NEW YORK (GenomeWeb) – In a pair of papers appearing online today in the American Journal of Human Genetics, independent research teams provided analytical evidence suggesting Neanderthal admixture with human populations outside of Africa was more complicated than previously realized.
"One explanation that could've been tidy and fit everything? It turns out it doesn't fit all of the parts of the data," University of California at Los Angeles researcher Kirk Lohmueller told GenomeWeb. "So we're left with there needing to be a more complex explanation."
From the low level of Neanderthal ancestry initially found in the genomes of non-African populations tested so far, researchers originally believed modern humans may have participated in one round of mixing with Neanderthals outside of Africa — perhaps in the Middle East.
But recent studies — including papers published in Science and Nature last January —revealed slightly higher levels of Neanderthal ancestry in the genomes of individuals from East Asia compared to those of Europeans.
The source of this disproportional Neanderthal sequence is debatable.
Some speculated that it reflects distinct natural selection efficiencies in East Asian and European populations. If the populations had experienced different purifying selection rates after they diverged, for example, slightly deleterious Neanderthal sequences could have been weeded out of European genomes a bit more stringently.
Others suspect another explanation: that ancestral East Asians obtained extra Neanderthal sequences after diverging from Europeans — either by mixing with Neanderthals again or indirectly through admixture with another population carrying additional Neanderthal sequences.
At first blush, the former 'one pulse followed by selection differences' explanation fits what's known about the demographic history of the East-Asian population, which is believed to have undergone a relatively pronounced population bottleneck, Lohmueller noted.
"If East Asians have had a more severe population bottleneck, what that means is they could have more genetic drift than Europeans," he explained. "If Neanderthals' ancestry is weakly deleterious, the thinking is that it will be selected out less efficiently from East Asians — and maybe that's why East Asians would have more [Neanderthal ancestry]."
Lohmueller and his colleague Bernard Kim, also based at UCLA, got drawn into the debate through their ongoing interest in understanding the interplay between population history and natural selection.
In an effort to determine whether selection differences and demographic history were sufficient to explain present-day Neanderthal sequence representation in East-Asian genomes, the pair performed a series of simulations.
After modeling a single pulse of Neanderthal admixture, the researchers added in various selection and demography events and simulated forward to the present day, looking at how much Neanderthal ancestry is expected to remain in each population after European or East Asian population bottlenecks.
"We did this for a variety of different models of population history because we don't actually know the true demographic history of these populations," Lohmueller explained. "And we also don't know how deleterious Neanderthal ancestry is within humans."
As it turned out, a single pulse of Neanderthal admixture did not lead to the observed levels of Neanderthal ancestry in East Asian populations under any of the simulations tested, hinting at a more complicated mixing scenario.
"The obvious possibility is that you could have more complex admixture scenarios, likely or possibly involving an additional wave of admixture into East Asia," Lohmueller said. "But that's not to say there aren't other, more complex demographic scenarios … that maybe could explain it."
University of Washington genome sciences researcher Joshua Akey and Benjamin Vernot reached a similar conclusion when they analyzed whole-genome sequence data from 379 European individuals and 286 East-Asian individuals for their AJHG study.
That team first stratified the human genome according to estimates of purifying selection strength. It then made demographic inferences that took into account whether a particular region of the genome appeared to be under strong purifying selection, under weak selection, or was not affected by selection.
Based on those patterns, Akey and Vernot, too, concluded that selection differences between populations are not sufficient to explain the distinct Neanderthal ancestry observed in present-day populations.
Again, their analysis suggested a second round of mixing may have gone on between Neanderthals and ancestral East Asians after European ancestors diverged or migrated elsewhere.
"We have strong evidence that a two-pulse model, or two hybridization event model, fits the data better than a one hybridization event model, but that doesn't necessarily mean that's the correct model," Akey told GenomeWeb.
His team tested another scenario for the over-representation of Neanderthal sequences in East Asians: the so-called "dilution" model, which suggests Neanderthal sequences could have been swamped out of the European genome through mixing with a third ancestral group.
That model also produced patterns that were fairly consistent with current population patterns — but only when the researchers assumed mixing between early Europeans and an ancestral group that carried no Neanderthal sequences, leaving Akey leaning more heavily toward the two-pulse Neanderthal mixing hypothesis.
"I'd say the two-pulse model is still the best representation right now," he said, "but the main point is that if you look hard enough you can find other models that fit the data."
He and his colleagues are continuing to study human genomes for hints about past admixtures between modern humans and archaic hominins using thousands of existing genome sequences from geographically diverse human populations.
They have also generated new sequence data for individuals from Melanesia, who have been previously shown to carry both Neanderthal and Denisovan sequences.
In particular, Akey's team hopes to learn more about archaic hominin sequences that have influenced human traits. "Understanding how hybridization helped our species survive is something we're really interested in," he said. "Now that we have pretty complete catalogs of Neanderthal variation, we can ask, 'What is the phenotypic legacy of hybridization with Neanderthals?'"