Newswise — Compared with other world groups, the DNA of Melanesian populations carries some of the largest percentage of ancestry from now-extinct Neanderthals and Denisovans. A genomic study of Melanesians suggests that certain genetic variants inherited from archaic humanlike species may have helped these modern people adapt to their tropical island environment.

The Melanesians live in the Bismarck Archipelago and Bougainville Island east of New Guinea. Their ancestors in this geographical area were isolated from other populations for about 50,000 years; contact with western people occurred only in the past 3,000 years. After the people who became the Melanesians migrated to their present location, they needed to adapt to local environments, including resistance to pathogens and parasites, to survive.

Interbreeding between Neanderthals, Denisovans, and anatomically modern humans took place in Eurasia when these species came into contact. Today, contemporary people who have ancestors from Europe, Asia, and Australia commonly have DNA from these two archaic species, making up 1-4% of their genome. Prehistoric African humans did not seem to live in places where these two archaic human species existed.

An international research team led by PingHsun Hsieh and Evan Eichler, genome scientists at the University of Washington School of Medicine, were interested to discover structural changes in the DNA of modern-day Melanesians that might have been inherited from Neanderthal and Denisovan ancestors. This team specifically focused on a structural change called copy-number variants, which occur when a large stretch of DNA sequence in the genome becomes duplicated or deleted.

Their findings were published Oct. 18 in Science.

The researchers searched for archaic copy-number variants that have become enriched in the Melanesians when compared with other contemporary human populations. They aimed to determine whether any such variants have been favored by natural selection. Such patterns are predicted to be rare because larger copy-number variants tend to be quickly eliminated due to stronger selective pressure than do single-base DNA mutations, they explained.

The assumption is that beneficial genetic variants would increase in frequency and become sustained in a population over generations. These variants are more likely to be advantageous in surviving and reproducing in an environment where that population settles or migrates.

Using whole-genome comparative analyses combined with long-read DNA-sequencing data, population-genetics inference, and other methods, they found 19 copy-number variations in Melanesians that likely were introduced through interbreeding with Neanderthals or Denisovans in prehistoric times.

These copy-number variants, they said, were significantly associated with signals of positive selection. Many of these copy-number variants mapped near or inside of genes associated with metabolism, embryonic development, cell signaling, and immune responses. Nevertheless, the researchers say, these association patterns are complex and more work is needed to understand their biological meaning to present-day or historical populations.

Two of the most complex copy-number variants that the Melanesians inherited are missing from most other human populations. One of the largest, mapping to chromosome 16p11.2, is enormous by normal human genetic variation standards. Melanesians carry an additional 383,000 base pairs of DNA that appear to have originated in Denisovans. It was introduced into the genome of the ancestral Melanesian population some 60,000 to 170,000 years ago.

The investigators estimate that this variant is now present in 79% of a diverse group of Melanesians. This large duplication is adjacent to human-specific duplications that are a prime spot for rearrangements that can predispose to diseases, including autism, the researchers noted.

The other large Neanderthal-like haplotype was found on chromosome 8p21.3, encompassing a deletion and a duplication. It was introduced into non-African human populations 40,000 to 120,000 years ago. This copy-number variation also occurs in a relatively high frequency of 44% of Melanesians and also shows signatures of positive natural selection.

Remarkably both copy-number variants were large enough to carry entirely new copies of genes. Using long-read DNA sequencing and transcriptome data, the scientists discovered previously unknown duplicated genes that also show signs consistent with positive selection. The genes belong to gene families important in both cell proliferation and programmed cell death. However, the researchers note, “Our limited understanding of genotype-phenotype relationships makes it difficult to predict the functional consequences of these copy-number variants, although the genetic signatures lead us to believe that these additional genes have been beneficial.”

The scientists hypothesize that large copy-number variants appearing first in Neanderthal or Denisovan ancestors may have helped human populations adapt to their local environments as they spread out across the planet. Neanderthal and Denisova are thought to have colonized parts of the world long before modern-day humans arrived, so it follows that Neanderthals and Denisovans successfully adapted genetically to these environments before we did. Interbreeding with them provided access to a reservoir of beneficial variants, including newly minted genes that were introduced back into us.

“We believe that copy-number variants represent an untapped gold mine of such adaptive mutations,” the authors said, “and that the story has repeated itself multiple times in other human populations whose ancestors made contact with archaic species.”

This study was partially funded by the National Institutes of Health (R01HG002385), a National Health and Medical Council C. J. Martin Fellowship, and the Howard Hughes Medical Institute.



Investigators for this paper also represented these institutions:
Dipartimento di Biologia, Università degli Studi di Bari “Aldo Moro,” Bari, Italy.

Fondation Jean Dausset–Centre d’Etude du Polymorphisme Humain, Paris, France.

Pacific Biosciences of California, Inc., Menlo Park, CA, USA.