Mummies, Neanderthals, and Humans, Oh My!

; Svante E. Pääbo, PhD

Disclosures

April 13, 2015

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Raiders of the Egyptian Pyramids

Eric J. Topol, MD: I am Eric Topol, editor-in-chief of Medscape, speaking with Svante Pääbo, who is head of the genetics department at the Max Planck Institute in Leipzig, Germany. He is a pioneer, the main force trying to understand the genomics of Neanderthals in human evolution. Dr Pääbo is, in every way, one of the most fascinating people in medicine. Svante, I would first like to discuss your interest in tracing the biology of human origins. How did you get into this?

Svante E. Pääbo, PhD: Like many kids, I was fascinated by ancient Egypt and imagined that I was Indiana Jones and discovered pyramids and mummies. At university, I had to learn a lot of ancient Egyptian verb forms and hieroglyphs and things. Then I didn't know what to do, so I ended up going to medical school and studying molecular biology. At the time, cloning of DNA was new, and possible, and I started thinking about whether I could retrieve DNA from ancient Egyptian mummies. It started as a hobby project.

Dr Topol: Your book Neanderthal Man: In Search of Lost Genomes (Basic Books, 2014), is fascinating. You wrote about how your mother took you to Egypt as a teenager.

Dr Pääbo: That trip with my mother to Egypt was what convinced me that ancient Egypt was what I wanted to study.

Dr Topol: You happen to have a little bit of science in your genes, with your father being a Nobel laureate and your mother being a biochemist. Take us through how you started to get samples and do sequencing in a place that no one had been before.

Dr Pääbo: I started with Egyptian mummies, working at my lab bench like all other graduate students, and got some DNA sequences out of them. Those were also published. In hindsight I realized that it was all confirmation of DNA from me. It has become clear that a dust particle in a room is largely skin fragments from humans, and a single dust particle can contain much more DNA than the half-gram of bone that I was trying to extract it from. That gradually became clear.

I shifted from working with ancient human remains to extinct animals, because if you study mammoths and find something elephant-like that is not identical to elephants, you can be pretty certain that you have the right DNA sequence. Over many years I developed the techniques using extinct animals. Only then (10-15 years later) did we go back to studying ancient humans, particularly the Neanderthals.

Breaking the Neanderthal Code

Dr Topol: You hit it big then. You were able to overcome the issues of contamination. What was the first breakthrough with the Neanderthal?

Dr Pääbo: We first studied the mitochondrial DNA that is maternally inherited and which has the advantage that every cell contains hundreds, or even thousands, of copies. There is a much bigger chance that some fragments of mitochondrial DNA would survive for thousands of years. Then in 1997, in a particular piece of the nuclear genome, we were able to reconstruct a part of the mitochondrial genome on the Neanderthals. We found it to be quite different from the mitochondrial genomes of present-day people.

Dr Topol: You were comparing the mitochondrial DNA of Neanderthals to that of humans?

Dr Pääbo: We were able to reconstruct a piece of the mitochondrial genome and found it to be quite different from that of present-day humans. All mitochondrial genomes of present-day people go back to an ancestor between 100,000 and 200,000 years ago. This went back about half a million years. That was the first piece of DNA from any extinct human that was actually sequenced. It has given no indication that it was any special mixing between Neanderthals and other humans, but it gave us an estimate of when humans had a common ancestry more than half a million years ago.

"I Think My Husband Is a Neanderthal"

Dr Topol: When did you start to realize that there had indeed been mixing of Neanderthals and humans?

Dr Pääbo: This has been a debate since the cave and paleontology experts built their careers arguing for one or the other. In 2005, we were very lucky to be able to convince funding agencies in Germany that one would be able, perhaps, to reconstruct a large part of the Neanderthal genome if we were allowed to develop the techniques and apply them on a large scale. We did that, and in 2010 we had the first overview of the Neanderthal genome. Then, to my surprise, we found that the Neanderthals shared more mitochondrial DNA with Europeans than with Africans, and because there had never been any Neanderthals in Africa, this suggested gene flow mixing between the Neanderthals and the ancestors of the Europeans. Even more surprising to me was that we found the same situation in China and out in the Pacific—actually, in any person whose roots were outside of Africa. We thought a lot about that and tried to exclude all sorts of biases in the data and consider other explanations.

