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

Autor:	Geier A; Department of Medicine II, Division of Hepatology, University Hospital Wurzburg, Würzburg, Germany geier_a2@ukw.de stephan_schiffels@eva.mpg.de., Trost J; Department of Medicine II, Division of Hepatology, University Hospital Wurzburg, Würzburg, Germany., Wang K; Department Archaeogenetics, Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany.; School of Life Sciences, Fudan University, Shanghai, China., Schmid C; Department Archaeogenetics, Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany.; International Max Planck Research School for the Science of Human History, Max Planck Institute for Geoanthropology, Jena, Germany., Krawczyk M; Department of Medicine II, Saarland University Hospital and Saarland University Faculty of Medicine, Homburg, Germany.; Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland., Schiffels S; Department Archaeogenetics, Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany geier_a2@ukw.de stephan_schiffels@eva.mpg.de.
Jazyk:	angličtina
Zdroj:	Gut [Gut] 2024 May 10; Vol. 73 (6), pp. 1008-1014. Date of Electronic Publication: 2024 May 10.
DOI:	10.1136/gutjnl-2023-331594
Abstrakt:	Objective: Fat deposition is modulated by environmental factors and genetic predisposition. Genome-wide association studies identified PNPLA3 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. Design: 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 PNPLA3 p.I148M. To quantify changes through time, logistic and, by grouping individuals according to geography and age, linear regression analyses were performed. Results: We find that archaic human individuals (Neanderthal, Denisovan) exclusively carried a fixed PNPLA3 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. Conclusion: Archaic human individuals exclusively carried a fixed PNPLA3 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 PNPLA3 p.I148M. Competing Interests: Competing interests: None declared. (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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