by Pbo, Svante
On the first of March we received comments from three reviewers, and almost three weeks later we received comments from a fourth reviewer. It isn’t unusual for reviewers to find many things to complain about in a manuscript. In this case, however, they didn’t have much to say: the two years we spent trying to find flaws in each other’s work had allowed us to find most of the weak points ourselves. Nevertheless, there was quite a lot of back and forth about the text with the editor. In the end, the paper appeared on May 7, 2010, complete with its 174 pages of supplementary material.{59} The paper was “more like a book than a scientific paper,” as one paleontologist put it.
On the day the paper appeared, the two major institutions in the world that provide the scientific community with access to genome sequences, the European Bioinformatics Institute in Cambridge, England, and the Genome Browser maintained by the University of California at Santa Cruz in the United States, made the Neanderthal genome freely available to all. In addition, we made available in a public database all of the DNA fragments we had sequenced from the Neanderthal bones, including those that we had judged to be of bacterial origin. I wanted everyone to be able to check every detail of what we had done. And I wanted them to do a better job if they could.
With the appearance of the paper came the anticipated media frenzy. However, my previous dealings with journalists had left me somewhat jaded so I left Ed, David, Johannes, and the others in the consortium to deal with the press. In fact, the day our paper was published, I was scheduled to give a big lecture at Vanderbilt University in Nashville, Tennessee. That trip, which had been planned for a long time, was a convenient way for me to avoid the hype. But the excitement did rub off on my very friendly hosts in Nashville. When they learned that someone who sounded rather odd had called asking for me at my hotel, they worried about my safety, thinking of Christian fundamentalists who might be opposed to an evolutionary origin of humans. They had the police trace the phone call. It had come from the university campus; for some reason, this made them even more nervous so they had two police officers in civilian clothes follow me around everywhere I went on campus. This was the first time I have had bodyguards when giving a talk. I appreciated the concern for my safety, and the attention made me feel important. But those two huge men, in their dark suits and earpieces, eyeing everyone who approached me with suspicion, made the after-lecture mingling with faculty and students slightly awkward.
As it happened, the Neanderthal paper appeared the week before the 2010 Cold Spring Harbor Genome Meeting, so I went straight from Nashville to Long Island. I very much enjoyed presenting our main findings in the same auditorium where, four years earlier, I had announced our intention to do the project. I ended my talk by saying that I hoped the Neanderthal genome would prove a useful resource for scientists in the future. As it happened, the future came only five minutes after I had stepped down from the stage.
The speaker who followed me was Corey McLean, a graduate student from Stanford University. As I sat down, I vaguely thought to myself that I didn’t envy him; following a talk that attracted a lot of attention was never easy. Very quickly I came to regret this condescending attitude. Corey gave a brilliant presentation. He had analyzed the genomes of humans and apes and identified a total of 583 large chunks of DNA lost in humans but present in the apes. He had then looked at what genes were in those regions and identified several interesting genes that had been lost in humans. One of these encoded a protein expressed in penile spines, which are structures on the penises of apes that cause males to ejaculate very quickly. These spines are not present in humans, which enables us to enjoy prolonged intercourse. The gene Corey had found to be lost might well be the reason for that. Another chunk that humans had lost encoded a protein that might limit the extent to which neurons divide and might have something to do with how the brain got larger in humans. This was fascinating! But what was most satisfying to me was that, in just the few days the Neanderthal genome had been publicly available, Corey had already checked the Neanderthal genome to see which of the deletions present-day humans share with Neanderthals. This was precisely how I had hoped our work would be applied, as a tool that would allow others to extend their own research by timing when changes had happened during human evolution. Corey had found that the Neanderthals did indeed have the penile spine deletion, so we immediately learned something about the intimate anatomy of Neanderthals that the fossil record couldn’t tell us. The deletion involved in brain size was also shared with Neanderthals, a finding that we would have anticipated given our knowledge from fossils that their brains were as large as ours. But some of the other chunks that he hadn’t yet investigated were not deleted in Neanderthals. Future work would show whether they truly were absent in all humans today and, if so, whether they had some likely consequences for how present-day humans differed from Neanderthals.
I couldn’t find Corey after the session because of the many people wanting to talk to him as well as to me, but the next day I found him and told him how much I appreciated his work. I was so emotional about what he had done that I had to stop myself from hugging him. As far as I knew, he was the first person who had put our genome to use in his research.
This Neanderthal genome paper received far more reaction from the scientific community than any other paper I had published. Almost everyone was positive. The most positive comment came from John Hawks at the University of Wisconsin–Madison. A paleontologist trained by Milford Wolpoff, John is one of the architects of the multiregional hypothesis. He is quite influential in anthropology through his blog, where he thoughtfully and insightfully discusses new papers and ideas in anthropology. “These scientists have given an immense gift to humanity,” he wrote on his blog. “The Neanderthal genome gives us a picture of ourselves, from the outside looking in. We can see, and now learn about, the essential genetic changes that make us human—the things that made our emergence as a global species possible. . . . This is what anthropology ought to be.” Our group was pleased, of course. Only Ed tried to keep a cool distance: he e-mailed the entire consortium, saying, “Can somebody get John Hawks some oxygen?”
