A major insight that emerged from comparing the Neandertal and Denisovan genomes to the genomes of modern humans was that the ancestors of all modern non-Africans met and interbred with archaic humans approximately 55,000 years ago. As a result, approximately 2% of the DNA in the genomes of all non-Africans comes from Neandertals, and in addition about 5% of the genomes of present-day Oceanian people can be traced back to the Denisovans.

A number of recent studies have addressed whether this archaic DNA contributes to phenotypic variation in modern humans. While it seems that archaic DNA was, on average, negative for modern human carriers, and much has been removed by natural selection, the DNA that persists in the genomes of present-day people has been shown to contribute to a number of modern human phenotypes. Neandertal and/or Denisovan alleles modify modern human immunity, metabolism, and skin pigmentation, as well as contributing to altitude and climatic adaptation.

Introgressed archaic DNA can influence modern human phenotypes by changing the amino acid sequences of modern human proteins, or by modifying regulatory sequences that control gene expression. We sought in our study to determine the extent to which each of these two mechanisms is affected by archaic variants.

Archaic variants contribute substantially to gene expression variation in modern humans – with archaic variants explaining regulatory differences in several hundred genes

We show that while there are a number of archaic variants that modify protein sequences, the predicted effect of such protein sequence changes is generally small. In contrast, archaic variants contribute substantially to gene expression variation in modern humans – with archaic variants explaining regulatory differences in several hundred genes – more than non-archaic variants at comparable frequencies.

We also show that archaic-variants influence gene expression in multiple tissues and that these expression differences underlie variation in modern human phenotypes including autoimmune disorders, innate immunity and metabolism. A separate recent study found evidence for specific downregulation of transcripts carrying Neandertal alleles in brain and testis, suggesting negative implications for Neandertal sequences in these tissues.

Taken together the ongoing efforts to understand the fate and to determine the functional impacts of archaic DNA in modern humans is providing insights into the origins of modern human disease and phenotypic variation, including the identification of potentially modern human specific traits.