Neanderthals.

 Modern Europe's Genetic History Starts in Stone Age

April 23, 2013    By Ker Than    for National Geographic News

Europeans as a people are younger than we thought, a new study suggests.

DNA recovered from ancient skeletons reveals that the genetic makeup of modern Europe was established around 4,500 B.C. in the mid-Neolithic—or 6,500 years ago—and not by the first farmers who arrived in the area around 7,500 years ago or by earlier hunter-gatherer groups.

"The genetics show that something around that point caused the genetic signatures of previous populations to disappear," said Alan Cooper, director of the Australian Centre for Ancient DNA at the University of Adelaide, where the research was performed.

"However, we don't know what happened or why, and [the mid-Neolithic] has not been previously identified as [a time] of major change," he said.

Furthermore, the origins of the mid-Neolithic populations that did form the basis of modern Europe are also unknown.

"This population moves in around 4,000 to 5,000 [B.C.], but where it came from remains a mystery, as we can't see anything like it in the areas surrounding Europe," Cooper said.

The surprising findings are part of a new study, published in this week's issue of the journal Nature Communications, that provides the first detailed genetic history of modern Europe.

The study shows that "relatively recent migrations seem to have had a significant genetic impact on the population of Central Europe," said study co-author Spencer Wells, who leads National Geographic's Genographic Project. (Read about Europe's "Wild Men" in National Geographic magazine.)

Genetic Signature

In the study, Cooper and his colleagues extracted mitochondrial DNA—which children inherit only from their mothers—from the teeth and bones of 39 skeletons found in central Germany. The skeletons ranged in age from about 7,500 to 2,500 years old.

The team focused on a group of closely related mitochondrial lineages—mutations in mitochondrial DNA that are similar to one another—known as haplogroup H, which is carried by up to 45 percent of modern Europeans.

Cooper and his colleagues focused on haplogroup H because previous studies have indicated the mutations might have been present in Europeans' genetic makeup for several thousand years.

It's unclear how this haplogroup became dominant in Europe. Some scientists have proposed that it spread across the continent following a population boom after the end of the last ice age about 12,000 years ago.

But the new data paint a different picture of the genetic foundation of modern Europe: Rather than a single or a few migration events, Europe was occupied several times, in waves, by different groups, from different directions and at different times.

The first modern humans to reach Europe arrived from Africa 35,000 to 40,000 years ago. By about 30,000 years ago, they were widespread throughout the area while their close cousins, the Neanderthals, disappeared. Hardly any of these early hunter-gatherers carried the H haplogroup in their DNA.

About 7,500 years ago during the early Neolithic period, another wave of humans expanded into Europe, this time from the Middle East. They carried in their genes a variant of the H haplogroup, and in their minds knowledge of how to grow and raise crops. (Related: "Egypt's Earliest Farming Village Found.")

Archeologists call these first Central European farmers the linear pottery culture (LBK)—so named because their pottery often had linear decorations.

The genetic evidence shows that the appearance of the LBK farmers and their unique H haplogroups coincided with a dramatic reduction of the U haplogroup—the dominant haplogroup among the hunter-gatherers living in Europe at that time.

Farmers Move In

The findings settle a longstanding debate among archaeologists, said Wells, who is also a National Geographic explorer-in-residence.

Archaeology alone can't determine whether cultural movements—such as a new style of pottery or, in this case, farming—were accompanied by the movements of people, Wells said in an email.

"In this study we show that changes in the European archaeological record are accompanied by genetic changes, suggesting that cultural shifts were accompanied by the migration of people and their DNA."

The LBK group and its descendants were very successful and spread quickly across Europe. "They became the first pan-European culture, if you like," Cooper said.

Given their success, it would be natural to assume that members of the LBK culture were significant genetic ancestors of many modern Europeans.

But the team's genetic analysis revealed a surprise: About 6,500 years ago in the mid-Neolithic, the LBK culture was itself displaced. Their haplogroup H types suddenly became very rare, and they were subsequently replaced by populations bearing a different set of haplogroup H variations.

