[Modern humans and more ancient hominins interbred many times
throughout Eurasia and Africa, and the genetic flow went both ways.]



 Jordana Cepelewicz 
 August 29, 2019
Quanta Magazine

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 _ Modern humans and more ancient hominins interbred many times
throughout Eurasia and Africa, and the genetic flow went both ways. _ 

 We carry genes from our ancestors’ encounters with ancient people
like the Neanderthals, but the Neanderthals already carried some
modern human genes from even earlier encounters with vanished groups.,
Olena Shmahalo/Quanta Magazine 


Humans today are mosaics, our genomes rich tapestries of interwoven
ancestries. With every fossil discovered, with every DNA analysis
performed, the story gets more complex: We, the sole survivors of the
genus _Homo_, harbor genetic fragments from other closely related but
long-extinct lineages. Modern humans are the products of a sprawling
history of shifts and dispersals, separations and reunions — a
history characterized by far more diversity, movement and mixture than
seemed imaginable a mere decade ago.

But it’s one thing to say that Neanderthals interbred with the
ancestors of modern Europeans, or that the recently discovered
Denisovans interbred with some older mystery group, or that they all
interbred with each other. It’s another to provide concrete details
about when and where those couplings occurred. “We’ve got this
picture where these events are happening all over the place,”
said Aylwyn Scally
[https://www.gen.cam.ac.uk/directory/aylwyn-scally], an evolutionary
geneticist at the University of Cambridge. “But it’s very hard for
us to pin down any particular single event and say, yeah, we’re
really confident that that one happened — unless we have ancient

You think you’re just looking at a Neanderthal, but you’re
actually looking at a mixture of Neanderthal and modern human. 

Adam Siepel, Cold Spring Harbor Laboratory

The events that do get pinned down therefore tend to be relatively
recent, starting with the migration of modern humans out of Africa
60,000 years ago, during which they interacted with hominin relatives
(like the Neanderthals and Denisovans) they met along the way.
Evidence of interbreeding during any migrations before then, or during
events that transpired earlier within Africa, has been elusive.

Now that’s starting to change. In part because of greater
computational power, “we’re starting to see the next wave of
methods development,” said Joshua Akey
[https://lsi.princeton.edu/joshua-akey], a professor of genomics at
the Lewis-Sigler Institute for Integrative Genomics at Princeton
University. “And that’s allowing us to start making new inferences
from the data … that the previous generation of methods couldn’t

As scientists peer further back in time and uncover evolutionary
relationships in unprecedented detail, their findings are complicating
the narrative of human history and rescuing some formerly missing
chapters from obscurity. Clues are emerging about the unexpected
influence of gene flow from ancient hominins on modern human
populations before the latter left Africa. Some researchers are even
identifying the genetic contributions modern humans might have made to
those other lineages, in a complete reversal of the usual scientific
focus. Confusing and intertwined as these many effects can be, all of
them shaped humanity as we now know it.

Old Humans, New Tricks

When researchers first recovered DNA from Neanderthal bones, the
available techniques for making sense of it were powerful but
relatively simple. Scientists compared ancient and modern sequences,
tallied up shared sites and mutations, and conducted bulk statistical
analyses. That’s how they discovered in 2010 that Neanderthal DNA
makes up approximately 2% of the genome of people today of non-African
descent, a result of interbreeding that occurred throughout Eurasia
beginning 50,000-60,000 years ago. That’s also how they discovered
that Denisovan DNA makes up approximately 3% of the genome of people
in Papua New Guinea and Australia.

“But that kind of very simple approach isn’t very good at sorting
out the complexity” of how those lost populations interacted,
said John Hawks [http://johnhawks.net/weblog/hawks.html], a
paleoanthropologist at the University of Wisconsin, Madison. Nor does
it allow researchers to test specific hypotheses about how that
interbreeding unfolded.

Population geneticists could backtrack through the DNA data to
identify common ancestors from hundreds of thousands of years ago, and
they could detect recent incidents of gene flow from the past few tens
of thousands of years. But discerning interbreeding that occurred
between those periods, from events “old enough not to be recent but
young enough not to be ancient,” Hawks said, “that actually takes
an extra trick.” That’s because the more recent events smear their
footprints over the older ones; the DNA sequences left behind from
those older events are so fragmented and mutated that they are
difficult to recognize, and even more difficult to label with a date
and location.

