Triangulating evidence to detect signatures of stabilizing selection acting on protein levels in humans
Open accessAbstract
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 signatures of stabilizing selection on the circulating levels of 2'923 plasma proteins in up to 50'000 UK Biobank participants by integrating complementary evidence across evolutionary timescales. We combine genetic signatures of selection accumulated over generations with associations between protein abundance and contemporary fitness-related outcomes. Genetic evidence was assessed using the frequency-dependent architecture of common variants with LDpred2 and a newly developed likelihood-based framework leveraging rare loss-of-function variant burdens. Contemporary evidence was obtained through quadratic associations between protein abundance and three fitness proxies: reproductive success, somatic health, and parental longevity. Across all approaches, negative selection coefficients predominated. Among significant estimates, 100% of common-variant and 92.4% of rare-variant estimates were consistent with stabilizing selection, compared with 99.8% for somatic health, 97.7% for parental longevity, and 89.3% for reproductive success. Despite capturing distinct aspects of selection, the approaches showed partial convergence. Rare-variant-based estimates correlated with health-score-derived coefficients (rho = 0.36, p = 5.2 x 10^-6) and independent measures of evolutionary constraint, including protein heritability, loss-of-function intolerance, and cross-species transcript evolutionary rates. Together, our findings suggest that stabilizing selection is widespread across the human plasma proteome and highlight the value of integrating genetic architecture with fitness-related phenotypes to understand evolutionary constraints on molecular variation.
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Cites
Sudlow, C., Gallacher, J., Allen, N., Beral, V., Burton, P., Danesh, J., Downey, P., Elliott, P., Green, J., Landray, M., et al. (2015) · PLOS Medicine · doi:10.1371/journal.pmed.1001779 · Cited by 12,728 · see citing works
The mutational constraint spectrum quantified from variation in 141,456 humans
Karczewski, K. J., Francioli, L. C., Tiao, G., Cummings, B. B., Alföldi, J., Wang, Q., Collins, R. L., Laricchia, K. M., Ganna, A., Birnbaum, D. P., et al. (2020) · Nature · doi:10.1038/s41586-020-2308-7 · Cited by 9,434 · see citing works
The UK Biobank resource with deep phenotyping and genomic data
Bycroft, C., Freeman, C., Petkova, D., Band, G., Elliott, L. T., Sharp, K., Motyer, A., Vukcevic, D., Delaneau, O., O’Connell, J., et al. (2018) · Nature · doi:10.1038/s41586-018-0579-z · Cited by 8,876 · see citing works
The measurement of selection on correlated characters
Lande, R., & Arnold, S. J. (1983) · Evolution · doi:10.1111/j.1558-5646.1983.tb00236.x · Cited by 5,437 · see citing works
Insights into the regulation of protein abundance from proteomic and transcriptomic analyses
Vogel, C., & Marcotte, E. M. (2012) · Nature Reviews Genetics · doi:10.1038/nrg3185 · Cited by 4,195 · see citing works
Gene Flow and the Geographic Structure of Natural Populations
Slatkin, M. (1987) · Science · doi:10.1126/science.3576198 · Cited by 3,867 · see citing works
Glypican-1 identifies cancer exosomes and detects early pancreatic cancer
Melo, S. A., Luecke, L. B., Kahlert, C., Fernandez, A. F., Gammon, S. T., Kaye, J., LeBleu, V. S., Mittendorf, E. A., Weitz, J., Rahbari, N., et al. (2015) · Nature · doi:10.1038/nature14581 · Cited by 2,880 · see citing works
Correlation between Fitness and Genetic Diversity
Reed, D. H., & Frankham, R. (2003) · Conservation Biology · doi:10.1046/j.1523-1739.2003.01236.x · Cited by 2,489 · see citing works
Natural selection and random genetic drift in phenotypic evolution
Lande, R. (1976) · Evolution · doi:10.1111/j.1558-5646.1976.tb00911.x · Cited by 1,828 · see citing works
