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Noncommunicable diseases (NCDs) are on the rise worldwide. Obesity, cardiovascular disease, and type 2 diabetes are among a long list of lifestyle diseases that were rare throughout human history but are now common. The evolutionary mismatch hypothesis posits that humans evolved in environments that radically differ from those we currently experience; consequently, traits that were once advantageous may now be mismatched and disease causing. At the genetic level, this hypothesis predicts that loci with a history of selection will exhibit genotype by environment (GxE) interactions, with different health effects in ancestral versus modern environments. To identify such loci, we advocate for combining genomic tools in partnership with subsistence-level groups experiencing rapid lifestyle change. In these populations, comparisons of individuals falling on opposite extremes of the matched to mismatched spectrum are uniquely possible. More broadly, the work we propose will inform our understanding of environmental and genetic risk factors for NCDs across diverse ancestries and cultures.

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., Competing Interests: Competing interests The authors declare no competing interests.