Old DNA, New Tricks

Over the past decade, researchers have learned to reconstruct ancient DNA from fossils.  In December 2013, we were stunned to learn that refinements in techniques made it possible to restore human DNA from as far back as 400,000 years ago. 

Quickly on the heels of that advance, another new development has been announced in the 27-31 January online edition of PNAS.  Scientists at the University of Uppsala, in cooperation with the pioneering team in Leipzig, have developed a way to separate the old DNA sequences from contamination.

Photo Credit: Creative Commons, posted by Archaeogenetics, no restrictions.

Why is that important?  Because contamintion is a leading problem when it comes to reconstructing ancient DNA.  Literally thousands of fossils fill draws and shelves in museums around the world.  They contain DNA, too much of it, in fact, to be of any use.  Bits of ancient DNA are surrounded by more modern DNA from humans and from other organisms.  Now, researchers have learned to separate the old from the new. 
 
What makes the new breakthrough exciting is that now, at least some DNA information from many of these old fossils might be retreivable. 

"Many extremely interesting DNA data sets from ancient humans never see the light of day because of contamination. The idea behind this method was to change that," says Pontus Skoglund, a lead author at Uppsala University.
 
To test the new technique, the researchers used it to reconstruct the mitochondrial DNA from a previously unusuable Neandertal bone from the Altai Mountain region of Siberia.  The sample compared well with other known Neandertal DNA sequences in contrast to more modern humans.
 
It is hard to predict just where this new technology will lead.  At the very least, it seems to unlock the file boxes of museums throughout the world.  Previously discovered fossils, some of them very well dated, might be analyzed for the DNA.  Who knows what we will learn.

"There are many really interesting ancient human remains that we can rescue from severe contamination with this method. And the method is not limited to Neanderthals, even remains of anatomically modern humans that are contaminated by modern-day humans can be rescued," says co-investiagor Mattias Jakobsson in a press release from the University of Uppsala.
 
The new technique is described in a paper entitled "Separating endogenous ancient DNA from modern day contamination in a Siberian Neandertal." Skoglund, P.; Jakobsson, M.; Northoff, B.H.; Pääbo, S.; Krause, J.; Shunkov, M.V.; Derevianko, A.P; PNAS Online Early Edition the week of Jan 27-Jan31, 2014.

Human-Neandertal Interbreeding: When and Where?

Comparison between Neandertal and anatomically modern human genomes shows a history of interbreeding. Some living human beings—those with ancestry in Europe and Asia—carry the results of that interbreeding in their DNA. Those with ancestry in sub-Saharan Africa typically do not.

We also know that Neandertals lived in Eurasia from 230,000 until about 30,000 years ago. Where they came from or why they disappeared remains an open question. And we know that anatomically modern humans first appear in Africa at least 200,000 years ago. Some of them made their way to Asia and Europe sometime in the last 100,000 years.

So when did modern human/Neandertal interbreeding last occur? Did it occur deep in our past, before modern humans and Neandertal ancestors left Africa? Or did it occur after both left Africa, sometime—in other words—within the past 100,000 years?

A new study claims to find evidence that the interbreeding occurred out of Africa. Researchers argue that on the basis careful analysis of the shared DNA, the most recent interbreeding occurred sometime between 37,000 and 86,000 years ago.

Caption: Reconstruction of a Neandertal, 2006, by Stefan Scheer, from Stefanie Krull, Neanderthal Museum Picture Library, Mettmann, Germany

If so, it is pretty strong evidence that the interbreeding occurred after anatomically modern human left Africa. This may have occurred in the Middle East, researchers point out, but probably not just at the beginning of the modern human migration out of Africa. The most recent interbreeding, they conclude, occurs well after this 100,000 date, suggesting ”a more recent period, possibly when modern humans carrying Upper Paleolithic technologies expanded out of Africa.”

In that case, the conceptual challenge posed by the modern human/Neandertal interbreedng remains clearly in front of us. What is the human species? Were Neandertals human? And what are we to make of our new insight into modern human diversity. All puzzling questions, to put it mildly.

The article, "The Date of Interbreeding between Neandertals and Modern Humans," is published in the current issue of PLOS Genetics, where it is available free to the public.