The quantitative biologist Adam Siepel and his team at Cold Spring
Harbor Laboratory campus searched through contemporary and fossil DNA
for signs of gene flow from modern humans into Neanderthals. Constance

Adam Siepel [http://siepellab.labsites.cshl.edu/], a quantitative
biologist at Cold Spring Harbor Laboratory in New York, and his
colleagues decided to focus on such gaps in the narrative. They were
particularly interested in looking for signs of gene flow from modern
humans into Neanderthals. That flow of genetic information is harder
to study than the reverse, not only because of how long ago it
happened, but also because there are fewer genomes to refer to: Think
of all the present-day genomes at researchers’ disposal, versus the
handful of Neanderthal genomes left intact, or the single genome
recovered from Denisovan remains. The challenge again prompted the
need for new methods.

Using one such new technique, first in 2016
[https://doi.org/10.1038/nature16544] and then again in a preprint
posted earlier this summer [http://dx.doi.org/10.1101/687368], Siepel
and his team found that around 3% of Neanderthal DNA — and possibly
as much as 6% — came from modern humans who mated with the
Neanderthals more than 200,000 years ago. The same group who gave rise
to modern humans throughout the world also furnished Neanderthals with
(at least a little) more DNA than the Neanderthals would later give
them. “You think you’re just looking at a Neanderthal,” Siepel
said, “but you’re actually looking at a mixture of Neanderthal and
modern human.”

“That’s cool,” Hawks said. Such a high level of genetic
admixture, he added, “is like saying 6% of the cars on the road that
you see are red, but somehow you never noticed any red cars. You ought
to notice that.” And yet the methods in general use had not. To
Hawks, the omission suggests that there may be a lot more shared
genetic material still to find even if it can’t yet be quantified
accurately. More advanced techniques may change that.

More Than a One-Off

The finding also adds to the already compelling body of evidence that
there were multiple migrations of modern humans out of Africa,
stretching back over hundreds of thousands of years. Modern humans
were thought to have evolved in Africa after the departure of
Neanderthals and Denisovans, and to have remained on the continent
until their well-known out-of-Africa diaspora 60,000 years ago. But
recently, fossil evidence has indicated otherwise: A human jawbone in
Israel, reported last year to date back to 180,000 years ago, and a
skull fragment in Greece that’s even older, indicate earlier human

In fact, with that piece of skull, archaeologists may have stumbled
across a possible member of the long-ago exodus that Siepel and his
team inferred in their genomic study. The fossil, which was classified
as Neanderthal when it was unearthed in Greece in the 1970s,
was analyzed last month
[https://doi.org/10.1038/s41586-019-1376-z] by the
paleoanthropologist Katerina Harvati
[https://uni-tuebingen.de/en/faculties/faculty-of-science/departments/geosciences/work-groups-contacts/urgeschichte-naturwissenschaftliche-archaeologie/research-department/paleoanthropology/personnel/harvati-papatheodorou-katerina/] of
the University of Tübingen and her colleagues. Structurally, it
looked somewhat like a modern human skull, but it was estimated to be
about 210,000 years old — supposedly too old to be modern at that
location. (Because the structural similarities to modern skulls show
up in reconstructive models of the Greek fossil, the conclusion is
controversial and will probably continue to be until DNA can be
recovered for a genetic study to confirm it.)

The Apdima 1 skull fossil found in Greece has many modern structural
features but is 210,000 years old — too ancient to be from any of
the modern humans who left Africa only 60,000 years ago. It may have
come from a hypothesized earlier exodus that left no survivors.
Photograph by Nicholas Thompson, ©️ Katerina Harvati, University of

Now the DNA evidence seems to back up this revised migration narrative
as well. In retrospect, “it seems quite natural,” Scally said,
“to say that human populations and evolution were just as messy
200,000 years ago, and just as subdivided and structured … as they
are today.”

“It makes it hard to argue that there was ever some … special
evolutionary event or genetic event that triggered the evolution of
humans as we know them,” he added. Humans have been continuously
evolving through the mixing of varied populations for hundreds of
thousands of years. (In fact, Scally posits that our species did not
originally evolve from a single population
[https://doi.org/10.1016/j.tree.2018.05.005] in Africa, but rather
from many interconnected populations spread out across the continent.)

“This is telling us, ‘Oh, this is not a weird one-off,’” Hawks
said. “It’s a continuing interaction.”

Clues are emerging about the unexpected influence of gene flow from
ancient hominins on modern human populations before the latter left

What is curious is that the only migration that seems to have left
modern human descendants in Europe and Asia was the one from 60,000
years ago. The groups that migrated earlier apparently all died out or
got absorbed into Neanderthal or other ancient populations. “If
there were earlier events,” Scally said, “they left essentially no
ancestry or negligible ancestry in us today.”

