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Following the Dynamics of Structural Variants in Experimentally Evolved Populations

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Published on: February 3, 2023

Mutation-selection-drift balance models of complex diseases.

Jeremy J Berg^1,2, Xinyi Li², Kellen Riall²

¹Department of Human Genetics, The University of Chicago, Chicago, IL 60637, United States.

|October 10, 2025

Summary

This summary is machine-generated.

Complex disease genetic architecture is shaped by mutation-selection-drift balance, not just directional selection. Common variants are influenced by stabilizing selection, while rare variants may be affected by directional selection.

Keywords:

complex disease genetic drift mutation selection

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Area of Science:

Evolutionary biology
Genetics
Population genetics

Background:

Genetic variation influences complex disease susceptibility through mutation, natural selection, and genetic drift.
The mutation-selection-drift balance (MSDB) model has been applied to monogenic diseases but not complex diseases.
Understanding MSDB is crucial for explaining disease prevalence and genetic architecture.

Purpose of the Study:

To develop and apply an MSDB model for complex disease susceptibility.
To investigate the impact of selection on common and rare genetic variants influencing complex diseases.
To re-evaluate disease heritability estimates in light of evolutionary processes.

Main Methods:

Developed a novel MSDB model incorporating the liability threshold model for complex diseases.
Assumed disease risk is polygenic with a substantial fitness cost.
Focused on diseases that are neither extremely common nor exceedingly rare.

Main Results:

Common genetic variation for complex diseases is minimally affected by directional selection.
Pleiotropic stabilizing selection on other traits significantly shapes common variant architecture.
Directional selection may have a more substantial impact on rare, large-effect variants.
Current heritability estimates for complex diseases may be biased.

Conclusions:

The study provides a new framework for understanding the evolutionary forces shaping complex disease genetics.
Stabilizing selection plays a key role in the architecture of common complex disease variants.
Further research is needed to refine heritability estimates and understand selection on rare variants.