Neanderthal Man (41 page)

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Authors: Svante Pbo

Tags: #In Search of Lost Genomes

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Postscript

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Three years later, as I write this, we still do not know what happened to the other part of the finger bone that Anatoly sent to Berkeley. Perhaps one day it can be used for dating so that we will know when the Denisova girl lived.

Anatoly and his team have continued to unearth amazing bones in Denisova Cave. They have found another huge molar that contains Denisovan DNA. They have also found a toe bone that turned out to come from a Neanderthal.

David Reich and his postdoc Sriram Sankararaman have used genetic models to date the admixture between Neanderthals and modern humans to sometime between 40,000 and 90,000 years ago.
{65}
This shows that actual interbreeding between Neanderthals and modern humans has caused the extra similarity between the Neanderthal genome and the genomes of people in Europe and Asia, not the more complicated scenario of ancient substructure in Africa that we also considered in 2010.

Matthias Meyer, something of a technical wizard in our lab, has developed new and amazingly sensitive methods to extract DNA and make libraries. This has allowed us to use the tiny leftover fragments of the Denisova finger bone to sequence its genome to a total coverage of 30-fold.
{66}
Recently, we have followed up by sequencing the Neanderthal genome from the toe bone found in Denisova Cave to 50-fold coverage. These ancient genomes are now of higher accuracy than most genomes determined from people living today.

When we compare the Neanderthal genome to the genome of the Denisovan girl, we see that she carried a component in her genome from a hominin that diverged from the human lineage earlier than Neanderthals and Denisovans. We also see that Denisovans mixed with Neanderthals, and that they contributed small amounts of DNA not only to people in Melanesia but also to people who live on mainland Asia today. These were subtle signals of past mixing that we could not see in 2010, when we worked with genomes of lower quality. The picture that emerges is that there was plenty of mixing among several types of humans in the late Pleistocene, but mostly of small proportions.

Together with new data from the 1,000 Genomes Project, these two archaic genomes of high quality now allow us to create a near-complete catalog of sites in the genome where all people today are different from Neanderthals and Denisovans as well as from the apes. This catalog contains 31,389 single nucleotide changes and 125 insertions and deletions of a few nucleotides. Of these, 96 change amino acids in proteins, and perhaps 3,000 affect sequences that regulate how genes are turned on and off. There are surely some nucleotide differences, particularly in repetitive parts of the genome, that we have missed, but it is clear that the genetic “recipe” for making a modern human is not very long. The next big challenge is to find out what the consequences of these changes are.

George Church, a brilliant technical innovator at Harvard University, has suggested that scientists should use our catalog to modify a human cell back to the ancestral state and then use that cell to recreate or “clone” a Neanderthal. In fact, already when we announced that we had completed the Neanderthal genome sequencing at the AAAS meeting in 2009, George was quoted by the
New York Times
as saying that “a Neanderthal could be brought to life with present technology for about $30 million.” He added that if someone were eager to supply the financing, he “might go along with it.” To his credit, he acknowledged that there are ethical problems with such a project, but suggested that to avoid those, one could use not a human cell but a chimpanzee cell!

This, as well as later statements to the same effect, I write off as George’s tendency to be provocative. Nevertheless, they point to a dilemma. How do we study traits specific to humans—for example, language or aspects of intelligence—when for both technical and ethical reasons we cannot do what George suggests? The way forward is, on the one hand, the introduction of human and Neanderthal genetic variants into the genomes of human and apes cells that can then be used not to clone individuals but to study their physiology in a plastic dish in the laboratory and, on the other hand, the introduction of such variants into laboratory mice. Our laboratory in Leipzig has already taken the first steps in that direction. In 2002, we found that the protein made from a gene called
FOXP2,
which Tony Monaco’s group in Oxford, England, had shown to be involved in language ability in humans, differed at two amino-acid positions from the same protein in apes and almost all other mammals.
{67}
Encouraged by the fact that the mouse
FOXP2
protein is very similar to the
FOXP2
protein of the chimpanzee, we decided to introduce the two human changes into the mouse genome. It took several years of hard work by a talented student, then postdoc, then group leader in our lab, Wolfgang Enard, until the first mice that made the human version of the
FOXP2
protein were born. The results greatly exceeded my expectations. The peeps the pups produced at about two weeks of age when removed from the nest differed subtly but significantly from those of their non-humanized littermates, supporting the idea that these changes have something to do with vocal communication. This finding has led to much more work showing that the two changes affect how neurons extend outgrowths to contact other neurons and how they process signals in parts of the brain that have to do with motor learning.
{68}
At the moment, we are collaborating with George Church to put these changes into human cells that can be differentiated to neurons in the test tube.

Although the two changes in
FOXP2
are actually shared with Neanderthals and Denisovans,
{69}
these experiments nevertheless point to how, in the future, we may sort out which changes are crucial for what makes modern humans special. One can imagine putting such changes into cell lines, and into mice, alone and in different combinations, in order to “humanize” and “neanderthalize” biochemical pathways or intracellular structures, and then to study their effects. One day, we may then be able to understand what set the replacement crowd apart from their archaic contemporaries, and why, of all the primates, modern humans spread to all corners of the world and reshaped, both intentionally and unintentionally, the environment on a global scale. I am convinced that parts of the answers to this question, perhaps the greatest one in human history, lies hidden in the ancient genomes we have sequenced.

About the Author

____________________________

Svante Pääbo
is the director of the Department of Genetics at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. He has been featured in the
New York Times, Newsweek,
National Geographic
, and
The Economist,
as well as on NPR, PBS, and the BBC. In 2009,
Time
named him one of the 100 Most Influential People in the World. Pääbo lives in Leipzig.