Mysterious Turnover

The details of this "genetic turnover" event are murky. Scientists don't know what prompted it, or even where the new colonizers came from.

"The extent or nature of this genetic turnover are not clear, and we don't know how widespread it is," Cooper said.

If this turnover were widespread, it could have been prompted by climate change or disease, he said.

"All we know is that the descendants of the LBK farmers disappeared from Central Europe about 4,500 [B.C.], clearing the way for the rise of populations from elsewhere, with their own unique H signatures."

Peter Bogucki, an archeologist at Princeton University who has studied early farming societies in Europe, called the finding "really interesting" and noted the timing of the genetic turnover is curious.

"At the end of the fifth millennium—[about] 4,000 B.C.—there are a lot of changes in the archeological record," said Bogucki, who was not involved in the study.

For example, the long houses that LBK farmers and their descendants favored became less common. Also, the settlement patterns of people living in Central Europe began changing, as did their stone tools.

"There are major transformations during this time that haven't really been all that well explained in interior Central Europe," Bogucki said.

"It looks like the whole system of agricultural settlement that got established with the LBK ran its course through the fifth millennium and something caused people to change."

Of Unknown Origins

Bogucki agrees that climate change might have been a trigger for the change in Europe's genetic makeup, but he thinks it was only a factor and not the sole cause.

One thing that is clear from the genetic data is that nearly half of modern Europeans can trace their origins back to this mysterious group.

"About [4,500 B.C.], you start seeing a diversity and composition of genetic signatures that are beginning to look like modern [Central] Europe," Cooper said. "This composition is then modified by subsequent cultures moving in, but it's the first point at which you see something like the modern European genetic makeup in place."

Whatever prompted the replacement of genetic signatures from the first pan-European culture, Cooper is clearly intrigued. "Something major happened," he said in a statement, "and the hunt is now on to find out what that was."

Correction: The original version of this article stated that the genetic makeup of modern Europeans emerged 4,500 years ago. The text has been updated to reflect the correct timing as 4,500 B.C., or 6,500 years ago.

 Ancient DNA reveals secrets of human history:  Modern humans may have picked up key genes from extinct relatives.

9 August 2011 Ewen Callaway For nature.com

For a field that relies on fossils that have lain undisturbed for tens of thousands of years, ancient human genomics is moving at breakneck speed. Barely a year after the publication of the genomes of Neanderthals1 and of an extinct human population from Siberia2, scientists are racing to apply the work to answer questions about human evolution and history that would have been unfathomable just a few years ago.

The past months have seen a swathe of discoveries, from details about when Neanderthals and humans interbred, to the important disease-fighting genes that humans now have as a result of those trysts.

Neanderthals were large-bodied hunter-gatherers, named after the German valley where their bones were first discovered, who roamed Europe and parts of Asia from 400,000 years ago until about 30,000 years ago. The Neanderthal genome — shepherded by Svante Pääbo at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany — indicates that their evolutionary story began to split from the lineage of modern humans less than half a million years ago, when their common ancestor lived in Africa (see 'The human strain'). In December last year, Pääbo's team released the genetic blueprint of another population of ancient humans — unlike ourselves or the Neanderthals — that was based on DNA recovered from a 30,000–50,000-year-old finger bone found in a cave in Denisova in southern Siberia2. Palaeoanthropologists call these groups archaic humans, distinguishing them from modern Homo sapiens, which emerged in Africa only around 200,000 years ago.

Pääbo is amazed at how quickly the Neanderthal genome has been mined. At a genomics meeting last year, for example, Cory McLean, a graduate student at Stanford University in California, was scheduled to talk immediately after Pääbo presented the Neanderthal genome. Inspired, McLean had trawled through the just-released genome in the days before his talk. He discovered that Neanderthals, like humans, lacked a stretch of DNA that orchestrates the growth of spines on the penises of other primates, and promptly presented the find just after Pääbo presented his3.