Genes, Hybrids, and Giant Tortoises

Charles Darwin visited the Galápagos Islands in 1835. As he moved from island to island, he saw the subtle differences between finches, tortoises, and other animals. These observations led to the discovery of the theory of evolution as an expanding “tree of life,” first sketched by Darwin in his notebook entry dated just two years later in 1837.

The great tortoises of the Galápagos could not fail to impress. The greatest of all, the tortoise Chelonoidis elephantopus, can live to be a hundred years old and grow to six feet and almost 900 pounds.

Until now, it was believed that whalers hunted the great C. elephantopus to extinction shortly after Darwin’s visit. Now, however, new research suggests that a few of the great tortoises may still be alive.

Caption: G. Becky tortoises are native to Isabela Island in the Galapagos chain and have more domed shape shell. Credit: Courtesy Yale University.

Researchers have found what they believe are direct offspring of purebred C. elephantopus tortoises. By testing the genes of living tortoises, researchers concluded that they were studying hybrids. One parent was from a related species, C. becki. But the other parent was clearly C. elephantopus. And since the living tortoises were still quite young, researchers were drawn to the obvious conclusion that the C. elephantopus parent lived until a few decades ago and may still be roaming the slopes of Isabela Island.

So now it’s a race against time to find surviving purebred C. elephantopus tortoises in hopes that enough of them still exist so the species—truly one of the great animal species—can be brought back from what seemed like extinction. According to the report, “purebred tortoises of the recently ‘extinct’ C. elephantopus from Floreana Island are very likely still alive today.”

Caption: This tortoise is a hybrid of G. Becky and C. elephantopus, a species native to Floreana Island some 200 miles away and thought to be extinct. Genetic analysis of tortoise population on Isabela Island suggests purebred individuals of C. elephantopus must still be alive on Isabela. Credit: Courtesy of Yale University

One interesting parallel. Using a similar approach, researchers have recently concluded that human beings are also hybrids. For example, many of us contain genes from our Neandertal ancestors. The big difference, of course, is that our interbreeding occurred tens of thousands of years ago. In either case, hybridization or interbreeding occurs when the twigs at the end of Darwin's tree of life come together. As evolutionary biologists are discovering, speciation (or branching) is critical to evolution, but so is interbreeding or hybridization.

According to the report, “To our knowledge, this is the first rediscovery of a species by way of tracking the genetic footprints left in the genomes of its hybrid offspring.” The report, "Genetic rediscovery of an ‘extinct’ Galápagos giant tortoise species," appears in the January 9, 2012 issue of Current Biology.

Human Nature, Human Self-Creation

When I spoke at the University of South Florida-St Petersburg last week, I summarized various ways in which the Human Genome Project has opened new perspectives on recent human evolution.

Evidence is mounting the anatomically modern humans (AMH) interbred with archaic humans, such as Neandertals, within the past 80,000 years and perhaps as recently as 30,000 years ago. Not only that, but in the view of some experts, this interbreeding was widespread, possibly more the rule than the exception.

The title of my talk was “Finding the Human in the Genome.” I presented visual images of early human art, including the recent report of the discovery of the 100,000 “artist workshop” in South Africa.

Looking at ancient art can be inspiring and moving, but for us today, the question comes back more forcefully than ever. What are we? Where are we going as a species? Are we in danger of destroying ourselves, not by violence but by modification, by engineering future humans that are not exactly human anymore?

I suggested that our past is somewhat more complex than we thought. Our future, likewise, is a bit more open-ended. We are not clearly defined at either end, either in our origins or in our destiny. As science discovers a complex past, technology opens an uncharted future.

At that point in the talk, I turned to the prescient words of Giovanni Pico della Mirandola, the author of the Oration on the Dignity of Man. Writing in 1486, Pico praises the greatness of the Creator, the “Great Artisan,” who creates human beings with no defined or determinate nature, except the need for self-creation:

Finally, the Great Artisan mandated that this creature who would receive nothing proper to himself shall have joint possession of whatever nature had been given to any other creature. He made man a creature of indeterminate and indifferent nature, and, placing him in the middle of the world, said to him "Adam, we give you no fixed place to live, no form that is peculiar to you, nor any function that is yours alone. According to your desires and judgment, you will have and possess whatever place to live, whatever form, and whatever functions you yourself choose. All other things have a limited and fixed nature prescribed and bounded by our laws. You, with no limit or no bound, may choose for yourself the limits and bounds of your nature. We have placed you at the world's center so that you may survey everything else in the world. We have made you neither of heavenly nor of earthly stuff, neither mortal nor immortal, so that with free choice and dignity, you may fashion yourself into whatever form you choose. To you is granted the power of degrading yourself into the lower forms of life, the beasts, and to you is granted the power, contained in your intellect and judgment, to be reborn into the higher forms, the divine.

