Stone Age Gene Swap

Sex with Neanderthals gave modern humans an immune boost.

November/December 2011

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Stone Age Gene Swap

THE HLA TEAM: Parham with research associates Lisbeth Guethlein and Paul Norman. Photo: Rod Searcey

When the Neanderthals and other prehistoric human cousins went extinct around 30,000 years ago, they didn't disappear completely. A little part of them lives on in many of us.

In 2010, scientists revealed that sporadic couplings between our ancestors and the Neanderthals (as well as a related group, the Denisovans) left many of us with traces of their DNA in our genomes. But the evolutionary impact was unclear. Now a team of scientists —led by Peter Parham, professor of structural biology and of microbiology and immunology—has shown that these genetic exchanges significantly strengthened modern human immune systems.

"This is really the first evidence that there was something functional that was contributed from this admixture that was useful for modern humans," says Laurent Abi-Rached, a research associate in Parham's lab and first author on the report in Science. 

Parham has long suspected that some immune genes might have an ancient origin. He studies the Class I human leukocyte antigen genes (HLA-A, HLA-B and HLA-C), which are known for their role in transplant rejection and for their incredible diversity. Each HLA gene comes in hundreds or thousands of versions, called alleles; two unrelated people rarely have the exact same set. This diversity provides a safety net against extinction, because HLA proteins vary in their ability to fight different pathogens. For example, some people who carry an HLA-B*57 allele can keep an HIV infection in check without drugs. "That tells us that if we didn't have modern medicine, somebody would survive. It would be a major cull, but somebody would survive," Parham says. HLA diversity is so important that it may even influence mate selection: Studies show that people are attracted to the scents of prospective sexual partners with disparate HLA types.

In 1993, while sequencing HLA genes, Parham came across a mysterious variant: HLA-B*73. "It stood out like a sore thumb," he says. Unlike other HLA alleles, HLA-B*73 resembled genes found in chimpanzees and gorillas, suggesting that it was at least 16 million years old (predating the split between humans and chimpanzees). But it had surprisingly little diversity in people, suggesting that it had been evolving only a short time. It was as if an ancient gene had recently been dropped into the human gene pool. The most likely explanation: Modern humans picked up the gene from a single mating between Homo sapiens and a related subspecies. There was no way to prove this theory, however, and it conflicted with the dominant thinking of the time—which was that our ancestors had replaced, but never mated with, archaic humans.

Then, last year, technological advances allowed scientists to sequence the genomes of three Neanderthal females who lived in Croatia more than 40,000 years ago. They found that Europeans and Asians, but not Africans, can trace 1 to 4 percent of their heritage to Neanderthals. Thus, modern humans likely bred with Neanderthals as they migrated out of Africa 50,000 to 80,000 years ago. "It wasn't a massive intermingling. It was probably more on the edges and at certain times," Parham says. But it's not surprising that it occurred, he adds. "All the data you can glean from the modern human population is that whenever related populations come together, if there is physical compatibility, they interbreed."

On the heels of this discovery, scientists unveiled the genome of a Denisovan. The Denisovans are related to, but distinct from, the Neanderthals; they were only discovered in 2008, when archeologists unearthed a girl's pinky finger and tooth in the Denisova cave in Siberia. The genetic evidence again pointed to prehistoric mixing with modern humans—certain populations in Papua New Guinea can trace 4 to 6 percent of their lineage to Denisovans.

Parham's group immediately seized the opportunity to mine the genome data for HLA sequences. They reanalyzed sequence data for HLA-A, HLA-B and HLA-C. Stunningly, the Denisovan genome yielded an answer to the long-standing mystery of HLA-B*73. Though it did not contain HLA-B*73, it contained two HLA-C alleles that HLA-B*73 is almost invariably paired with in modern humans. "They just inferred that it must have been present from the linkage with C. It's a bit of inference, but it looks like it's going to be true," comments immunology expert John Trowsdale, professor of pathology at the University of Cambridge. "So, that's particularly interesting from an immunology point of view."

Even more astounding, most of the Neanderthal and Denisovan alleles were identical to alleles found in humans today. "When I first started looking, it was quite clear that we were finding alleles that are found in modern humans. And that's when we realized that it was more than just B*73," Abi-Rached says. The alleles are common in Europe and Asia, but rare in Africa, suggesting that they were introduced into the human population during the migration out of Africa and not simply inherited from a common ancestor.

The frequency in modern populations was particularly surprising, Abi-Rached says. For example, 50 to 60 percent of the HLA-A alleles found in some populations in China and Papua New Guinea are HLA-A*11, one of the Neanderthal alleles. Altogether, Parham's team predicted that 50 percent of the HLA-A alleles found in Europeans, up to 80 percent in Asians, and up to 95 percent in Papua New Guineans have an archaic origin.

"This demonstrates that genes that were most likely inherited from archaic humans have been advantageous and have spread throughout the human population," Trowsdale concludes. "Direct proof of cause is extremely difficult, because you're just looking at four [archaic] individuals. But I think these are interesting, attractive hypotheses at the moment, and they fit with the information we have."

A map of Europe and the Eastern Hemisphere. It is colored blue starting in Africa and grades slowly to red in Siberia and Oceania.The predicted worldwide distribution of archaic HLA-A alleles illustrates the extent to which modern human immune systems have been shaped by interbreeding with archaic humans. (Image: Courtesy Science/AAAS) 

The alleles may have conferred several survival advantages. When modern humans migrated out of Africa, they faced a severe genetic bottleneck, as small groups seeded new populations in Europe and Asia. Interbreeding helped restore HLA diversity, Abi-Rached says. Neanderthals and Denisovans left Africa 200,000 years before modern humans did, so their immune genes also would have been better adapted to local pathogens. "Obviously modern humans could have adapted with time," Abi-Rached says. "But if they acquire the alleles preformed, it's a shortcut."

Many of the archaic HLA proteins also have unique properties that may have conferred evolutionary benefits, Abi-Rached says. For example, many bind strongly to natural killer cells. Natural killer cells are important to innate immunity—the body's first defense against infection. They also have essential nonimmune functions in the body; for example, they play a role in reproduction.

Neanderthal (or Denisovan) proteins continue to live on and function inside us, and this also may have a downside, Parham notes. Neanderthals evolved separately from us for a few hundred thousand years, so their proteins may be somewhat mismatched to our immune systems and could play a role in autoimmune disease. Autoimmunity is poorly understood but known to be related to HLA types. "This is all just speculation. But we have been apart for all this time, so it would be very surprising if there weren't differences," Parham says. "It would solve a long-standing puzzle."

Kristin Sainani, MS '99, PhD '02, is a freelance writer and clinical assistant professor in the department of health research and policy.

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