Yanina Timasheva1,2,3, Kaido Lepik3,4,5, Orsolya Liska6,7,8, Balázs Papp6,7,9 and Zoltán Kutalik3,4,5 1Institute of Biochemistry and Genetics, Ufa Federal Research Center of Russian Academy of Sciences, 450054 Ufa, Russia; 2Department of Medical Genetics, Bashkir State Medical University, 450008 Ufa, Russia; 3Department of Computational Biology, University of Lausanne, CH-1015 Lausanne, Switzerland; 4Center for Primary Care and Public Health, University of Lausanne, CH-1010 Lausanne, Switzerland; 5Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland; 6HCEMM-BRC Metabolic Systems Biology Lab, H-6726 Szeged, Hungary; 7Synthetic and Systems Biology Unit, National Laboratory of Biotechnology, Institute of Biochemistry, Biological Research Centre, HUN-REN, H-6726 Szeged, Hungary; 8Doctoral School of Biology, University of Szeged, H-6726 Szeged, Hungary; 9National Laboratory for Health Security, Institute of Biochemistry, Biological Research Centre, HUN-REN, H-6726 Szeged, Hungary Corresponding author: zoltan.kutalikunil.ch Abstract

Natural selection acts ubiquitously on complex human traits, predominantly constraining the occurrence of extreme phenotypes (stabilizing selection). These constraints propagate to DNA sequence variants associated with traits under selection. The genetic signatures of such evolutionary events can thus be detected via combining effect size estimates from genetic association studies and the corresponding allele frequencies. Although this approach has been successfully applied to high-level traits, the prevalence and mode of selection acting on molecular traits remain poorly understood. Here, we estimate the action of natural selection on genetic variants associated with metabolite levels, an important layer of molecular traits. By leveraging summary statistics of published genome-wide association studies with large sample sizes, we find strong evidence of stabilizing selection for 15 out of 97 plasma metabolites, with nonessential amino acids displaying especially strong selection signatures. Mendelian randomization analysis reveals that metabolites under stronger stabilizing selection display larger effects on a range of clinically relevant complex traits, suggesting that maintaining a disease-free profile may be an important source of selective constraints on the metabolome. Metabolites under strong stabilizing selection in humans are also more conserved in their concentrations among diverse mammalian species, suggesting shared selective forces across micro- and macroevolutionary timescales. Overall, this study demonstrates that variation in metabolite levels among humans is frequently shaped by natural selection and this may act through their causal impact on disease susceptibility.

Footnotes

[Supplemental material is available for this article.]

Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.278756.123.

Freely available online through the Genome Research Open Access option.

Received November 20, 2023. Accepted August 8, 2024.