This could mean, he said, that “this Neanderthal legacy could be the
only descendants that those people had.” Furthermore, when the
Neanderthals then interbred with modern humans during later
migrations, perhaps some of that DNA got mixed back into the modern
human genome, embedding older signals of _Homo sapiens_ history into
the genetic material of individuals alive today.

According to Siepel’s analysis, that sort of nested mixing seems to
have been exactly what happened with the Denisovans. When the team
looked at the Denisovan genome, they found fragments of DNA in it from
an even earlier hominin, vestiges of some population whose own genome
has not been found or sequenced. It might have been _Homo erectus_,
which split off from the ancestors of modern humans and spread across
Eurasia about 1 million years ago. The contribution from this
unidentified group “was at the limits of our detection power,”
according to Siepel, because it constituted only about 1% of the
Denisovan genome. During later interbreeding events, tiny pieces of
that 1% got passed on to modern humans in Southeast Asia, Papua New
Guinea and some parts of East Asia. “A small set of extremely
divergent DNA sequences present in modern humans, if our analysis is
correct, would have been passed through two interbreeding events,”
Siepel said.

A Return to Africa

“Basically,” Akey summed it up, “the lesson is that when
populations meet, they mix.” Serena Tucci
[https://serenatucci.wordpress.com/], a postdoctoral researcher in
Akey’s lab, said the work shows “the need that we have for more
sophisticated computational approaches, for a computational framework
to make inferences about our past.”

In Siepel’s case, that meant testing a vast number of hypotheses by
inferring the branching inheritance patterns of various genes. Other
scientists are starting to rely on different probabilistic approaches
[http://dx.doi.org/10.1101/657247]. “As computational power
continues to become more sophisticated, these types of methods will
become increasingly accessible and feasible to do,” Akey said.
“And really, you can’t do better than these models. They use all
the features of the data.”

It suggests that maybe Neanderthals actually are us. As different as
they are, maybe they’re just another version of us. 

John Hawks, University of Wisconsin, Madison

Siepel now hopes to apply his approach to other elusive aspects of
history. He’s particularly interested in prehistoric population
dynamics on the African continent. How ancient genetic admixture
events affected modern African genomes has been little studied —
although a pair of researchers recently reported in _PLOS Genetics_
[https://doi.org/10.1371/journal.pgen.1008204] that humans in Africa
interbred with another ancient hominin group both before and after the
ancestors of European and Asian populations split off and migrated
away. By the scientists’ estimates, DNA from that unknown group now
makes up somewhere between 4% and 8% of modern human ancestry.

That said, Siepel’s technique could perhaps provide deeper insights
into those statistics and what they mean: For example, researchers
studying how that ancient DNA made its way out of Africa into other
populations might follow its trail to map out, if only sketchily,
migrations as yet unknown.

“I think Africa is one of the areas that’s going to give a lot
more data in the future,” said Chris Stringer
an anthropologist at the Natural History Museum in London and a member
of the research team that studied the Greek fossil.

Siepel is also using his algorithm to look for signs of natural
selection acting on these DNA sequences: Were ancient hominins any
better or worse off for carrying more genes from modern ones? So far,
his team has found no evidence for either positive or negative
selection in the flow of genes from modern humans into Neanderthals
200,000 years ago, which indicates that “most of this gene flow …
is just a signature of populations in contact,” according to Hawks.

“It suggests that maybe Neanderthals actually are us,” he said.
“As different as they are, maybe they’re just another version of

That’s something that can be studied in other species as well:
Siepel has already started to look into the forces at work in the
speciation of certain birds. “What we should be doing is taking
these more complicated models that we have now, this messy picture …
and applying that to other species,” Scally said.

Of course, inferring these population histories is a complicated
process. “There is a limit to what genetics can infer, too,” Akey
said. Sometimes, alternative historical scenarios have basically the
same effects on the genomic record, and in those situations, even
better methods of genetic analysis will be hard-pressed to squeeze
answers out of the data. Still, he added, we’re a long way off from
reaching that limit.

Scally agreed. “There is an enormous amount of information in human
diversity today,” he said. “There’s plenty of stuff still for us
to discover.”

Jordana Cepelewicz is a staff writer at _Quanta Magazine _who covers
biology. Her writing about mathematics, neuroscience and other
subjects has also appeared in _Nautilus _and _Scientific American_.
Before entering the world of science reporting, Jordana did editorial
work at _Harper’s Magazine_, _Politico _and _Tea Leaf Nation_.
She graduated from Yale University in 2015 with bachelor’s degrees
in mathematics and comparative literature.

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