The Strength of Phenotypic Selection in Natural Populations
Kingsolver, J. G., Hoekstra, H. E., Hoekstra, J. M., Berrigan, D. A., VIGNIERI, S. N., Hill, C. E., Hoang, A., Gibert, P., & Beerli, P. (2001) · The American Naturalist · doi:10.1086/319193 · Cited by 1,806 · see citing works
Cellular Actions of the Insulin-Like Growth Factor Binding Proteins
Firth, S. M., & Baxter, R. C. (2002) · Endocrine Reviews · doi:10.1210/er.2001-0033 · Cited by 1,754 · see citing works
Molecular Signatures of Natural Selection
Nielsen, R. (2005) · Annual Review of Genetics · doi:10.1146/annurev.genet.39.073003.112420 · Cited by 1,644 · see citing works
Computationally efficient whole-genome regression for quantitative and binary traits
Mbatchou, J., Barnard, L., Backman, J., Marcketta, A., Kosmicki, J. A., Ziyatdinov, A., Benner, C., O’Dushlaine, C., Barber, M., Boutkov, B., et al. (2021) · Nature Genetics · doi:10.1038/s41588-021-00870-7 · Cited by 1,502 · see citing works
The distribution of fitness effects of new mutations
Eyre‐Walker, A., & Keightley, P. D. (2007) · Nature Reviews Genetics · doi:10.1038/nrg2146 · Cited by 1,444 · see citing works
Phylogenetic comparative analysis: a modeling approach for adaptive evolution
Butler, M. A., & King, A. A. (2004) · The American Naturalist · doi:10.1086/426002 · Cited by 1,438 · see citing works
Review Lecture: Mammalian mating systems
Clutton-Brock, T. H. (1989) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1989.0027 · Cited by 1,413 · see citing works
Stabilizing selection and the comparative analysis of adaptation
Hansen, T. F. (1997) · Evolution · doi:10.1111/j.1558-5646.1997.tb01457.x · Cited by 1,361 · see citing works
Unpredictable Evolution in a 30-Year Study of Darwin's Finches
Grant, P. R., & Grant, B. R. (2002) · Science · doi:10.1126/science.1070315 · Cited by 1,360 · see citing works
geiger v2.0: an expanded suite of methods for fitting macroevolutionary models to phylogenetic trees
Pennell, M. W., Eastman, J. M., Slater, G. J., Brown, J. W., Uyeda, J. C., FitzJohn, R. G., Alfaro, M. E., & Harmon, L. J. (2014) · Bioinformatics · doi:10.1093/bioinformatics/btu181 · Cited by 1,128 · see citing works
The role of regulatory variation in complex traits and disease
Albert, F. W., & Kruglyak, L. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3891 · Cited by 1,047 · see citing works
The UK10K project identifies rare variants in health and disease
The UK10K Consortium, Writing group, Walter, K., Min, J. L., Huang, J., Crooks, L., Memari, Y., McCarthy, S., Perry, J. R. B., Xu, C., et al. (2015) · Nature · doi:10.1038/nature14962 · Cited by 1,040 · see citing works
Beall, C. M., Cavalleri, G. L., Deng, L., Elston, R. C., Gao, Y., Knight, J., Li, C., Li, J. C., Liang, Y., McCormack, M., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1002443107 · Cited by 845 · see citing works
The maintenance of genetic variability by mutation in a polygenic character with linked loci
Lande, R. (1975) · Genetics Research · doi:10.1017/s0016672300016037 · Cited by 828 · see citing works
Why highly expressed proteins evolve slowly
Drummond, D. A., Bloom, J. D., Adami, C., Wilke, C. O., & Arnold, F. H. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0504070102 · Cited by 815 · see citing works
Dosage sensitivity and the evolution of gene families in yeast
Papp, B., Pál, C., & Hurst, L. D. (2003) · Nature · doi:10.1038/nature01771 · Cited by 807 · see citing works
Self-citationStructure and function of aggrecan
Kiani, C., Chen, L., Yao Jiong, W. U., Yee, A., & Yang, B. B. (2002) · Cell Research · doi:10.1038/sj.cr.7290106 · Cited by 764 · see citing works
Evolution in Mendelian populations
Wright, S. (1990) · Bulletin of Mathematical Biology · doi:10.1016/s0092-8240(05)80011-4 · Cited by 615 · see citing works
Reevaluation of SNP heritability in complex human traits