Since then, scientists have fleshed out the details of one of the biggest surprises from the Neanderthal genome: humans living outside Africa owe up to 4% of their DNA to Neanderthals. One explanation might be that humans migrating out of Africa mated with Neanderthals, probably resident in the Middle East, before their offspring fanned out across Europe and Asia.

“These genomes are publicly available. There’s nothing stopping high-school students from doing this.”

By comparing individual DNA letters in multiple modern human genomes with those in the Neanderthal genome, the date of that interbreeding has now been pinned down to 65,000–90,000 years ago. Montgomery Slatkin and Anna-Sapfo Malaspinas, theoretical geneticists from the University of California, Berkeley, presented the finding at the Society for Molecular Biology and Evolution meeting in Kyoto, Japan, held on 26–30 July.

Slatkin says that their result agrees with another study presented at the meeting that came from the group of David Reich, a geneticist at Harvard Medical School in Boston, Massachusetts, who was involved in sequencing both the Neanderthal and Denisova genomes. The dates also mesh with archaeological finds bookending early human migrations out of Africa to between about 50,000 and 100,000 years ago. Reich's team is now developing tools to find signs of more recent interbreeding that might have occurred after humans arrived in Asia and Europe.
More than genes

The denizens of Denisova also bred with contemporary humans, according to Pääbo and Reich's analysis2. But the only traces of their DNA to be found in modern humans were in residents of Melanesia, thousands of miles away from Denisova, suggesting that the Denisovans had once lived across Asia. In 2008, Pääbo's team set up a lab in Beijing to screen fossils that might contain Denisovan DNA, in the hope of learning more about them and their interactions with modern humans. Currently, the bone that yielded the Denisovan genome, and a single molar from the same cave, are their only known fossil remains, but other archaic human fossils from Asia could bear traces of this group.
Most of the Neanderthal genome was sequenced from bones found in Vindija cave, Croatia.Most of the Neanderthal genome was sequenced from bones found in Vindija cave, Croatia.Max Planck Inst. Evol. Anthropol.

Even before the Neanderthal genome made its debut in May 2010, scientists had argued that humans may have acquired not just DNA from archaic humans, but useful traits too. Human gene variants linked to brain development and speech were proposed as candidates, only to be scotched after closer inspection of the Neanderthal genome. However, a study presented at a Royal Society symposium in London in June suggests that humans owe important disease-fighting genes to Neanderthals and Denisovans. Interbreeding endowed humans with a 'hybrid vigour' that helped them colonize the world, said Peter Parham, an immunogeneticist at Stanford University School of Medicine, California, at the symposium.

Parham's team compared a group of diverse immune genes — the human leukocyte antigen (HLA) genes — in Neanderthals, Denisovans and human groups from around the world. In several cases, Neanderthals and Denisovans carried versions of HLA genes that are abundant in modern humans in parts of Europe and Asia, but less common in Africans. Varying degrees of interbreeding could explain the mismatch, Parham says. He estimates that Europeans owe 50% of variants of one class of HLA gene to interbreeding, Asians 70–80%, and Papua New Guineans up to 95%.

"It does mean that some of us owe part of our immune-system function to Neanderthals," says Pääbo. However, John Hawks, a biological anthropologist at the University of Wisconsin-Madison, notes that many HLA genes pre-date humans' split from Neanderthals and Denisovans, and that the differences may have arisen by chance as the groups evolved.

Hawks, too, has been digging into the archaic genomes, and his team has already discovered that Neanderthals and Denisovans lack certain forms of genes that may help modern humans to fend off epidemic diseases, such as measles. This is hardly surprising: the low population density of hunter-gatherers meant that epidemics were unlikely, so they probably would not have benefited from these immune genes.

