As recently as 2008, scientists thought that Neanderthals and modern humans had never mated.

Then, last year, they said that the two species had, but that the few Neanderthal genes that survived in modern human DNA were not functional.

Now researchers believe that key versions of immune system genes in modern humans appear to have been passed down by archaic relatives, including Neanderthals, after all.

Indeed, DNA inherited from Neanderthals and newly discovered hominids dubbed the Denisovans has contributed to key types of immune genes still present among populations in Europe, Asia and Oceania. And scientists speculate that these gene variants must have been highly beneficial to modern humans, helping them thrive as they migrated throughout the world.


This DNA has had “a very profound functional impact in the immune systems of modern humans,” said study first author Laurent Abi-Rached, a postdoctoral researcher in the lab of senior author Peter Parham of the Stanford University School of Medicine.

Neanderthals were stocky hunter-gatherers who populated Europe and parts of Asia until about 30,000 years ago. In 2010, a team of biologists led by Svante Paabo of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, sequenced the Neanderthal genome via DNA extracted from ancient bones.

From this, they estimated that 1% to 4% of modern Eurasian genomes came from our close hominid relatives.

No one knows what Denisovans looked like: The only confirmed evidence of the group, which is thought to have split from the Neanderthals about 350,000 years ago and migrated east, are a tooth and a pinkie finger bone found in a Siberian cave in 2008.


When Paabo and coworkers sequenced DNA extracted from the pinkie in 2010, they calculated that 4% to 6% of modern Melanesian genomes came from Denisovans.

In the new study, Abi-Rached and coauthors decided to focus on a small set of genes on chromosome 6 known as the human leukocyte antigen (HLA) class I genes.

HLA genes carry instruction for making HLA proteins, which help the immune system spot evidence of problems in cells — infection or cancer, for instance — so that it can wipe out abnormalities to fight disease. The genes come in many forms that vary in frequency around the world, probably because our genomes have been tailored by evolution to fight specific disease threats that exist in particular places.

Physicians regularly screen HLA types to find donor matches for transplant patients, providing a rich lode of data for the researchers. Millions of people around the world have had their HLA class I genes typed, giving the team a way to look for ancient Neanderthal and Denisovan HLA variants in present-day people, said coauthor Ed Green, a genome scientist at UC Santa Cruz.


The researchers carefully analyzed the region of the archaic genomes where the HLA genes were located. Then they compared them with the HLA regions of modern-day human populations of different parts of the world.

From the analysis, the scientists estimated, for example, that more than half of the genetic variants in one HLA gene in Europeans could be traced to Neanderthal or Denisovan DNA. For Asians, that proportion was more than 70%; in people from Papua New Guinea, it was as much as 95%.

“We expected we’d see some, but the extent that these contributed to the modern [genomes] is stunning,” Abi-Rached said of the findings, released Thursday by the journal Science.

Though the researchers haven’t proved it, the vast reach of these gene variants in people today suggests that they probably gave some early modern humans an advantage over others, he said.


Our ancestors’ HLA systems may have been perfectly tailored for Africa but naive to bacteria, viruses and parasites that existed in Europe or Asia, rendering them susceptible to disease.

Mating and mixing their genomes with those of their Neanderthal and Denisovan relatives could have been a speedy way to set up their immune systems to combat new, unencountered threats.

“If there are parasites or whatever in Europe, the way [for humans migrating out of Africa] to adapt to them is to mate with Neanderthals and get their genes,” said University of Utah anthropologist Henry Harpending, who was not involved in the research.

Paabo of the Max Planck Institute said that he had some “minor quibbles” with the authors’ conclusions but that he was happy to see another group using the ancient genomes his lab had produced to further our knowledge of the evolution of Homo sapiens and its closest relatives.


“This is, of course, exactly why we sequenced the genomes,” he said.

Harvard Medical School geneticist David Reich, who worked on the reconstruction of the Denisovan genome, said that the new paper was “exciting, if it turns out to be right,” but that he was not yet convinced that the genes really came from Denisovans.

Of most interest to one outside scientist is what these kinds of studies mean for the future of research on the origins of our species. Seemingly overnight, the endeavor has become a lot more than looking over fossilized bones.

“It’s like suddenly you’ve discovered the New World,” said John Hawks, an anthropologist at the University of Wisconsin, “and you’re wandering around and seeing what’s there.”


eryn.brown@latimes.com