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Many of our most onerous health burdens today are driven by complex and poorly understood interactions between a person’s genetic makeup and their environment. In other words, genetic variation may predispose individuals toward physiological sensitivity or resilience in the face of environmental perturbations. Our modern environments are deeply diverged from the ancestral selective pressures that have shaped human genetic variation through evolutionary time, raising the question of how much the “mismatch” between our genomes and modern life is responsible for the non-communicable diseases that plague modern societies. This concept, known as the evolutionary mismatch hypothesis, has become a central tenet of evolutionary medicine, however, this hypothesis has been difficult to robustly test in practice. Under a mismatch model, we would expect genetic variation that was neutral or beneficial in past environments to become disease-causing in modern environments; in other words, we would expect this mismatch to generate “genotype-by-environment” (GxE) interactions, such that some genetic effects on health are environmentally dependent.

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