But Hawks's team is now using the find to test whether the defensive genes are linked to autoimmune diseases. In September, Hawks and his colleague Aaron Sams are scheduled to present data at a meeting of the European Society for the Study of Human Evolution in Leipzig, Germany, showing that the Denisovans lacked nearly all of the gene variants linked to coeliac disease, a gut autoimmune disorder present in modern humans. Hawks suspects that the variants may actually be in the same genes that are linked to epidemic resistance — if they are, further study could reveal how recently such autoimmune diseases arose in humans.

Unlike most scientists mining the ancient genomes, Hawks has reported some of his more prosaic findings — Denisovans didn't have red hair, for example — on his blog (see go.nature.com/irclra). "These genomes are publicly available. There's nothing stopping high-school students from doing this, and the kind of stuff that I'm putting out on my blog is the stuff that a smart high-school student could do." More significant (and closely guarded) insights will come from developing new methods for analysing ancient genomes to test hypotheses about evolution, he says.

Pääbo, Reich and the other scientists involved in sequencing the ancient genomes are eager to see others run with their data, but caution that they need to be aware of the limitations. "They're really terrible-quality genomes", chock-full of gaps and errors and sections in which short stretches of DNA sequence have been put in the wrong place, says Reich. "There are a lot of traps in using these data, and if people are not careful they'll find all sorts of interesting things that are wrong." Pääbo's team is working on improving the quality of the sequences and including data from more Neanderthals and — he hopes — Denisovans.

Pääbo says that he and his team regularly receive e-mails from scientists asking them questions about using the ancient genomes, which they have attempted to make as user-friendly as possible. But if the first year of ancient human genomics is any indication, these requests will multiply as scientists find new applications for the genomes. "Maybe we should write a little booklet called archaic genomics for dummies," Pääbo says.

Green, R. E. et al. Science 328, 710-722 (2010). | Article | PubMed | ISI | ChemPort |
Reich, D. et al. Nature 468, 1053-1060 (2010). | Article | PubMed | ISI | ChemPort |
McLean, C. Y. et al. Nature 471, 216-219 (2011). | Article | PubMed | ISI | ChemPort |


 Fossil genome reveals ancestral link: A distant cousin raises questions about human origins.

22 December 2010    Ewen Callaway    For nature.com

The ice-age world is starting to look cosmopolitan. While Neanderthals held sway in Europe and modern humans were beginning to populate the globe, another ancient human relative lived in Asia, according to a genome sequence recovered from a finger bone in a cave in southern Siberia. A comparative analysis of the genome with those of modern humans suggests that a trace of this poorly understood strand of hominin lineage survives today, but only in the genes of some Papuans and Pacific islanders.
A finger bone and a tooth (inset) from Denisova Cave have illuminated a mysterious strand of hominin.A finger bone and a tooth (inset) from Denisova Cave have illuminated a mysterious strand of hominin.B. VIOLA, MPI EVA

Named after the cave that yielded the 30,000–50,000-year-old bone, the Denisova nuclear genome follows publication of the same individual's mitochondrial genome in March1. From that sequence, Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and his colleagues could tell little, except that the individual, now known to be female, was part of a population long diverged from humans and Neanderthals.

Her approximately 3-billion-letter nuclear genome, reported in this issue of Nature2, now provides a more telling glimpse into this mysterious group. It also raises previously unimagined questions about its history and relationship to Neanderthals and humans. "The whole story is incredible. It's like a surprising Christmas present," says Carles Lalueza Fox, a palaeogeneticist at Pompeu Fabra University in Barcelona, Spain, who was not involved in the research.

When the ancient genome was compared to a spectrum of modern human populations, a striking relationship emerged. Unlike most groups, Melanesians — inhabitants of Papua New Guinea and islands northeast of Australia — seem to have inherited as much as one-twentieth of their DNA from Denisovan roots. This suggests that after the ancestors of today's Papuans split from other human populations and migrated east, they interbred with Denisovans, but precisely when, where and to what extent is unclear.

