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

Fat deposition in human liver is modulated by environmental and genetic factors including the PNPLA3 p.I148M variant. When and how this variant evolved in humans has not been studied to date. Here we re-analyse ancient DNA to track the history of this allele throughout human history.

Published 6444 ancient and 3943 present-day genomes were used for analysis after extracting genotype calls for PNPLA3 p.I148M. To quantify changes through time and space, logistic and linear regression analyses were performed. To compare these changes with expected changes due to neutral factors such as genetic drift, we compiled a reference dataset of 1000 randomly selected SNPs for genome wide analysis.

The ancestral (reference) allele is fixed among all great apes. In contrast, on the human lineage, all available Neanderthal (n=21) and Denisovan individuals (n=2) either exclusively carried the risk allele or had missing data (n=7) suggesting fixation of the allele in the ancestor of all archaic humans. 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, including a high frequency in the Americas even in the earliest samples from 10,000BP. Logistic regression analyses did not yield signals of natural selection.

Our observation might underscore the advantage of fat storage in cold climate, particularly for Neanderthal under ice age conditions. The negative genome-wide analysis without signals of natural selection during modern human history does not support the thrifty gene hypothesis.

Publication History

Article published online:
23 January 2024