PNPLA3 fatty liver allele was fixed in Neanderthals and segregates neutrally in humans

• Published in: Gut p. gutjnl-2023-331594
• Main Authors: Geier, Andreas, Trost, Jonas, Wang, Ke, Schmid, Clemens, Krawczyk, Marcin, Schiffels, Stephan
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group LTD 01.06.2024
• Subjects: Alleles; Datasets; Environmental factors; Fatty liver; Gene frequency; Genes; Genome-wide association studies; Genomes; Genotype & phenotype; Genotypes; Hominids; Ice ages; Liver cancer; Liver diseases; Metabolism; Natural selection; Population genetics; Regression analysis; Steatosis; Czech Republic; Romania; Belgium; Asia; Europe; China; Russia; nutrition; fatty liver; genetics; lipid metabolism
• ISSN: 0017-5749; 1468-3288
• DOI: 10.1136/gutjnl-2023-331594

Fat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified p.I148M (rs738409) as a common variant that increases risk of developing liver steatosis. When and how this variant evolved in humans has not been studied to date. Here we analyse ancient DNA to track the history of this allele throughout human history. In total, 6444 published ancient (modern humans, Neanderthal, Denisovan) and 3943 published present day genomes were used for analysis after extracting genotype calls for p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed. We find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed risk allele, whereas allele frequencies in modern human populations range from very low in Africa to >50% in Mesoamerica. Over the last 15 000 years, distributions of ancestral and derived alleles roughly match the present day distribution. Logistic regression analyses did not yield signals of natural selection during the last 10 000 years. Archaic human individuals exclusively carried a fixed allele associated with fatty liver, whereas allele frequencies in modern human populations are variable even in the oldest samples. Our observation might underscore the advantage of fat storage in cold climate and particularly for Neanderthal under ice age conditions. The absent signals of natural selection during modern human history does not support the thrifty gene hypothesis in case of p.I148M.