We came up with a model of what happened when modern humans came out of Africa: They passed by the Middle East where they met Neanderthals, and then they mixed with Neanderthals. These people were then ancestors of everybody outside of Africa. They carried this Neanderthal component with them out into the rest of the world, to the extent that somewhere between 1% and 2% of your genome (if your roots are outside of Africa) comes from Neanderthals.

Dr Topol: There has been a lot of joking since your findings that some people have more Neanderthal genome than others. You told a great joke today at the Future of Genomic Medicine about men and women; can you recount that?

Dr Pääbo: When our paper came out, we were amazed by how much interest there was among the general public and how many people started writing to us, self-identifying as Neanderthals and offering to send us blood samples. Then I noticed another pattern. The responders were mainly men who self-identified as Neanderthals, but very few women. After I presented that to my research group (who are particularly critical of everything), they said that it was just bias in my data. They said that men were more interested in genetics and so they write to you more often than women, but I went back and found that that was not the case, because plenty of women had written to me to say they are married to Neanderthals, whereas the other way around hardly occurs at all. That says something about our ideas of how Neanderthals might have behaved, and that that behavior might be even slightly attractive in men but not so much in women.

If You Give a Mouse a Mutation...

Dr Topol: That's a great story. You made a discovery about FOXP2, which is an important gene for human speech. Can you tell us about that?

Dr Pääbo: FOXP2 is a gene that encodes a transcription factor. When one copy is lost in present-day humans, they have a rather specific problem with speech and language. That makes it very interesting in terms of thinking about the origin of the language and speech. We found that the protein encoded there has two amino acid differences from that of other primates. Humans have two specific amino acid changes in an otherwise very conserved protein.

We engineered these amino acid changes into a transgenic mouse. We now have a mouse that, essentially from its own FOXP2, makes a human protein. Amazingly, one of the first things that we found was that it actually vocalizes slightly differently; it has a deeper voice. You can also see differences in the neurons in certain parts of the brain—they have longer dendrites and different electrophysiologic properties. Just last year, people at Massachusetts Institute of Technology, who worked with our mice, discovered that these mice even learned certain motor tasks quicker than their otherwise typical litter mates, particularly in the automating of their movements. It's very tempting to speculate that this has to do with learning to articulate. It is probably the most sophisticated coordination of muscle movements that we do as a species.

Dr Topol: It's extraordinary. At your presentation you mentioned that you were making the Neanderthal genome open to the research community, which is fantastic because it hasn't been so supported through other means. We will be able to learn more about conserved genes and variations from this relationship of human to Neanderthal and to other Hominidae. Do you think this will help us understand diseases that we have not yet cracked?

Dr Pääbo: Two things we have learned from Neanderthals are very interesting. One is that sometimes they have contributed variance to present-day people that can be both protective against diseases and cause diseases. For type 2 diabetes, for example, a risk was recently found in Asians and Native Americans that comes from the Neanderthals. It is also very interesting to look across the genome where we would statistically expect to find Neanderthal fragments, but we don't.

In the future it would be interesting to study the reasons for that. Many people speculate that a disease such as autism may affect something very specific to modern humans: our hypersociality, how we put ourselves in other people's shows, manipulate other people's minds and opinions, start lying, go into politics, and so forth. It might be that this is an additional inroad to some of these traits.

Dr Topol: That is an extraordinary path going forward regarding what we can learn. You have had remarkable persistence and tenacity to take the field forward after facing those initial issues of contamination. Now you have a vision that this can lead to further important knowledge. What are your next steps?

Dr Pääbo: We will take two directions. One is to study all Neanderthal genomes and go back in time to Neanderthal and modern human ancestors. We will begin to get the first DNA sequences from 400,000 years ago, almost 10 times older than the Neanderthals we studied. It is probably some Neanderthal ancestor in Spain. The other direction is to study the function of these parts of the genome and the changes unique to modern humans that we do not share with Neanderthals as our closest relatives, and to focus on that from a genetic point of view and define us as a group and as a species relative to all other organisms.

Dr Topol: We have already learned a lot from you and all of your colleagues at the Max Planck Institute, and I know we will continue to do so. You clearly have set a path that defines one of the most interesting people in medicine and science, so we are grateful to you for joining us on this One-on-One segment on Medscape.

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