Genetic dietary adaptation in Neandertal, Denisovan and Sapiens revealed by gene copy number variation

Abstract Dietary adaptation involves evolving an efficient system to digest food available in an ecosystem. The diet of archaic humans is traditionally reconstructed by isotopic analyses of human remains combined with the faunal assemblages found on the sites, and, recently, from metagenomic analyses of dental calculus. Here, we propose a new computational approach to find the genetic basis for human dietary adaptation. We searched 15 genomes from Neandertal, Denisovan and Early Sapiens for food digestion genes that tend to have more or fewer copies than the modern human reference genome. We identify 50 genes, including 10 gene clusters, with discernible copy number variation (CNV) trends at the population level, from an analysis of the full set of 20,000 human genes. The genomic variation of 19 of these genes shows how metabolic pathways for carbohydrates, lipids, liver lipids and brown fat in archaic humans adapted to metabolize food from animal or plant sources. The remaining 31 genes are all highly expressed in tissues of the digestive apparatus and are involved in immune response, environmental response and obesity. Analysis of the CNV profiles, compared to 64 modern human individuals belonging to distinct ethnic groups in Eurasia, Africa, Oceania, suggests that Homo sapiens may have had an evolutionary advantage compared to Neandertal and Denisovan in adapting to cold and temperate ecosystems. Significance Statement Understanding dietary strategies and foraging behaviors of past populations are among the goals of paleoanthropological and prehistoric studies. Based on a new computational approach, we seek for the genetic basis for human dietary adaptation. Gene copy number variation (CNV) is a major type of structural genome variation that we used as indicator of efficient metabolic processes for food digestion. By analysing billions of short sequences from 15 archaic human genomes and 64 modern human ones, across the full set of 20,000 human genes, we identify 50 genes whose population-wide discernable CNV trends point to lipid metabolism as being crucial for Neandertal, the efficiency in carbohydrate metabolism for Sapiens’ diet, and the importance of lipid metabolism and brown fat metabolism for both Neandertal and early Sapiens compared to modern humans. Preprint availability: an early version, where the CNV analysis of ancient genomes was conducted on the human reference genome hg19, was deposited on BioRxiv on November 2, 2021 (DOI: 10.1101/2021.10.30.466563 ). The current version, which utilises CNV estimates based on the human reference genome hg38 and includes comparisons with modern human populations, was deposited in BioRxiv in November 2024.