Only one solidly negative reaction came to my attention, from the well-known paleontologist Erik Trinkaus. Knowing that he tended to be negative about whether the study of genetics could make a real contribution to anthropology, I had sent him our paper a few days before publication to allow him some time to study it before journalists called to ask his opinion about it. I had hoped that reading our paper might convince him that we had done a good job, and we had even exchanged two e-mails in which I tried to resolve what I felt were his misunderstandings about what we had said in the paper. Given my efforts to reach out to Erik, I was disappointed when I got an e-mail from a journalist in Paris asking me for my reactions to excerpts from what must have been quite extensive comments that Erik Trinkaus had sent her about our paper. She quoted him as saying: “Briefly, we have had abundant fossil anatomical evidence of gene flow between Neanderthals and early modern humans, most likely as a result of Neanderthal populations being absorbed into those of expanding modern human ones around 40,000 years ago. In other words, the new DNA data and analysis [add] almost nothing new to the discussion. . . . Most of the authors of the new article are simply ignorant of that literature and do not understand the fossil data, living human diversity, or the behavioral/archeological context of the human evolutionary changes. . . . To sum up, the paper is the result of a very expensive, technologically complicated analysis that advances the study of modern human origins and of the Neanderthals very little and in some ways regresses it.”
I was amazed that Erik could actually think we knew less after sequencing the Neanderthal genome than we had before. I ended up saying, “I am sad that Dr. Trinkaus thinks this adds so little to our knowledge of Neanderthals.” Despite his reaction, I was confident that others would see that genetics and paleontology could complement each other.
There were many others who were interested in
the Neanderthal genome—perhaps most surprisingly, some fundamentalist Christians in the United States. A few months after our paper appeared, I met Nicholas J. Matzke, a doctoral candidate at the Center for Theoretical Evolutionary Genomics at UC Berkeley. Unbeknownst to me and the other authors, our paper had apparently caused quite a flurry of discussion in the creationist community. Nick explained to me that creationists come in two varieties. First, there are “young-earth creationists,” who believe that the earth, the heavens, and all life were created by direct acts of God sometime between 5,700 and 10,000 years ago. They tend to consider Neanderthals as “fully human,” sometimes saying they were another, now extinct “race” that was scattered after the fall of the Tower of Babel. As a consequence, young-earth creationists had no problem with our finding that Neanderthals and modern humans had mixed. Then there are the “old-earth creationists,” who accept that the earth is old but reject evolution by natural, nondivine means. One major old-earth ministry is “Reasons to Believe,” headed by a Hugh Ross. He believes that modern humans were specially created around 50,000 years ago and that Neanderthals weren’t humans, but animals. Ross and other old-earth creationists didn’t like the finding that Neanderthals and modern humans had mixed. Nick sent me a transcript from a radio show in which he commented on our work, saying interbreeding was predictable “because the story of Genesis is early humanity getting into exceptionally wicked behavior practices,” and that God may have had to “forcibly scatter humanity over the face of the Earth” to stop this kind of interbreeding, which he compared to “animal bestiality.”
Clearly our paper was reaching a broader audience than we had ever imagined. But most people weren’t shocked by the idea that their ancestors had interbred with Neanderthals. In fact, many seemed to find the idea intriguing—some, as had happened before, even volunteering to be examined for Neanderthal heritage. By early September, I started to notice a pattern: it was mostly men who wrote to me. I went back through my e-mails and found that forty-seven people had written to say they thought they were Neanderthals—and of these, forty-six were men! When I told my students, they suggested that perhaps men were more interested in genomic research than women. But that didn’t seem to be the case, as twelve women had written to me not because they thought they were Neanderthals but because they thought their spouses were! Interestingly, not a single man had written to make such a claim about his wife (since then, however, one man has actually done so). I joked that some interesting genetic inheritance patterns were at work here that we needed to investigate. But what we were obviously seeing were the effects of the cultural ideas about what Neanderthals were like. In popular lore, Neanderthals are big, robust, muscular, somewhat crude, and perhaps a little simple. Some of these characteristics might be seen as acceptable or even positive in men, but they were clearly not conventionally seen as attractive in women. This idea was brought home to me when Playboy magazine called to ask for an interview about our work. I accepted, thinking that this would probably be my one and only chance to appear in Playboy. The magazine ended up writing a four-page story called “Neanderthal Love: Would You Sleep with This Woman?” The accompanying illustration was of a sturdy, very dirty woman wielding a spear on a snowy mountain ridge. That distinctly unattractive image probably explains why hardly any men volunteer the opinion that they are married to Neanderthals.
