Mutation–selection–drift balance models of complex diseases

article Mutation–selection–drift balance models of complex diseases published yes Jeremy J. Berg author Xinyi Li author Kellen Riall author Laura Hayward author fc885ee5-24bf-11eb-ad7b-bcc5104c0c1b Guy Sella author NiBa department Genetic variation that influences complex disease susceptibility is introduced into the population by mutation and removed by natural selection and genetic drift. This mutation–selection–drift balance (MSDB) shapes the prevalence of a disease and its genetic architecture. To date, however, MSDB has been modeled only for monogenic (Mendelian) diseases. Here, we develop an MSDB model for complex disease susceptibility: we assume that genotype relates to disease risk according to the canonical liability threshold model and that the selection on variants affecting risk stems from the fitness cost of the disease. We focus on diseases that are highly polygenic, entail a substantial fitness cost, and are neither extremely common in the population nor exceedingly rare. The comparison of model predictions with genome-wide association studies and other observations in humans indicates that common genetic variation affecting complex disease susceptibility is little affected by directional selection and instead shaped by pleiotropic stabilizing selection on other traits. In turn, directional selection may exert a more substantial effect on rare, large-effect variants. Our results also suggest that current estimates of disease heritability are likely biased. The model thus provides a better understanding of the evolutionary processes that shape the architecture and prevalence of complex diseases. https://research-explorer.ista.ac.at/download/20848/20863/2025_Genetics_Berg.pdf application/pdfno Oxford University Press2025 eng Genetics 0016-6731 1943-2631 4107387910.1093/genetics/iyaf220 2314 J.J. Berg, X. Li, K. Riall, L. Hayward, G. Sella, Genetics 231 (2025). Berg JJ, Li X, Riall K, Hayward L, Sella G. Mutation–selection–drift balance models of complex diseases. Genetics. 2025;231(4). doi:<a href="https://doi.org/10.1093/genetics/iyaf220">10.1093/genetics/iyaf220</a> Berg, Jeremy J., Xinyi Li, Kellen Riall, Laura Hayward, and Guy Sella. “Mutation–Selection–Drift Balance Models of Complex Diseases.” Genetics. Oxford University Press, 2025. <a href="https://doi.org/10.1093/genetics/iyaf220">https://doi.org/10.1093/genetics/iyaf220</a>. Berg, Jeremy J., et al. “Mutation–Selection–Drift Balance Models of Complex Diseases.” Genetics, vol. 231, no. 4, iyaf220, Oxford University Press, 2025, doi:<a href="https://doi.org/10.1093/genetics/iyaf220">10.1093/genetics/iyaf220</a>. Berg JJ, Li X, Riall K, Hayward L, Sella G. 2025. Mutation–selection–drift balance models of complex diseases. Genetics. 231(4), iyaf220. Berg, J. J., Li, X., Riall, K., Hayward, L., & Sella, G. (2025). Mutation–selection–drift balance models of complex diseases. Genetics. Oxford University Press. <a href="https://doi.org/10.1093/genetics/iyaf220">https://doi.org/10.1093/genetics/iyaf220</a> J. J. Berg, X. Li, K. Riall, L. Hayward, and G. Sella, “Mutation–selection–drift balance models of complex diseases,” Genetics, vol. 231, no. 4. Oxford University Press, 2025. 208482025-12-21T23:01:34Z2025-12-29T11:29:16Z