Speed, D., Cai, N., Johnson, M. R., Nejentsev, S., & Balding, D. J. (2017) · Nature Genetics · doi:10.1038/ng.3865 · Cited by 436 · see citing works
Kimura, M. (1968) · Genetics Research · doi:10.1017/s0016672300011459 · Cited by 390 · see citing works
Systematic differences in discovery of genetic effects on gene expression and complex traits
Mostafavi, H., Spence, J. P., Naqvi, S., & Pritchard, J. K. (2023) · Nature Genetics · doi:10.1038/s41588-023-01529-1 · Cited by 336 · see citing works
The human gene damage index as a gene-level approach to prioritizing exome variants
Itan, Y., Shang, L., Boisson, B., Patin, É., Bolze, A., Moncada‐Vélez, M., Scott, E., Ciancanelli, M. J., Lafaille, F. G., Markle, J., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1518646112 · Cited by 271 · see citing works
The Genotype-Tissue Expression (GTEx) project
Lonsdale, J., Thomas, J., Salvatore, M., Phillips, R., Lo, E., Shad, S., Hasz, R., Walters, G., Garcia, F., Young, N., et al. (2013) · Nature Genetics · doi:10.1038/ng.2653 · Cited by 263 · see citing works
Glypicans in growth control and cancer
Filmus, J. (2001) · Glycobiology · doi:10.1093/glycob/11.3.19r · Cited by 227 · see citing works
Whole-genome sequencing of 490,640 UK Biobank participants
Manuscript Writing Group, Carss, K., Halldórsson, B. V., Hou, L., Liu, J. Z., Wheeler, E., Lo, Y., Kundu, K., Huang, Z., Lacey, B., et al. (2025) · Nature · doi:10.1038/s41586-025-09272-9 · Cited by 223 · see citing works
Natural selection on gene expression
Gilad, Y., Oshlack, A., & Rifkin, S. A. (2006) · Trends in Genetics · doi:10.1016/j.tig.2006.06.002 · Cited by 218 · see citing works
Author Correction: A genomic mutational constraint map using variation in 76,156 human genomes
Chen, S., Francioli, L. C., Goodrich, J. K., Collins, R. L., Kanai, M., Wang, Q. S., Alföldi, J., Watts, N. A., Vittal, C., Gauthier, L. D., et al. (2024) · Nature · doi:10.1038/s41586-024-07050-7 · Cited by 208 · see citing works
Spatial patterns of variation due to natural selection in humans
Novembre, J., & Di Rienzo, A. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2632 · Cited by 205 · see citing works
Evidence for Widespread Degradation of Gene Control Regions in Hominid Genomes
Keightley, P. D., Lercher, M. J., & Eyre‐Walker, A. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030042 · Cited by 198 · see citing works
Ancient and Recent Positive Selection Transformed Opioid cis-Regulation in Humans
Rockman, M. V., Hahn, M. W., Soranzo, N., Zimprich, F., Goldstein, D. B., & Wray, G. A. (2005) · PLoS Biology · doi:10.1371/journal.pbio.0030387 · Cited by 197 · see citing works
Optimization of gene expression by natural selection
Bedford, T., & Hartl, D. L. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0812009106 · Cited by 191 · see citing works
Evidence of directional and stabilizing selection in contemporary humans
Sanjak, J. S., Sidorenko, J., Robinson, M. R., Thornton, K., & Visscher, P. M. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1707227114 · Cited by 179 · see citing works
The Impact of College Education on Fertility: Evidence for Heterogeneous Effects
Brand, J. E., & Davis, D. (2011) · Demography · doi:10.1007/s13524-011-0034-3 · Cited by 172 · see citing works
Selection against variants in the genome associated with educational attainment
Kong, A., Frigge, M. L., Thorleifsson, G., Stefansson, H., Young, A. I., Zink, F., Jonsdottir, G. A., Okbay, A., Sulem, P., Masson, G., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1612113114 · Cited by 168 · cited 1× · see citing works
“For the number of children (n.children), we added two more covariates: educational attainment (EA) and the interaction EA × sex, because educational attainment is emerging as a strong determinant of an individual’s reproductive outcomes, especially for women (hence the interaction term) 51,52 .”