More answers could come from a closer look at Denisovan, human and even Neanderthal DNA. So far, conclusions about interbreeding have been drawn from a relatively small number of human genomes using conservative DNA-analysis methods, says David Reich, a geneticist at Harvard Medical School in Boston, Massachusetts, who led the Denisova analysis. "There may have been many more interactions," he says. Pääbo says it may be possible to determine roughly when humans interbred with Denisovans by examining the length of DNA segments lurking in various human genomes, with shorter segments corresponding to more shuffling of genes and a longer elapsed time.

A molar discovered in the same cave also yielded mitochondrial DNA resembling that of the finger bone. But the Denisovans were probably more widespread, says Pääbo. Some fossils from China, for example, resemble neither Neanderthals nor modern humans — nor Homo erectus, an earlier human ancestor. Pääbo wonders whether they could be more closely related to Denisovans. His Russian collaborators plan to search for more complete Denisovan fossils that could be matched to others from China.


Chris Stringer, a palaeoanthropologist at London's Natural History Museum, agrees that Asian fossils, such as the 200,000-year-old Dali skull from central China, could have links to the Denisovans. But he says that firm conclusions about such relationships will have to await the discovery of more complete Denisovan fossils.

Preserved DNA from other Asian fossils would also provide a clearer picture of the Denisovans, which Pääbo, to sidestep controversy, has opted not to call a new species or subspecies of hominin. The challenge will be to make sense of such discoveries and put them in the context of ancient human history, says Lalueza Fox. Palaeoanthropologists are just beginning to scrutinize the Neanderthal genome published earlier this year3 for clues to ancient human history. With the Denisova genome, "they will need to deal with another surprise", he says.

See also News & Views, p.1044

Krause, J. et al. Nature 464, 894-897 (2010). | Article | PubMed | ChemPort |
Reich, D. et al. Nature 468, 1053-1060 (2010). | Article
Green, R. E. et al. Science 328, 710-722 (2010). | Article | PubMed | ChemPort |


 Human history writ large in a single genome

The first humans to leave Africa continued to interbreed with Africans for tens of thousands of years.

13 July 2011    Ewen Callaway    For Nature.com
crowdThe genomes of everyone living today contain a record of the history of our species.Scott Hortop Travel/Alamy

Stored inside Craig Venter's genome are clues to the history of humankind, including global migrations and population crashes. Researchers have mined the genomics pioneer's publicly available DNA sequence, and those of 6 others, to reveal major milestones in human history.

"You can take a single person's genome and learn an entire population's history from it," says David Reich, a geneticist at Harvard Medical School in Boston, Massachusetts, who was not involved in the study. "This is one of the dreams we've had as a community."

The analysis, published today in Nature1, suggests that descendants of the first humans to leave Africa dwindled to little more than 1,000 reproductively active individuals before rebounding. The study also suggests that, contrary to assumptions made from archaeological evidence, these early humans continued to breed with sub-Saharan Africans until as recently as 20,000 years ago.
Maternal ties

Geneticists eager to plumb human history have traditionally compared DNA sequences from numerous people around the world to determine how different populations relate to one another and when they might have gone their separate ways. For instance, studies of DNA from maternally inherited cell structures called mitochondria established that all humans can trace their maternal lineage back to one woman — a mitochondrial Eve — who lived in Africa around 200,000 years ago2.

But, just as mitochondria can lead us back to a single woman, parts of a person's genome inherited from both their mother and father can also be followed back in time, with individual genes traced back to points before any mutations had developed, when just one version — a common ancestor — of that gene existed. Because of the way a person's maternal and paternal chromosomes shuffle together to create diversity in their sperm or egg cells, some parts of a person's genome inevitably share common ancestors more recently than other parts.

"Each little piece of the genome has its own unique bit of history and goes to a unique ancestor as you go further and further back," explains John Novembre, a population geneticist at the University of California, Los Angeles, who was not involved in the study. "As you look at different parts of the genome, you get access to different parts of history."

