[Paper Review] Evolutionary mismatch and the role of GxE interactions in human disease

Amanda J. Lea, Andrew G. Clark+19 more|arXiv (Cornell University)|Jan 12, 2023

Genetic Associations and EpidemiologyBiochemistry, Genetics and Molecular Biology3 citations

TL;DR

This paper proposes leveraging evolutionary mismatch—where genetic predispositions selected in ancestral environments become maladaptive in modern settings—by studying genotype-by-environment (GxE) interactions in transitioning small-scale populations. By analyzing genetic and environmental shifts in subsistence groups moving toward industrialized lifestyles, the authors advocate for a principled framework to uncover the genetic architecture of non-communicable diseases (NCDs) across diverse ancestries.

ABSTRACT

Globally, we are witnessing the rise of complex, non-communicable diseases (NCDs) related to changes in our daily environments. Obesity, asthma, cardiovascular disease, and type 2 diabetes are part of a long list of "lifestyle" diseases that were rare throughout human history but are now common. A key idea from anthropology and evolutionary biology--the evolutionary mismatch hypothesis--seeks to explain this phenomenon. It posits that humans evolved in environments that radically differ from the ones experienced by most people today, and thus traits that were advantageous in past environments may now be "mismatched" and disease-causing. This hypothesis is, at its core, a genetic one: it predicts that loci with a history of selection will exhibit "genotype by environment" (GxE) interactions and have differential health effects in ancestral versus modern environments. Here, we discuss how this concept could be leveraged to uncover the genetic architecture of NCDs in a principled way. Specifically, we advocate for partnering with small-scale, subsistence-level groups that are currently transitioning from environments that are arguably more "matched" with their recent evolutionary history to those that are more "mismatched". These populations provide diverse genetic backgrounds as well as the needed levels and types of environmental variation necessary for mapping GxE interactions in an explicit mismatch framework. Such work would make important contributions to our understanding of environmental and genetic risk factors for NCDs across diverse ancestries and sociocultural contexts.

Motivation & Objective

• To address the rising global burden of non-communicable diseases (NCDs) such as obesity, type 2 diabetes, and cardiovascular disease.
• To investigate how evolutionary mismatch—where ancestral genetic adaptations become detrimental in modern environments—contributes to NCD susceptibility.
• To identify genetic loci with differential effects in ancestral versus modern environments through GxE interactions.
• To promote research partnerships with small-scale, subsistence-level populations undergoing environmental transitions to enable robust GxE mapping.
• To enhance understanding of NCD risk across diverse genetic and sociocultural contexts by integrating evolutionary biology with genomics.

Proposed method

• Focus on populations currently transitioning from traditional, ancestral-like environments to modern, industrialized ones.
• Utilize natural experiments in human populations where genetic backgrounds remain diverse and environmental shifts are measurable and recent.
• Apply genomic analysis to detect loci showing differential health effects in ancestral versus modern environments (GxE interactions).
• Prioritize populations with clear environmental transitions—e.g., dietary shifts, reduced physical activity, urbanization—over historical inference.
• Integrate longitudinal phenotypic, environmental, and genomic data to model GxE interactions within an evolutionary mismatch framework.
• Use evolutionary theory to prioritize candidate loci under recent positive selection for GxE analysis, enhancing biological plausibility.

Experimental results

Research questions

• RQ1 Which genetic variants exhibit differential effects on non-communicable disease risk in ancestral versus modern environments?
• RQ2 How do measurable environmental transitions in subsistence populations reveal GxE interactions linked to NCDs?
• RQ3 To what extent do loci under recent positive selection contribute to disease risk in mismatched modern environments?
• RQ4 Can populations undergoing lifestyle transitions serve as natural models for identifying GxE interactions in NCDs?
• RQ5 How can evolutionary mismatch theory be operationalized in genomic studies to improve discovery of genetic risk factors across diverse ancestries?

Key findings

• The evolutionary mismatch hypothesis provides a strong theoretical foundation for understanding the genetic basis of modern NCDs through GxE interactions.
• Populations transitioning from subsistence to industrialized lifestyles offer unique opportunities to map GxE interactions due to concurrent genetic and environmental variation.
• Loci under recent positive selection are predicted to show stronger GxE effects, making them high-priority targets for NCD genetic studies.
• Environmental shifts such as dietary changes and reduced physical activity are key drivers of mismatch and should be systematically measured in GxE studies.
• Studying diverse, non-Western populations enhances the generalizability of genetic risk models beyond European-ancestry cohorts.
• The framework enables a principled, evolutionarily informed approach to identifying genetic risk factors for NCDs across sociocultural and genetic diversity.