Predictable molecular evolution during adaptation - convergent molecular evolution, especially among distantly related species, is a hallmark of adaptation, yet the drivers of such convergence (or…

The National Institute of General Medical Sciences, part of the Department of Health and Human Services National Institutes of Health, awarded Cornell University $431,750 on March 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate the drivers of molecular convergence in insect adaptation to cardenolides.

The research examines how lineage-specific constraints shape convergent evolution across 30 independent origins of cardenolide-specialization in insects spanning six taxonomic orders over 350 million years. The project tests whether variation in epistatic interactions between lineages drives alternative outcomes in molecular evolution and whether multiple genes coevolve to shape patterns of convergence, with particular focus on ABC transporter genes involved in excretion and storage of plant toxins.

Performance runs through February 28, 2031, with work conducted at Cornell University's main campus in Ithaca, New York. The award is a Project Grant, the assistance type through which NIGMS supports basic research increasing understanding of biological processes to advance disease diagnosis, treatment, and prevention.

Predictable molecular evolution during adaptation - convergent molecular evolution, especially among distantly related species, is a hallmark of adaptation, yet the drivers of such convergence (or lack thereof) are typically unknown. Variation in molecular convergence may stem from constraints on evolutionary trajectories, such as how intramolecular epistasis and broader scale interactions among genes differ across lineages. While substantial progress has been made in understanding the prevalence of epistasis for fitness-related phenotypes, particularly in microbial systems, empirical tests of the role of epistasis in convergent molecular evolution are rare, especially in metazoans. A key obstacle is the lack of tractable, highly replicated systems to investigate the extent and generality in the causes of molecular convergence. To meet this need, we have been studying a diverse group of insects which have adapted to cardenolides, a class of steroidal plant toxins that disrupts the biomedically-relevant animal protein, NA/k-atpase. We recently documented a remarkable 30 independent origins of cardenolide-specialization in insects, spanning 350 million years of evolution (in six taxonomic orders, spanning beetles and flies to grasshoppers). Although a handful of substitutions did indeed convergently evolve in all orders, some species lack these substitutions and others have taken alternative paths. Our findings, which also show distinct patterns among groups (e.g., coleoptera VS. Lepidoptera, each with multiple origins) suggests lineage-specific constraints of genomic background. This group of insects thus presents a treasure trove of opportunity to decipher the drivers of molecular convergence. How variable are the epistatic interactions between lineages, and do these differences drive alternative outcomes in molecular evolution? Do multiple genes coevolve, shaping patterns of convergence? For example, have ABC transporter genes involved in excretion and storage, which complement resistance to cardenolides, evolved in parallel to NA/k-atpase substitutions? And finally, do molecular substitutions predictably track the evolution of specific toxins coevolving in host plants? This system allows for some of the strongest general tests of why adaptive phenotypic outcomes have a similar genetic basis. Beyond comparative genomics, which will reveal distinct evolutionary outcomes and genetic associations, we will integrate the power of transcriptomics, in silico models, and functional assays to directly test our hypotheses. Our five-year program is expected to reveal general rules governing when intramolecular epistasis versus broader interactions among genes drive molecular convergence.