On the basis of this principle, Richard Durbin, a genome scientist at the Wellcome Trust Sanger Institute near Cambridge, UK, and his then post-doc Heng Li determined a way to calculate, from the ages of different segments of a single person's genome, changes in the population size of their ancestors.

The genomes of Venter and two others of European ancestry, two Asian men and two West African men all tell the same story up until about 100,000 years ago, when their populations began to split and then plummet in size, probably reflecting the first human migrations out of Africa.

The ancestors of Asians and Europeans dwindled by a factor of ten to roughly 1,200 reproductively active people between 20,000 and 40,000 years ago, Durbin and Li calculate. African populations also crashed, but by nowhere near the same extent, dropping to around 5,700 breeding individuals. Other studies have recorded population crashes at around the same time, Reich says.

In a different analysis, Durbin and Li compared an X chromosome from an African with one from a non-African to determine when their ancestors stopped interbreeding after the first humans left Africa and colonized other parts of the world. Human remains and artefacts unearthed in Europe, Asia and Australia seem to suggest humans rapidly colonized these places by about 40,000 years ago, diminishing the opportunities to interbreed with Africans.

However, Durbin and Li suggest that these groups continued to interbreed until as recently as 20,000 years ago. One possible explanation, Durbin says, is that after the first humans left Africa some 60,000 years ago, successive waves of Africans followed suit, interbreeding with the ancestors of the earlier migrants.
Mix and match

Chris Stringer, a palaeoanthropologist at the Natural History Museum in London, says that human populations outside Africa were probably small and widely dispersed 20,000–50,000 years ago, so regular interbreeding with Africans seems unlikely. "There could have been surges of gene flow at particular times, driven by innovations or environmental change, but it would be surprising if these continued right through that period," he says.

Mining individual genomes can't reveal every chapter of human history, notes Reich, who now works with Li at the Broad Institute of Harvard and MIT in Cambridge, Massachusetts. The approach reveals little about upheavals of the last 20,000 years, such as the peopling of the Americas, because few chunks of the genome are young enough. Similarly, Durbin and Li's method can't deduce the history of human ancestors who existed before about 2 million years ago because few regions of the genome are much older.

Despite these limitations, Reich plans to lean heavily on the new approach, not least for work on ancient genomes belonging to Neanderthals3 and a mysterious sister population, known as Denisovans, discovered through DNA recovered from a 30,000–50,000-year-old finger bone found in a Siberian cave4. Reich and his colleagues have been unable to determine when Neanderthals and Denisovans stopped breeding with one another, and the new approach has the potential to answer that question.

Li, H. & Durbin, R. Nature doi:10.1038/nature10231 (2011).
Cann, R. L., Stoneking, M. & Wilson, A. C. Nature 325, 31-36 (1987). | Article | PubMed | ISI | ChemPort |
Green, R. E. et al. Science 328, 710-722 (2010). | Article | PubMed | ISI | ChemPort |
Krause, J. et al. Nature 464, 894-897 (2010). | Article | PubMed | ChemPort |


 First Aboriginal genome sequenced: 1920s hair sample reveals Aboriginal Australians' explorer origins.

22 September 2011    Ewen Callaway    For Nature.com

A 90-year-old tuft of hair has yielded the first complete genome of an Aboriginal Australian, a young man who lived in southwest Australia.

He, and perhaps all Aboriginal Australians, the genome indicates, descend from the first humans to venture far beyond Africa more than 60,000 years ago, and thousands of years before the ancestors of most modern Asians trekked east in a second migration out of Africa.

"Aboriginal Australians are descendents of the first human explorers. These are the guys who expanded to unknown territory into an unknown world, eventually reaching Australia," says Eske Willerslev, a palaeogeneticist at the University of Copenhagen, Denmark, who led the study. It appears online today in Science1.
Hanging on a hair

The oldest human remains in Australia date to around 50,000 years ago2, and yet older stone tools found in India and elsewhere hint at an early southern migration of anatomically modern humans out of Africa and through India and Southeast Asia.

