A Neandertal found in 1937 in this cave in Germany had inherited modern human mtDNA.

WOLFGANG ADLER, © PHOTO MUSEUM ULM

Neandertals and modern humans started mating early

For almost a century, Neandertals were considered the ancestors of modern humans. But in a new plot twist in the unfolding mystery of how Neandertals were related to modern humans, it now seems that members of our lineage were among the ancestors of Neandertals. Researchers sequenced ancient DNA from the mitochondria—tiny energy factories inside cells—from a Neandertal who lived about 100,000 years ago in southwest Germany. They found that this DNA, which is inherited only from the mother, resembled that of early modern humans.

After comparing the mitochondrial DNA (mtDNA) with that of other archaic and modern humans, the researchers reached a startling conclusion: A female member of the lineage that gave rise to Homo sapiens in Africa mated with a Neandertal male more than 220,000 years ago—much earlier than other known encounters between the two groups. Her children spread her genetic legacy through the Neandertal lineage, and in time her African mtDNA completely replaced the ancestral Neandertal mtDNA.

Other researchers are enthusiastic about the hypothesis, described in Nature Communications this week, but caution that it will take more than one genome to prove. “It’s a nice story that solves a cool mystery—how did Neandertals end up with mtDNA more like that of modern humans,” says population geneticist Ilan Gronau of the Interdisciplinary Center Herzliya in Israel. But “they have not nailed it yet.”

The study adds to a catalog of ancient genomes, including mtDNA as well as the much larger nuclear genomes, from more than a dozen Neandertals. Most of these lived at the end of the species’ time on Earth, about 40,000 to 50,000 years ago. Researchers also have analyzed the complete nuclear and mtDNA genomes of another archaic group from Siberia, called the Denisovans. The nuclear DNA suggested that Neandertals and Denisovans were each other’s closest kin and that their lineage split from ours more than 600,000 years ago.

But the Neandertal mtDNA from these samples posed a mystery: It was not like Denisovans’ and was closely related to that of modern humans—a pattern at odds with the ancient, 600,000 year divergence date. Last year Svante Pääbo’s team at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, offered a startling solution: Perhaps the “Neandertal” mtDNA actually came from modern humans.

In the new study, paleogeneticists Johannes Krause and Cosimo Posth of the Max Planck Institute for the Science of Human History in Jena, Germany, test this wild idea with ancient mtDNA from a Neandertal thighbone found in 1937 in the Hohlenstein-Stadel cave (HST) in Germany. Isotopes in animal bones found with the Neandertal suggest that it lived in a woodland known to have vanished at least 100,000 years ago.

Researchers compared the coding region of the HST Neandertal’s mtDNA with that of 17 other Neandertals, three Denisovans, and 54 modern humans. The HST Neandertal’s mtDNA was significantly different even from that of proto-Neandertals that date to 430,000 years ago at Sima de los Huesos in Spain, suggesting that their mtDNA had been completely replaced. But the HST sample was also surprisingly distinct from that of other Neandertals, allowing researchers to build a phylogenetic tree and study how Neandertal mtDNA evolved over time.

Using modern humans’ mtDNA mutation rate to calculate the timing, the researchers conclude that the HST mtDNA split from that of all other Neandertals at least 220,000 years ago. The ancient H. sapiens’ mtDNA must have entered the Neandertal lineage before this time, but after 470,000 years ago, the earliest date for when modern human and Neandertal mtDNA diverged. That’s early enough for the new form of mtDNA to have spread among Neandertals and replaced all their mtDNA.

“The mtDNA of Neandertals is not actually from Neandertals, but from an early modern human from Africa,” Krause says. The researchers speculate that this key mating may have happened in the Middle East, where early H. sapiens may have ventured. Other researchers find the scenario remarkable but plausible. “It seems magical but this type of thing happens all the time … especially if the populations are very small,” Gronau says. For example, the mtDNA in some grizzly bears has been completely replaced by that of polar bears, Krause says.

But some experts say DNA from other Neandertals is needed to prove that their mtDNA was inherited entirely from an early H. sapiens rather than from an ancient ancestor the two groups shared. “Is there other evidence of another [early] mtDNA introgression event?” asks Chris Stringer of the Natural History Museum in London.

Not yet, Posth says. Pääbo is seeking evidence of early gene swapping by trying to get nuclear DNA from the HST Neandertal and others. “We will learn a lot about the population history of Neandertals over the next few years,” he says.