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.
