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High-Coverage Neanderthal Genome Provides Look at Historical Mixing Events, Human-Specific Sequences

NEW YORK (GenomeWeb News) – In a study published online today in Nature, an international team described the human-specific sequences and ancient hominin inbreeding and interbreeding patterns that were identified with the help of a new high-quality Neanderthal genome sequence.

Researchers from Germany, the US, and elsewhere sequenced the genome of a female Neanderthal using DNA from a 50,000-year-old toe bone unearthed in a Siberian cave in the Altai Mountains — the same site where a finger bone from an archaic Denisovan hominin was found in 2008.

By comparing the sequence — the most complete Neanderthal genome sequences so far — to another new, low-coverage Neanderthal genome and to archaic and modern human sequences, they were able to tally up a relatively limited number of sites in the archaic genomes that differ from those in modern humans.

"This list of simple DNA sequence changes that distinguish all humans today from our nearest extinct relatives is comparatively short," co-corresponding author Svante Pääbo, director at the Max Planck Institute for Evolutionary Anthropology, said in a statement.

"It is a catalog of the genetic features that sets all modern humans apart from all other organisms, living or extinct," Pääbo said. "I believe that in it hide some of the things that made the enormous expansion of human populations and human culture and technology in the last 100,000 years possible."

In addition, the new sequence data made it possible for researchers to see signs of interbreeding and inbreeding between Neanderthals, Denisovans, and modern humans. It also hinted at gene flow from another archaic hominin group into the Denisovan group, consistent with findings from an ancient hominin sequencing study that Pääbo and his colleagues published in Nature earlier this month.

A draft version of the Neanderthal nuclear genome was published in 2010, providing the first evidence of interbreeding between that group of archaic hominins and the ancestors of modern human populations that moved out of Africa. Since then, mitochondrial and nuclear genome sequences have continued to highlight the extent of the archaic hominin diversity and mixing that once existed in various parts of the world.

For example, sequences from the Denisovan genome — originally sequenced in 2010 and improved in 2012 — point to mixing between that archaic group and the modern human ancestors of individuals in present-day Oceania. Meanwhile, a recent mitochondrial sequencing study on DNA from a 400,000-year-old hominin from Spain's Sima de los Huesos cave points to the existence of yet another archaic hominin group belonging to a mitochondrial lineage related to that of the Denisovans.

For the current study, researchers used Illumina's HiSeq 2500 to sequence five Neanderthal libraries prepared using DNA from the toe bone of a female Neanderthal whose remains were found in an older sediment layer of the cave housing the previously sequenced Denisovan finger bone.

The sequence data generated covered the Neanderthal genome to an average depth of 52-fold. To that, the team added 0.5-fold coverage of another Neanderthal genome, produced from a 60,000- to 70,000-year-old infant Neanderthal sample from the Caucuses, along with sequence data for 14 new human genomes.

The investigators also included 11 more existing modern human genomes in their subsequent analyses, as well as sequences from the Denisovan genome and the Neanderthal genome sequenced in 2010.

Within the genome of the newly sequenced Neanderthal woman, dubbed the "Altai Neanderthal," researchers picked up on telltale signs of inbreeding — namely, runs of homozygosity suggesting her parents could have been half siblings, for instance, or double first cousins. The homozygosity patterns detected also fit those expected from mixing between an aunt and nephew, an uncle and niece, or between a grandparent and grandchild.

The sequences offered clues about other historical inter-hominin mixing too, including signs of gene flow between Neanderthals and Denisovans. For instance, investigators estimated that Neanderthals contributed some 0.5 percent or more of the DNA sequences in the average Denisovan genome. Another 2.7 to 5.8 percent of Denisovan DNA appears to come from another archaic hominin ancestor.

Consistent with past studies, the team found that modern humans were involved in that ancient mixing, too: the new study suggests that in populations outside of Africa, individuals carry Neanderthal DNA that makes up between 1.5 percent and 2.1 percent of their genome, on average.

Those Neanderthal sequences in present-day human genomes appear to be more closely related to the Neanderthal from the Caucuses than to the Altai Neanderthal individual or the first Neanderthal sequenced, which came from Croatia, study authors noted.

As shown in the past, Denisovan sequences tend to turn up mainly in the genomes of individuals from Oceanic populations such as Aboriginal Australians, Papua New Guineans, and Pacific Islanders. But the new analysis also suggests that around 0.2 percent of sequences in the genomes of Native Americans and individuals from mainland Asia resembles Denisovan DNA sequences.

"The paper really shows that the history of humans and hominins during this period was very complicated," co-corresponding author Montgomery Slatkin, an integrative biology researcher at the University of California at Berkeley, said in a statement. "There was a lot of interbreeding that we know about and probably other interbreeding we haven't yet discovered."

Finally, when researchers searched for sites that were distinct in human genomes compared to the Neanderthal and Denisovan genomes, they found three human-specific duplications and thousands of substitutions or small insertions and deletions that turned up in humans but were missing in the archaic hominins or other great apes.

Relatively few human-specific sequences seemed to be fixed in the genome, though. The team tracked down around 3,000 variants suspected of regulating gene expression and 96 fixed amino acid changes affecting 87 human proteins, along with several dozen parts of the human genome that appear to have been prone to positive selection since the split from Neanderthals and Denisovans.

Such sites may ultimately provide information on human-specific traits, the study's authors explained, though they cautioned that further functional studies will be needed to explore that possibility.