Olivia Ghosh

All Publications

• Massively parallel experimental interrogation of natural variants in ancient signaling pathways reveals both purifying selection and local adaptation. bioRxiv : the preprint server for biology Aguilar-Rodríguez, J., Vila, J., Chen, S. A., Razo-Mejia, M., Ghosh, O., Fraser, H. B., Jarosz, D. F., Petrov, D. A. 2024

  Abstract

  The nature of standing genetic variation remains a central debate in population genetics, with differing perspectives on whether common variants are mostly neutral or have functional effects. We address this question by directly mapping the fitness effects of over 9,000 natural variants in the Ras/PKA and TOR/Sch9 pathways-key regulators of cell proliferation in eukaryotes-across four conditions in Saccharomyces cerevisiae. While many variants are neutral in our assay, on the order of 3,500 exhibited significant fitness effects. These non-neutral variants tend to be missense and affect conserved, more densely packed, and less solvent-exposed protein regions. They are also typically younger, occur at lower frequencies, and more often found in heterozygous states, suggesting they are subject to purifying selection. A substantial fraction of non-neutral variants showing strong fitness effects in our experiments, however, is present at high frequencies in the population. These variants show signs of local adaptation as they tend to be found specifically in domesticated strains adapted to human-made environments. Our findings support the view that while common variants are often neutral, a significant proportion have adaptive functional consequences and are driven into the population by local positive selection. This study highlights the potential to explore the functional effects of natural genetic variation on a genome scale with quantitative fitness measurements in the laboratory, bridging the gap between population genetics and functional genomics to understand evolutionary dynamics in the wild.

  View details for DOI 10.1101/2024.10.30.621178

  View details for PubMedID 39553990

  View details for PubMedCentralID PMC11565963

• Emergent evolutionary forces in spatial models of luminal growth and their application to the human gut microbiota. Proceedings of the National Academy of Sciences of the United States of America Ghosh, O. M., Good, B. H. 2022; 119 (28): e2114931119

  Abstract

  The genetic composition of the gut microbiota is constantly reshaped by ecological and evolutionary forces. These strain-level dynamics are challenging to understand because they depend on complex spatial growth processes that take place within a host. Here we introduce a population genetic framework to predict how stochastic evolutionary forces emerge from simple models of microbial growth in spatially extended environments like the intestinal lumen. Our framework shows how fluid flow and longitudinal variation in growth rate combine to shape the frequencies of genetic variants in simulated fecal samples, yielding analytical expressions for the effective generation times, selection coefficients, and rates of genetic drift. We find that over longer timescales, the emergent evolutionary dynamics can often be captured by well-mixed models that lack explicit spatial structure, even when there is substantial spatial variation in species-level composition. By applying these results to the human colon, we find that continuous fluid flow and simple forms of wall growth alone are unlikely to create sufficient bottlenecks to allow large fluctuations in mutant frequencies within a host. We also find that the effective generation times may be significantly shorter than expected from traditional average growth rate estimates. Our results provide a starting point for quantifying genetic turnover in spatially extended settings like the gut microbiota and may be relevant for other microbial ecosystems where unidirectional fluid flow plays an important role.

  View details for DOI 10.1073/pnas.2114931119

  View details for PubMedID 35787046