According to Pico, God speaks these words to the newly created Adam and Eve and, in effect, to all of us. Then Pico comments: “Imagine! The great generosity of God! The happiness of man! To man it is allowed to be whatever he chooses to be!”

Now, thanks in part to recent science, we can see just how far Pico was right.

Archaic Interbreeding? So What?

Later this week, I will be speaking at the University of South Florida—Saint Petersburg in their lecture series, a Celebration of the Genome.” My topic is “Finding the Human in the Genome.”

I start with the obvious: Our knowledge of human biology is increasing rapidly, thanks in large part to the Human Genome Project. We can now compare the DNA of one human being with another and ask questions about similarities and differences. We can compare human DNA with the full genomes of chimps and other species.

Most interesting to me is that we can also compare the genome of anatomically modern humans with that of extinct forms of humanity, such as Neandertals or their recently discovered cousins, the Denisovans. What we have found is that in a real sense, they are not extinct at all because their DNA lives on in us.

That leads to something less obvious but more profound. The more we know about human biology, the less we know about human nature. Put another way, the more information we have, the less confident we are that we really know what we mean when we talk about “humanity.”

So what is going on here? Does it really bother anyone—besides me, that is, and perhaps only because I am, after all, a “theologian”? I am asking myself this question a lot these days. Does it really matter that our ancestors interbred with Neandertals and Denisovans and, as time will probably tell, many other forms of archaic humanity?

So what’s the big deal? In some ways I guess it’s like the high school student who runs a paternity test and learns that daddy isn’t daddy.

Or maybe it’s more like this. Years ago, I remember hearing Kári Stefánsson speaking to a roomful of scientists and introducing deCODE Genetics, the Iceland DNA database. He explained the reasons for the project, such as excellent health records, small genetic diversity, and superb genealogical records going back 1,000 years. We Icelanders need to sell more than fish, he said. We want to mine our DNA for all kinds of gene-disease information. Then Stefánsson mentioned that the information sometimes disproved the genealogies. Everyone laughed when he said: “We are not responsible for what our Viking ancestors did back then during the long Icelandic winters.”

Is that it? Is that all that’s happened here, just some forced revisions of the family tree? So what if my ancient ancestors were not exactly what I thought? It happened, after all, some 40,000-100,000 years ago. I am not responsible.

But I am affected. My biology is different from what I once thought. Perhaps I am healthier as a result of the ancient interbreeding, as at least one report has suggested.

More than that, I am coming to see human beings as biologically more diverse and more complicated that we once thought. The diversity part is a bit scary. We have not done well as a species in dealing with our differences.

The complexity part—that’s more of a mystery than a fear. I don’t claim to hear the voices of my Neandertal ancestors calling out from my DNA or reverberating through my metabolic processes. At least not yet.

Complicating the Family Tree

Our view of our past keeps getting more complicated. Our family tree, it turns out, is more of a twisted vine than a neatly linear branch.

Evidence keeps building by the day that our anatomically modern human (AMH) ancestors interbred with earlier forms of “archaic” humans. In the 31 Oct 2011 early online issue of PNAS, Pontus Skoglund and Mattias Jakobsson present evidence for the view that the genetic legacy of the Denisovans is wider than ever thought before.

First is was the Neandertals. This branch of the human family diverged from our own somewhere around 500,000 years ago. Somewhere between 100,000 and just 50,000 years ago, however, AMHs and Neandertals interbred successfully. The result lives on today in our genes. For many of us, our DNA is 2-3% from our Neanderthal ancestors. The Neandertals may be extinct, but their DNA lives on in every cell in the human body.

