A Bayesian filtering method for estimating the fitness effects of nascent adaptive mutations

Abstract

The distribution of fitness effects (DFE) of new beneficial mutations is a key quantity that dictates the dynamics of adaptation. The barcode lineage tracking (BLT) approach is an important advance toward measuring DFEs. BLT experiments enable researchers to track the frequencies of [~]105 of barcoded lineages in large microbial populations and detect up to thousands of nascent beneficial mutations in a single experiment. However, reliably identifying adapted lineages and estimating the fitness effects of driver mutations remains a challenge because lineage dynamics are subject to demographic and measurement noise and competition with other lineages. We show that the commonly used Levy-Blundell method for analyzing BLT data and its improved version FitMut2 can produce biased fitness estimates, particularly if selection is strong. To address this problem, we develop a new method called BASIL (BAyesian Selection Inference for Lineage tracking data), which dynamically updates the belief distribution of each lineages fitness and size based on the number of barcode reads. We calibrate BASILs model of noise with new experimental data and find that noise variance scales non-linearly with lineage abundance. We test how BASIL and Fit-Mut2 perform on simulated data and on down-sampled data from the original BLT data by Levy et al and find that BASIL is both more robust and more accurate than FitMut2. Our work paves the way for a systematic inference of the distribution of fitness effects of new beneficial mutations from BLT experiments in a variety of scenarios. AUTHOR SUMMARYBeneficial mutations are rare but they are the ultimate drivers of evolution by natural selection. Evolutionary biologists seek to understand how many beneficial mutations an organism has access to in different environments and how these mutations affect fitness. Barcode lineage tracking (BLT) is a powerful experimental approach that tracks the frequencies of hundreds of thousands of subpopulations labeled with unique DNA barcodes and provides data that potentially enables researchers to identify and isolate many beneficial mutations arising in experimental microbial populations. However, analyzing these data is challenging because of the randomness of evolution and measurement noise. We found that existing methods for analyzing BLT data can lead to biased estimates of the fitness effects of beneficial mutations, especially when selection is strong. To overcome this issue, we developed a new method called BASIL, which uses a Bayesian approach that updates the estimated fitness and size of each lineage based on the measured barcode counts. We show that BASIL provides more accurate and robust estimates of the fitness effects of beneficial mutations in both simulated and real datasets than the existing alternatives. Thus, BASIL will facilitate a better understanding of beneficial mutations and adaptation more generally.