Neanderthal genetics study reveals missing link in human history

Ten years ago scientists published an analysis that changed our view of humanity.

The first whole-genome sequence of a Neanderthal revealed these ancient hominids were 99.7 percent identical to living humans — and that their DNA lives on as a result of interbreeding.

At the time, the team concluded that up to 2 percent of the DNA of modern people without African ancestry originated in Neanderthals. Today, we know that all living individuals' genes harbor this legacy.

The intervening years have revealed subsequent discoveries and caveats, but one essential element remained missing: the Y chromosomes of Neanderthals and Denisovans, another ancient hominid whose DNA is also carried by modern humans.

This was a problem largely borne out of chance. Many of the high-quality hominid fossils that DNA has been retrieved from have been female — and the Y chromosome is a paternal inheritance. There were bones and teeth of male Neanderthals and Denisovans with some DNA in them, but not enough for a comprehensive analysis of their Y chromosomes.

But on Thursday, researchers announced in the journal Science they were finally able to sequence Y chromosomes from two Denisovans and three Neanderthals. The results revise our understanding of humanity’s shared history and give insight into the children that resulted from these ancient humans interbreeding.

The hunt for Y chromosomes — Martin Petr, the paper’s first author and a postdoctoral candidate at the Max Planck Institute for Evolutionary Anthropology, and Janet Kelso, the paper’s senior author and professor at the Institute, tell Inverse they were “quite surprised” by the discovery.

The team knew from past studies that, when it came to familial relationships, Denisovans and Neanderthals were sister groups, while modern humans are their more distantly related “evolutionary cousins.” They expected the Y chromosomes to mirror that set-up.

But that's not what they found: Using an advanced method described as a targeted capture-based DNA sequencing approach, they were able to extract Y chromosome sequences from the ancient male specimens previously considered too poorly preserved to be of use. They discovered that the modern human and Neanderthal Y chromosomes were more related to each other, compared to the Denisovans' Y chromosomes.

“The fact that Neanderthal Y chromosomes are more similar to modern humans than Denisovans is very exciting as it provides us with a clear insight into their shared history,” Petr and Kelos explain.

Sequencing these chromosomes also gives a clearer timeline of ancient hominids' interactions with one another: The results suggest that, around 700,000 years ago, the Y chromosomes of Denisovans split from a lineage shared by Neanderthals and modern humans.

That result is consistent with the team’s hypothesis going into the study. What was a surprise was finding that the time when Neanderthals and modern human Y chromosomes shared a common ancestor was earlier than expected. They estimate the interbreeding with early modern humans that resulted in the replacement of the Neanderthal Y chromosome took place more than 100,000 years ago, and perhaps as much as 370,000 years ago.

“This led us to conclude that interbreeding between Neanderthals and very early modern humans resulted in replacement of the original Neanderthal Y chromosome with modern human Y chromosomes,” Kelso and Petr say.

This estimation is much older than what Kelos and Petr describe as the “already well-known interbreeding that contributed Neanderthal DNA to modern humans outside Africa, or that which contributed Denisovan DNA to people in Oceania.” Both took place considerably less than 100,000 years ago, they say.

"... it provides us with a clear insight into their shared history."

In 2016, analysis of a Neanderthal woman's toe bone suggested modern humans and Neanderthals met and interbred around 100,000 years ago — an encounter that likely happened in the Middle East. Previously, the first interaction between the two species was thought to have been in Europe, between 50,000 and 65,000 years ago.

An August 2020 study suggests that intermixing between Neanderthals and modern humans could have happened between 200,000 and 300,000 years ago. And a study released in January — the one that found everyone's a little bit Neanderthal — also suggests that for hundreds of thousands of years, Homo sapiens migrated back-and-forth out of Africa and into Africa, bringing with them children who carried genes from other species of hominid.

Together, the research suggests there were different waves of “intermixing events” — the flow of migration and mating between Neanderthals and Homo sapiens more of a branching, steady stream than a dammed river.

Kelso and Petr say it’s plausible that they didn’t see the same Y chromosome replacement in Denisovans “simply because the Denisovans were geographically further away.” The current view is that Denisovans likely inhabited much of Asia, while Neanderthals were primarily located in Europe and Western Asia.

“We speculate that perhaps Denisovans were so far East that they did not encounter these very early modern human groups.”

Cultural consequences — In a companion commentary also published Thursday, Mikkel Heide Schierup, a professor at Aarhus University who studies evolutionary genetics, writes that this study “unequivocally shows that both male and female H. sapiens contributed to gene flow, suggesting that both H. sapiens and Neanderthal populations accepted children of mixed heritage.”

Kelso and Petr acknowledge this is a “fascinating” proposition, but are hesitant to say it is true. Understanding the cultural consequences of introgression is difficult to do with genetics alone, they note, and perhaps experts in archeology and human evolution are better-placed to give that type of insight.

Instead, the most tangible genetics takeaway is that “offspring of this interbreeding between Neanderthals and modern humans must have been viable and fertile," they say.

“This is an important point because there has been historically a lot of debate about whether or not Neanderthals and modern humans were ‘genetically incompatible,’” they explain. “Similarly, there has been some suggestion that archaic human Y chromosomes perhaps carried some mutations which made successful mixture with modern humans less likely.”

The study strongly suggests that’s not the case, because it’s evidence that early modern human-like Y chromosomes successfully spread through the Neanderthal population.

Next, the team wants to sequence hominid Y chromosomes that are even older – especially those belonging to more ancient Neanderthal specimens, and Neanderthals from a wider range of known habitat. The three specimens analyzed in this study were all from Western Eurasia, and we know that their range extended (at least) through southwestern and central Asia.

Ideally, they also want analyze Denisovan and Neanderthal Y chromosomes unaffected by any genetic mixing. Those samples could inform what factors might have driven the replacement observed here and allow the team to “go beyond the theoretical simulations in our current study,” Kelso and Petr say.

That may prove challenging. While human history is consistently being rewritten by new discoveries like this one, one thing appears to be constant: Ancient humans had a habit of not limiting themselves to their own species for sex.

Abstract: Ancient DNA has provided new insights into many aspects of human history. However, we lack comprehensive studies of the Y chromosomes of Denisovans and Neanderthals because the majority of specimens that have been sequenced to sufficient coverage are female. Sequencing Y chromosomes from two Denisovans and three Neanderthals shows that the Y chromosomes of Denisovans split around 700 thousand years ago from a lineage shared by Neanderthals and modern human Y chromosomes, which diverged from each other around 370 thousand years ago. The phylogenetic relationships of archaic and modern human Y chromosomes differ from the population relationships inferred from the autosomal genomes and mirror mitochondrial DNA phylogenies, indicating replacement of both the mitochondrial and Y chromosomal gene pools in late Neanderthals. This replacement is plausible if the low effective population size of Neanderthals resulted in an increased genetic load in Neanderthals relative to modern humans.