Then it was the Denisovans, a recently discovered branch of the human family more closely related to Neandertals than to us. What about AMH-Denisovan iInterbreeding? An international team of researchers led by Svante Pääbo of the Max Planck Institute for Evolutionary Anthropology in Leipzig was able to extract Denisovan DNA from tiny fragments of remains. From the extracts, they reconstructed the Denisovan genome and compared it with the human genome. What they found was clear evidence of interbreeding. Some living human beings—those identified as Melanesians—carry Denisovan genes. That was reported in December 2010.

In September, however, Pääbo was joined by David Reich and Mark Stoneking and other colleagues in reporting that the legacy of Denisovan DNA extends beyond the Melanesians. It’s all over the islands that extend below Southeast Asia, including Australia. Not just Aboriginal Australians but Near Oceanians, Polynesians, Fijians, east Indonesians, and other groups as far as the Philippines are carriers of the Denisovan legacy.

According to this study, the genetic legacy of AMH-Denisovan admixture does not include East Asians. This led the authors to conjecture that there are at least two main waves of AMH migration into southeast Asia. The first wave interbred with Denisovans while the second, apparently, did not.

Their work appeared in the 7 Oct 2011 issue of the American Journal of Human Genetics. Reich discusses these findings in a video. Hint: start at minute 22:30.

But now a study published in the online early edition of the Proceedings of the National Academy of Sciences for the week of 31 Oct 2011 presents evidence that East Asians are also descended in part from the Denisovans. In the paper, the authors (Pontus Skoglund and Mattias Jakobsson) write that “we found a significant affinity between East Asians, particularly Southeast Asians, and the Denisova genome.”

Experts in the field will no doubt debate these findings. Just how widespread is the effect of AMH-Denisovan interbreeding? How widely did AMHs and archaic humans interbreed? To what extent does admixture provide any benefit? Does it shed any light on observable differences between different groups within the human family today?

According to Skoglund and Jakobsson, the “history of anatomically modern and archaic humans might be more complex than previously proposed.”

If our past is more complex than we thought, so is our present. What does it mean to be human? It no longer seems to mean that we are all part of a biological species. Whether we like to call ourselves "anatomically modern humans" (AMHs) or Homo sapiens, we are learning that the very concept of species is becoming unfocused by research. Should we speak of AMH-Denisovan "interbreeding" or "hybridization"? Does it matter? Are we separate species or one slightly-tangled humanity?

Still wondering..."What Defines Us?"

Last February the editors of Science marked the 10th anniversary of the publication of the complete human genome. They invited a dozen or so people to contribute short reflections on the meaning of this milestone.

I was given 250 words for my article, entitled “What Defines Us?” In that small space I tried to suggest two things. First I noted a simple irony: As we gain more scientific information about our genome and our evolution, the philosophical and religious concepts of humanity become blurred or defocused. Second, I suggested that this defocusing need not be a cause for discomfort. Precisely because we are humans—whatever exactly that means anymore—we switch almost immediately from discomfort to wonder and excitement. The quick switch is what makes us human. I ended by asking: “Who are we, and where will we go next?”

It is as if we are making ourselves up as we go along. Recent discoveries in human evolution intimate just such a view. Anatomically modern humans are now believed to have interbred with Neandertals and with the more recently discovered Denisovans. Many of us carry the DNA of these extinct forms of humanity in our own genome. In that sense they are not distinct at all but live on in every cell of our bodies. More recently, it has been suggested that similar interbreeding occurred in sub-Saharan Africa.

Interestingly, it has also been suggested that interbreeding enhanced us. In August, a research article in Science suggested that our immune systems are more resilient than they might have been. Why? Because our ancestors interbred with Neandertals and Denisovans.

The evolutionary tree of humanity is beginning to look less like a tree and more like a tangled vine. And now we are led to wonder whether it is the tangle that enhances us. What makes us less clearly Homo sapiens seems, paradoxically, to make us more extraordinary as a species. Well…we’re running far ahead of the science here, but (as I suggested in Science), wondering is what makes us human. It’s not just the DNA; it’s what we dare to do with it.

I have been thinking about this recently because I will be speaking on November 10 on this very topic at the University of South Florida Saint Petersburg. They have planned an exciting lecture series, Festival of the Genome: Celebrating the 10th Anniversary of the Sequencing of the Human Genome, showcasing various perspectives on human genome research.