# Predictable molecular evolution during adaptation

> **NIH GM R35** · CORNELL UNIVERSITY · 2026 · $431,750

## Abstract

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

## Key facts

- **NIH application ID:** 11260795
- **Project number:** 1R35GM161912-01
- **Recipient organization:** CORNELL UNIVERSITY
- **Principal Investigator:** Anurag  Agrawal
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** GM
- **Fiscal year:** 2026
- **Award amount:** $431,750
- **Award type:** 1
- **Project period:** 2026-03-01T00:00:00 → 2031-02-28T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11260795

## Citation

> US National Institutes of Health, RePORTER application 11260795, Predictable molecular evolution during adaptation (1R35GM161912-01). Retrieved via AI Analytics 2026-07-12 from https://api.ai-analytics.org/grant/nih/11260795. Licensed CC0.

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