CAREER: Quantifying Adaptation and Recombination in Pathogen Populations

This award is funded in whole or in part under the American Rescue Plan Act of 2021 (Public Law 117-2).
To usefully anticipate the evolution of pathogenic viruses and bacteria, quantitative theories that can connect it to the genetic sequencing data are needed. In this project, the PI will use mathematical models, computer simulations, and analysis of genetic data to determine the quantitative rules of pathogen evolution. The PI will focus on three main research objectives. First, the PI will understand how adaptations driven by large-effect mutations, such as is typical for immune escape or antibiotic resistance, interfere with pathogens' ability to simultaneously adapt in other ways, including via small-effect mutations and combinations of mutations. Second, the PI will find how interactions among mutations could have led to the sudden emergence of the Alpha, Beta, and Gamma SARS-CoV-2 Variants of Concern. In addition whether they likely evolved as the virus was passed from person to person, or within individual immuno-compromised people over the course of long-term infections will be studied. Third, the PI will find quantitative rules for how often bacteria within a species exchange genes with each other, using models together with a database of tens of thousands of genomes from the skin bacterium Staphylococcus aureus, including many methicillin-resistant (MRSA) samples. Quantitative theories for pathogen evolution will have substantial benefits for human health. The specific work in the proposed project will help us predict how much we need to limit the spread of the SARS-CoV-2 pandemic to avoid the potential emergence of Alpha-like adaptations on the Delta background, or even more complex adaptations. It will also help us predict which bacterial strains are likely to exchange genes, including those responsible for virulence and antibiotic resistance. The proposed middle-school science club will help encourage public interest in science, diversify the pool of future scientists, and train undergraduate and graduate students in scientific outreach and teaching The PI will also start a science enrichment program at a local middle school for refugee girls, leading hands-on lessons that will show that evolution follows regular patterns like all other natural phenomena.

In this project the PI will study the dynamics of adaptation and develop tools to be able to predict it from a set of measurements, primarily genetic sequencing. In the proposed work, the PI will find new ways to use sequencing data to infer potential genetic interactions, modes of evolution, and patterns of gene transfer. He will also find how much other adaptation one should infer to have been deferred by interference when rapid adaptation is observed in response to strong selection. These theories will be applicable to all microbial life, not only pathogens, and some aspects will be useful for understanding eukaryotic adaptation.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.