Triangulating evidence to detect signatures of stabilizing selection acting on protein levels in humans

Stabilizing selection is thought to maintain quantitative traits near evolutionary optima, yet the extent to which it constrains human molecular phenotypes remains largely unknown. Here, we investigate stabilizing selection on 2’923 plasma proteins by triangulating complementary signatures operating across evolutionary timescales in up to 54’000 UK Biobank participants. We contrasted genetic signatures reflecting selective constraint accumulated over generations with phenotypic evidence that deviations in protein abundance are associated with reduced contemporary fitness-related outcomes. Historical selection was assessed from the frequency-dependent architecture of protein levels using genome-wide common variants with LDpred2 and a newly developed rare loss-of-function burden framework. Contemporary evidence was obtained from quadratic associations between protein abundance and three fitness proxies: reproductive success, somatic health, and parental longevity. Among significant estimates, 100% and 92.4% supported stabilizing selection in the common- and rare-variant-based analysis, respectively, compared to 99.8% for somatic health, 97.7% for parental longevity, and 89.3% for reproductive success. Despite capturing distinct timescales and aspects of selection, the approaches showed convergence. Rare-variant-based estimates showed concordance with health-score-derived coefficients ( ρ = 0.36, p = 5.2 × 10 ^{− 6} ) and with independent measures of evolutionary constraint, including protein heritability ( ρ = 0.20, p = 5.2 × 10 ^{− 5} ), loss-of-function intolerance ( ρ = − 0.19, p = 6.1 × 10 ^{− 5} ), and cross-species transcript evolutionary rate ( ρ = 0.15, p = 2.4 × 10 ^{− 2} ). Our results suggest that stabilizing selection is a pervasive force shaping the human plasma proteome and demonstrate that integrating genetic architecture with fitness-related consequences can connect long-term evolutionary constraint with contemporary phenotypic variation.