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Human Gene Flow Patterns Point to Earlier-Than-Expected Neanderthal Mixing

NEW YORK (GenomeWeb) – A study appearing online today in Nature suggests modern humans and Neanderthals may have mixed and mingled much earlier than previously estimated.

Researchers from Germany, the US, Israel, and elsewhere considered the previously sequenced Altai Neanderthal and Denisovan genomes alongside hundreds of present-day African genomes. They also threw new Neanderthal chromosome 21 sequences into the mix, using 44,000-year-old and 49,000-year-old samples found in Vindija, Croatia and El Sidrón, Spain, respectively, searching for signs of gene flow from ancient modern humans into the archaic hominins.

Indeed, the team saw signs of modern human introgression into the Siberian Neanderthal that was missing from the other European Neanderthals, suggesting that ancestors of Altai Neanderthal may have encountered and mixed with humans around 100,000 years ago — long before the main human migration out of Africa some 60,000 years ago.

"One very interesting thing about our finding is that it shows a signal of breeding in the 'opposite' direction from that already known," co-corresponding author Adam Siepel, chair of the Cold Spring Harbor Laboratory's Simons Center for Quantitative Biology, said in a statement. "[W]e show human DNA in a Neanderthal genome, rather than Neanderthal DNA in human genomes."

The genome of the Altai Neanderthal from Denisova Cave in Siberia was first sequenced and reported in Nature by the Max Planck Institute for Evolutionary Anthropology's Svante Pääbo, a co-author on the current paper, and his colleagues in 2014. That genome appears to share more derived alleles with populations in Africa than does the Denisovan, another archaic hominin that split from Neanderthals more than 381,000 years ago.

Such findings have largely been attributed to potential mixing between the Denisovans and other archaic hominins. But Rosas and colleagues suspected that there may have been another explanation: a previously unappreciated round of human gene flow into the Altai Neanderthal population.

To explore that possibility, the researchers scanned nearly 16,000 sequence windows in the Altai Neanderthal and Denisovan genomes, comparing them with sequences from more than 500 modern day African individuals.

They also did phylogenetic analysis focused on potential human gene flow into the Altai Neanderthal or Denisovan individuals using data for individuals from Africa, Europe, and Asia.

Their results highlighted parts of the Denisovan genome that diverged from both Neanderthals and humans from Africa, consistent with gene flow into Altai Neanderthal ancestors from an early diverged human population.

Such signals weren't detected in the Denisovan genome. And the team's analyses of chromosome 21 sequences from the Vindija and El Sidrón Neanderthals — sequenced on the Illumina GAIIx instrument after multiple rounds of targeted capture — also failed to turn up the same sorts of human sequence variants.

Based on these and other analyses, the study's authors estimated that the Altai Neanderthal ancestors had a bout of mixing with ancient modern humans some 100,000 to 230,000 years ago, well before previously documented gene flow from Neanderthals into non-African humans.

"We knew from Neanderthal DNA found in the genomes of humans outside Africa that Neanderthals and humans have interbred," co-senior author Sergi Castellano, an evolutionary genetics researcher with the Max Planck Institute for Evolutionary Anthropology, said in a statement.

"This interbreeding is estimated to have happened less than 65,000 years ago, around the time that modern human populations spread across Eurasia from Africa. We now find evidence for a modern human contribution to the Neanderthal genome," Castellano explained. "This is likely the result of much earlier interbreeding."