However, genetic studies of contemporary Asians and Oceanians haven't always told the same story. The most comprehensive genetic analysis carried out so far pointed to a single migration that spawned all Asian populations, including Aboriginal Australians3. But estimated times of the separation of European and Asian ancestors in this population does not chime well with the archaeological evidence for the continuous settlement of Australia from much earlier times.

“These papers make an overwhelming case for multiple waves of migration.”

A complete genome from an Aboriginal Australian would settle this debate, Willerslev says. Many contemporary Aboriginal Australians also descend from Europeans because of recent interbreeding between Aboriginals and Australian colonists. To get a better picture of the ancient history of Aboriginals, Willerslev wanted to sequence the genome of someone who did not descend from Europeans.

About a year ago, his team obtained a hair sample originally collected by the British ethnologist Alfred Cort Haddon. Historical records suggest that Haddon got the hair from a young Aboriginal man in the early 1920s while on a train journey from Sydney to Perth.

Willerslev believes that the man offered his hair to Haddon willingly, and a Danish bioethics review board saw no problem with sequencing his genome. Willerslev later received the blessing of a committee that represents Aboriginal people in the region where the man probably lived.

An analysis of his genome indicates that his ancestors started their journey more than 60,000 years ago, branching off from humans who left Africa. The ancestors of contemporary Europeans and most other Asians probably went their separate ways less than 40,000 years ago, according to Willerslev's team.
Ancient relations

Like other populations outside Africa, the Australian Aboriginal man owes small chunks of his genome to Neanderthals4. More surprisingly, though, his ancestors also interbred with another archaic human population known as the Denisovans. This group was identified from 30,000–50,000-year-old DNA recovered from a finger bone found in a Siberian cave5. Until now, Papua New Guineans were the only modern human population whose ancestors were known to have interbred with Denisovans.

A second study incorporating genomic surveys from different Aboriginal Australians paints an even clearer picture of their ancestors' exploits with the Denisovans. Researchers led by Mark Stoneking at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, calculated the portion of Denisovan ancestry found in the genomes of 243 people representing 33 Asian and Oceanian populations. Patterns of Denisovan interbreeding in human populations could reveal human migration routes through Asia, reasoned the team. The paper is published today in the American Journal of Human Genetics6.

This comparison revealed a patchwork in which some populations, including Australian Aboriginals, bore varying levels of Denisovan DNA, while many of their neighbours, like the residents of mainland Southeast Asia, contained none.

Stoneking says that this pattern hints at at least two waves of human migration into Asia: an early trek that included the ancestors of contemporary Aboriginal Australians, New Guineans and some other Oceanians, followed by a second wave that gave rise to the present residents of mainland Asia. Some members of the first wave (though not all of them) interbred with Denisovans. However, the Denisovans may have vanished by the time the second Asian migrants arrived. This also suggests that the Denisovan's range, so far linked only to a cave in southern Siberia, once extended to Southeast Asia and perhaps Oceania.

"Put together, these two papers make an overwhelming case for multiple waves of migration," says David Reich, a population geneticist at Harvard Medical School in Boston, an author on the second study.

Alan Redd, a biological anthropologist at the University of Kansas in Lawrence, says that the peopling of Australia may have been more complicated than either paper suggests. Dingoes, for instance, were brought to the island continent by humans who arrived in the last 5,000 years. "It's certainly possible that people were trickling in at different times," he says.

Rasmussen, M. et al. Science http://10.1126/science.1211177 (2011).
Bowler, J. et al. Nature 421, 837-840 (2003). | Article | PubMed | ISI | ChemPort |
HUGO Pan-Asian SNP Consortium Science 326, 1541-1545 (2009). | Article | PubMed | ISI | ChemPort |
Green, R. E. et al. Science 328, 710-722 (2010). | Article | PubMed | ISI | ChemPort |
Reich, D. et al. Nature 468, 1053-1060 (2010).
Reich, D. et al. Am. J. Hum. Genet. 89, 1-13 (2011). | Article |




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