# Effects of genetic background on adaptive evolution

> **NIH NIH R01** · COLUMBIA UNIV NEW YORK MORNINGSIDE · 2022 · $329,561

## Abstract

Project Summary
To what extent is adaptive evolution predictable? Despite its importance in understanding the biology of human diseases,
including the evolution of viral and bacterial pathogens, the dynamics of genetic adaptation are still poorly understood. In
particular, few examples yet exist that have been dissected to the molecular level. Examples of adaptations from natural
systems and the use of model organisms are powerful tools that can be combined to make progress on this difficult
question. We have employed instances of “parallel evolution”, involving assemblages of species experiencing a common
regime of natural selection, to evaluate multiple outcomes of the process of adaptation. With this information, we can
learn about recurrent features of adaptation and infer constraints and regularities in the adaptive process. Our work
focused on the biomedically-important interaction between Na+,K+-ATPases and their regulatory steroidal-glycosides that
a large variety of plants and animals use as toxins to defend themselves from being eaten. Using a diverse set of animals
that have independently evolved resistance to steroidal-glycoside toxicity, including insects and vertebrates, we
discovered these diverse species most often evolve resistance via a small number of possible options (i.e. involving only
three of 41 possible sites in the protein that could be modified to confer resistance). These findings suggest that adaptive
evolution is often path-dependent, implying that the individual components of an adaptation must evolve in a prescribed,
and ultimately predictable, order. They also raise numerous questions about the nature of this path dependency, including
the extent to which it emerges from interactions among residues within a protein, or from the genomic background of the
species; whether it similarly constrains adaptation over short and longer time scales, and how generally it applies in
adaptive protein evolution. Here we propose three aims that address these questions, by combining approaches from
evolutionary genomics and molecular genetics. In Aim 1, we will use genome engineering in Drosophila to elucidate the
path dependence of the steroidal-glycoside resistance adaptation both at the level of its primary target (Na+,K+-ATPase)
and at the level of the whole genome. In Aim 2, we will determine which and how many genomic factors contribute to
naturally occurring variation within Drosophila populations. This information will reveal the relationship between within-
population and between-species genetic variation underlying the same trait, connecting short- and long-term dynamics of
the adaptive process. In Aim 3, we will use principles learned from molecular adaptation at Na+,K+-ATPase to
computationally predict and use genome engineering to functionally validate path dependent adaptation dynamics in
Drosophila for a diverse group of proteins, many of which (like Na+,K+-ATPase) have important roles in neurological
development an...

## Key facts

- **NIH application ID:** 10397123
- **Project number:** 5R01GM115523-06
- **Recipient organization:** COLUMBIA UNIV NEW YORK MORNINGSIDE
- **Principal Investigator:** Peter Andolfatto
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $329,561
- **Award type:** 5
- **Project period:** 2015-09-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10397123

## Citation

> US National Institutes of Health, RePORTER application 10397123, Effects of genetic background on adaptive evolution (5R01GM115523-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10397123. Licensed CC0.

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