P-cadherin and the journey to cancer metastasis
Vieira, A. F., & Paredes, J. (2015) · Molecular Cancer · doi:10.1186/s12943-015-0448-4 · Cited by 166 · see citing works
Lemos, B., Meiklejohn, C. D., Cáceres, M., & Hartl, D. L. (2005) · Evolution · doi:10.1111/j.0014-3820.2005.tb00900.x · Cited by 162 · see citing works
Natural selection in a contemporary human population
Byars, S., Ewbank, D. C., Govindaraju, D. R., & Stearns, S. C. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0906199106 · Cited by 158 · see citing works
Schoech, A. P., Jordan, D. M., Loh, P.-R., Gazal, S., O’Connor, L. J., Balick, D. J., Palamara, P. F., Finucane, H. K., Sunyaev, S. R., & Price, A. L. (2019) · Nature Communications · doi:10.1038/s41467-019-08424-6 · Cited by 157 · see citing works
Drost, H., Gabel, A., Große, I., & Quint, M. (2015) · Molecular Biology and Evolution · doi:10.1093/molbev/msv012 · Cited by 145 · see citing works
Zeng, J., Xue, A., Jiang, L., Lloyd-Jones, L. R., Wu, Y., Wang, H., Zheng, Z., Yengo, L., Kemper, K. E., Goddard, M. E., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21446-3 · Cited by 144 · see citing works
The strength and pattern of natural selection on gene expression in rice
Groen, S. C., Ćalić, I., Joly‐Lopez, Z., Platts, A. E., Choi, J. Y., Natividad, M. A., Dorph, K., Mauck, W. M., Bracken, B., Cabral, C. L. U., et al. (2020) · Nature · doi:10.1038/s41586-020-1997-2 · Cited by 138 · see citing works
A quantitative framework for characterizing the evolutionary history of mammalian gene expression
Chen, J., Swofford, R., Johnson, J., Cummings, B. B., Rogel, N., Lindblad-Toh, K., Haerty, W., Palma, F. D., & Regev, A. (2019) · Genome Research · doi:10.1101/gr.237636.118 · Cited by 128 · see citing works
P-cadherin expression in breast cancer: a review
Paredes, J., Correia, A. L., Ribeiro, A. S., Albergaria, A., Milanezi, F., & Schmitt, F. C. (2007) · Breast Cancer Research · doi:10.1186/bcr1774 · Cited by 118 · see citing works
Hou, Y., Wang, Z., Liu, P., Wei, X., Zhang, Z., Fan, S., Zhang, L., Han, F., Song, Y., Chu, L., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.10.001 · Cited by 110 · see citing works
Genetic and molecular architecture of complex traits
Lappalainen, T., Li, Y., Ramachandran, S., & Gusev, A. (2024) · Cell · doi:10.1016/j.cell.2024.01.023 · Cited by 108 · see citing works
Review Lecture Disruptive selection
Thoday, J. M. (1972) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1972.0070 · Cited by 100 · see citing works
Detecting signatures of selection on gene expression
Price, P. D., Droguett, D. H. P., Taylor, J. A., Kim, D. W., Place, E., Rogers, T. F., Mank, J. E., Cooney, C. R., & Wright, A. E. (2022) · Nature Ecology & Evolution · doi:10.1038/s41559-022-01761-8 · Cited by 83 · see citing works
Evidence for Weak Selective Constraint on Human Gene Expression
Glassberg, E. C., Gao, Z., Harpak, A., Lan, X., & Pritchard, J. K. (2018) · Genetics · doi:10.1534/genetics.118.301833 · Cited by 63 · see citing works
Genetic factors associated with reasons for clinical trial stoppage
Razuvayevskaya, O., López, I., Dunham, I., & Ochoa, D. (2024) · Nature Genetics · doi:10.1038/s41588-024-01854-z · Cited by 52 · see citing works
Rodrigue, N., & Lartillot, N. (2016) · Molecular Biology and Evolution · doi:10.1093/molbev/msw220 · Cited by 43 · see citing works
Liu, W., Zhu, P., Li, M., Li, Z., Yu, Y., Liu, G., Du, J., Wang, X., Yang, J., Tian, R., et al. (2023) · The EMBO Journal · doi:10.15252/embj.2022112740 · Cited by 29 · see citing works
Hawkes, G., Chundru, V. K., Jackson, L. M., Patel, K., Murray, A., Wood, A. R., Wright, C. F., Weedon, M. N., Frayling, T. M., & Beaumont, R. N. (2025) · Nature Genetics · doi:10.1038/s41588-025-02095-4 · Cited by 26 · see citing works
(2010) · Nature reviews. Neuroscience · doi:10.1038/nrn2908 · Cited by 24 · see citing works
Rodrigue, N., Latrille, T., & Lartillot, N. (2020) · Molecular Biology and Evolution · doi:10.1093/molbev/msaa265 · Cited by 20 · see citing works
Self-citationLatrille, T., Rodrigue, N., & Lartillot, N. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2214977120 · Cited by 16 · see citing works
Self-citationWidespread natural selection on metabolite levels in humansPreprint
Timasheva, Y., Lepik, K., Liska, O., Papp, B., & Kutalik, Z. (2024) · Genome Research · doi:10.1101/gr.278756.123 · Cited by 1 · see citing works
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- Authors
- Zanoaga, M.-D., Cavinato, T., Latrille, T., Liska, O., Schoeler, T., Papp, B., & Kutalik, Z.
- Affiliations
- SIB Swiss Institute of Bioinformatics (CH)
- University of Lausanne (CH)
- HUN-REN Szegedi Biológiai Kutatóközpont (HU)
- Corresponding author
- Kutalik, Zoltán
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2026-10-17
- OpenAlex
- W7222906596
- Cited by
- 0
- References
- 65
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- stabilizing selection, plasma proteins, protein abundance, evolutionary constraints, loss-of-function mutations, rare variant burden, common genetic variants, reproductive success, physical health, parental longevity, fitness proxies
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