Natural selection acting on complex traits hampers the predictive accuracy of polygenic scores in ancient samples

Abstract

The prediction of phenotypes from ancient humans has gained interest due to its potential to investigate the evolution of complex traits. These predictions are commonly performed using polygenic scores computed with DNA information from ancient humans along with genome-wide association studies (GWAS) data from present-day humans. However, numerous evolutionary processes could impact the prediction of phenotypes from ancient humans based on polygenic scores. In this work we investigate how natural selection impacts phenotypic predictions on ancient individuals using polygenic scores. We use simulations of an additive trait to analyze how natural selection impacts phenotypic predictions with polygenic scores. We simulate a trait evolving under neutrality, stabilizing selection and directional selection. We find that stabilizing and directional selection have contrasting effects on ancient phenotypic predictions. Stabilizing selection accelerates the loss of large-effect alleles contributing to trait variation. Conversely, directional selection accelerates the loss of small and large-effect alleles that drive individuals farther away from the optimal phenotypic value. These effects result in specific shared genetic variation patterns between ancient and modern populations which hamper the accuracy of polygenic scores to predict phenotypes. Furthermore, we conducted simulations that include realistic strengths of stabilizing selection and heritability estimates to show how natural selection could impact the predictive accuracy of ancient polygenic scores for two widely studied traits: height and body mass index. We emphasize the importance of considering how natural selection can decrease the reliability of ancient polygenic scores to perform phenotypic predictions on an ancient population.