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Neanderthals Reintroduced Alleles from Common Ancestor to Modern Humans

NEW YORK – A subset of the alleles that made their way into Eurasian populations through mixing with Neanderthals represent genetic variation that was shared in the common human-Neanderthal ancestor, but lost in humans after the lineages split, according to new research from researchers at Vanderbilt University and elsewhere.

For a paper appearing in Nature Ecology and Evolution on Monday, the researchers analyzed real and simulated genome sequences from archaic hominins and modern humans, focusing on the Eurasian populations. Their search highlighted variants that were lost in some human populations, but passed back from Neanderthals in humans that met and mixed with the archaic hominins outside of Africa.

The team's subsequent analyses suggested that those reintroduced variants appeared more prone to have a functional impact than variants derived in the Neanderthal lineage after the split from a shared common ancestor with humans. In particular, reintroduced Neanderthal alleles tended to turn up at active expression quantitative trait loci (eQTL), while Neanderthal-derived sequences appeared more prone to be pruned from the human genome over time.

"Our results demonstrate that Neanderthal populations served as reservoirs of hundreds of thousands of ancestral alleles that were lost to the ancestors of Eurasians (and, in some cases, all modern humans), and that many of these alleles have functional effects in Eurasians after being reintroduced by Neanderthal admixture," senior author John Anthony Capra, a biological sciences, genetics, biomedical informatics, and computer science researcher at Vanderbilt, and his colleagues wrote.

While bottlenecks such as the out-of-Africa migration have whittled down genetic diversity in modern humans, the team explained, archaic hominins that they encountered in Eurasia carried a collection of derived alleles as well as alleles stretching back to the common ancestor of them and modern humans.

Several studies have explored the consequences of these introgressed Neanderthal alleles, which have been implicated in a range of traits and conditions in modern humans. But less is known about the deeper origins of these Neanderthal alleles, and their potential ties to our own ancestors.

In an effort to find and characterize these ancestral hominin alleles in modern human genomes, the researchers relied on genome sequence data generated for individuals from East Asian, European, and South Asian populations for Phase 3 of the 1000 Genomes project, teasing out ancestral alleles reintroduced through mixing with Neanderthals as well as Neanderthal-derived alleles.

"[W]e sought ancestral variants in 1000 Genomes Phase 3 Eurasian populations that are present only on introgressed haplotypes," the authors explained, noting that the reintroduced variants had ancestral features despite containing Neanderthal variants.

The team's search led to more than 209,100 alleles that appeared to have been reintroduced through Neanderthal admixture — variants peppered over more than 80 percent of the Neanderthal-related haplotypes they analyzed. These reintroduced alleles appeared to be more common in populations from South Asia and East Asia than in European populations, perhaps reflecting the increased interactions with Neanderthals previously proposed in Asia after modern human migration out of Africa.

Consistent with predictions, the investigators saw signs that the Neanderthal-derived alleles tend to be more deleterious, while ancestral alleles brought back into the human genome often appeared to be functionally active. The latter variants were overrepresented at eQTLs, for example, and compared to the Neanderthal-derived alleles, they were more likely to coincide with loci linked to human traits or conditions through genome-wide association studies. 

Based on such findings, the authors suggest that the new study "demonstrates the importance of accounting for shared ancestral variation among hominin populations, and illustrates a way that hybridization events have the potential to modulate the effects of bottlenecks on allelic diversity."

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