Another question that attracted a great deal of interest was what it might mean that people outside of Africa carried some Neanderthal DNA. Again, it was obvious that Neanderthals seemed to have a bad reputation. Jeune Afrique, a weekly news magazine that covers political and cultural issues in French-speaking Africa, set the tone by ending its story about our results with the following: “But one thing is . . . certain: given the ape-like appearance of Neanderthals, those who still believe that sub-Saharan Africans are less advanced than white-skinned people do not understand anything.” {60}In general, I found that people’s reactions to our work said more about their worldview than about anything that we could possibly know about what happened 30,000 or 40,000 years ago. For example, there were many who asked what the benefits could be of the Neanderthal pieces of DNA that had come over to people outside Africa. Although this might be a relevant question, it still made me wary because it seemed to imply that there must be something positive about these segments of DNA because they existed in Europeans or Asians, who have often tended to regard themselves as superior to other populations. To me, the null hypothesis—that is, the baseline idea one starts out from when investigating a scientific issue—is always that a genetic change has no functional consequences whatsoever. One then tries to reject that hypothesis—for example, in this case, by studying patterns in how humans vary. Thus far, we had seen no hint of changes leading to a difference in function so my answer to those questions was that we had no reason to reject our null hypothesis. Maybe all we were seeing were the traces of the very natural act of intergroup relations in the distant past. Admittedly, we hadn’t looked very hard yet. In fact, within a year of the publication of the Neanderthal genome, others found something.
Peter Parham is one of the world’s foremost experts on the major histocompatibility complex (MHC), perhaps the most complicated genetic system in the human genome and the system on which I did my PhD work in Uppsala many years ago. The MHC encodes transplantation antigens, proteins that exist in almost all cells in our bodies. Their function is to bind fragments of proteins from viruses and other microbes that infect the cell and transport them to the cell surface, where they are recognized by immune cells. Such cells will then kill the infected cell, thus limiting the infection before it can spread throughout the body. The MHC was discovered not because of its normal function of fighting infections but because of the ferocious rejection reaction launched by the immune system against transplanted tissues such as skin, kidneys, or hearts. This rejection of transplanted tissues, which gave transplantation antigens their name, is possible because transplantation antigen proteins are extremely variable, encoded by MHC genes that exist in tens or even hundreds of different variants. So when a person receives a transplanted organ from an unrelated individual, the donor will always carry different transplantation antigen variants, and the recipient’s immune system will therefore recognize the graft as foreign and attack it. Lifelong immunosuppressive treatment is needed to counter this reaction, even if the transplant comes from a relative of the recipient and is hence not too genetically dissimilar. In contrast, transplantations can be made between genetically identical twins with almost no immunological complications since they carry identical MHC genes and hence transplantation antigens. Why transplantation antigens are so variable is not yet fully understood, but it’s probably because the presence of many different variants in individuals allows the immune system to better distinguish between infected and healthy cells.
Peter Parham looked at the fragments of Neanderthal DNA that mapped to the MHC genes encoding transplantation antigens, and Ed Green, who had by this point moved on to a faculty position at UC Santa Cruz, helped him to identify even more fragments that we had initially missed because of the unusual variability of these genes. A year after our paper appeared, they reported at a meeting that one particular MHC gene variant that is common in present-day Europeans and Asians but not yet seen in Africans was present in our Neanderthal genome. In fact, they claimed that about half of all copies of this gene carried by Europeans and 72 percent of those carried by people in China came from Neanderthals. Given that no more than 6 percent, at most, of the overall genomes of these people came from Neanderthals, this amazing increase in frequency of the MHC variants suggests that at least some helped the newly arrived replacement crowd survive. Peter suggested that because Neanderthals had already lived outside Africa for more than 200,000 years when first encountered by modern humans, their repertoire of MHC gene variants might have become adapted to fighting diseases local to Eurasia and perhaps absent in Africa. Thus, once a modern human received these genes
from Neanderthals, this advantage drove the genes to high frequencies. In August 2011, Peter and his colleagues published a paper in Science describing these findings.{61} On December 3, 2010, seven months after our paper appeared, I received an e-mail from Laura Zahn, the editor at Science who had handled our paper, with the news that it had been awarded the AAAS Newcomb Cleveland Prize. I had gotten a few scientific prizes in my career and they were always pleasant boosts for my self-confidence. But this was special to me. The Newcomb Cleveland Prize was established in 1923 and is awarded annually to the authors of the best research article or report published in Science. It had originally been called the $1,000 Prize, although by then it had been increased to $25,000. What pleased me most was that it was awarded to all the authors of the paper so it recognized what our consortium had collectively achieved. As Linda told me that night, “To publish a paper in Science is a big deal. But publishing the best paper in Science in a year? Most couldn’t even dream of that.”
I talked to David and Ed, the other two main authors of the paper, and we agreed to accept the prize together at the AAAS meeting in Washington, DC, in February 2011. We decided to use the money to organize a meeting in Croatia, where the members of the consortium could meet in the fall of 2011 to discuss which direction the analysis of the Neanderthal genome should go in the future. I anticipated this experience to be a repeat of the intense Dubrovnik meeting in 2009. In fact, by the time I received the e-mail from Laura Zahn, we knew that we had more than just the Neanderthal genome to discuss at such a meeting. We had the genome of another extinct human, from another part of the world.
