Stanford Advisors


All Publications


  • Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies ELIFE Phillips, A. M., Lawrence, K. R., Moulana, A., Dupic, T., Chang, J., Johnson, M. S., Cvijovic, I., Mora, T., Walczak, A. M., Desai, M. M. 2021; 10
  • Binding affinity landscapes constrain the evolution of broadly neutralizing anti-influenza antibodies. eLife Phillips, A. M., Lawrence, K. R., Moulana, A., Dupic, T., Chang, J., Johnson, M. S., Cvijovic, I., Mora, T., Walczak, A. M., Desai, M. M. 2021; 10

    Abstract

    Over the past two decades, several broadly neutralizing antibodies (bnAbs) that confer protection against diverse influenza strains have been isolated. Structural and biochemical characterization of these bnAbs has provided molecular insight into how they bind distinct antigens. However, our understanding of the evolutionary pathways leading to bnAbs, and thus how best to elicit them, remains limited. Here, we measure equilibrium dissociation constants of combinatorially complete mutational libraries for two naturally isolated influenza bnAbs (CR9114, 16 heavy-chain mutations; CR6261, 11 heavy-chain mutations), reconstructing all possible evolutionary intermediates back to the unmutated germline sequences. We find that these two libraries exhibit strikingly different patterns of breadth: while many variants of CR6261 display moderate affinity to diverse antigens, those of CR9114 display appreciable affinity only in specific, nested combinations. By examining the extensive pairwise and higher-order epistasis between mutations, we find key sites with strong synergistic interactions that are highly similar across antigens for CR6261 and different for CR9114. Together, these features of the binding affinity landscapes strongly favor sequential acquisition of affinity to diverse antigens for CR9114, while the acquisition of breadth to more similar antigens for CR6261 is less constrained. These results, if generalizable to other bnAbs, may explain the molecular basis for the widespread observation that sequential exposure favors greater breadth, and such mechanistic insight will be essential for predicting and eliciting broadly protective immune responses.

    View details for DOI 10.7554/eLife.71393

    View details for PubMedID 34491198

  • High-resolution lineage tracking reveals travelling wave of adaptation in laboratory yeast NATURE Ba, A., Cvijovic, I., Echenique, J., Lawrence, K. R., Rego-Costa, A., Liu, X., Levy, S. F., Desai, M. M. 2019; 575 (7783): 494-+

    Abstract

    In rapidly adapting asexual populations, including many microbial pathogens and viruses, numerous mutant lineages often compete for dominance within the population1-5. These complex evolutionary dynamics determine the outcomes of adaptation, but have been difficult to observe directly. Previous studies have used whole-genome sequencing to follow molecular adaptation6-10; however, these methods have limited resolution in microbial populations. Here we introduce a renewable barcoding system to observe evolutionary dynamics at high resolution in laboratory budding yeast. We find nested patterns of interference and hitchhiking even at low frequencies. These events are driven by the continuous appearance of new mutations that modify the fates of existing lineages before they reach substantial frequencies. We observe how the distribution of fitness within the population changes over time, and find a travelling wave of adaptation that has been predicted by theory11-17. We show that clonal competition creates a dynamical 'rich-get-richer' effect: fitness advantages that are acquired early in evolution drive clonal expansions, which increase the chances of acquiring future mutations. However, less-fit lineages also routinely leapfrog over strains of higher fitness. Our results demonstrate that this combination of factors, which is not accounted for in existing models of evolutionary dynamics, is critical in determining the rate, predictability and molecular basis of adaptation.

    View details for DOI 10.1038/s41586-019-1749-3

    View details for Web of Science ID 000498812200050

    View details for PubMedID 31723263

  • Experimental Studies of Evolutionary Dynamics in Microbes TRENDS IN GENETICS Cvijovic, I., Ba, A., Desai, M. M. 2018; 34 (9): 693–703

    Abstract

    Evolutionary dynamics in laboratory microbial evolution experiments can be surprisingly complex. In the past two decades, observations of these dynamics have challenged simple models of adaptation and have shown that clonal interference, hitchhiking, ecological diversification, and contingency are widespread. In recent years, advances in high-throughput strain maintenance and phenotypic assays, the dramatically reduced cost of genome sequencing, and emerging methods for lineage barcoding have made it possible to observe evolutionary dynamics at unprecedented resolution. These new methods can now begin to provide detailed measurements of key aspects of fitness landscapes and of evolutionary outcomes across a range of systems. These measurements can highlight challenges to existing theoretical models and guide new theoretical work towards the complications that are most widely important.

    View details for DOI 10.1016/j.tig.2018.06.004

    View details for Web of Science ID 000441411000004

    View details for PubMedID 30025666

    View details for PubMedCentralID PMC6467257

  • The Effect of Strong Purifying Selection on Genetic Diversity GENETICS Cvijovic, I., Good, B. H., Desai, M. M. 2018; 209 (4): 1235–78

    Abstract

    Purifying selection reduces genetic diversity, both at sites under direct selection and at linked neutral sites. This process, known as background selection, is thought to play an important role in shaping genomic diversity in natural populations. Yet despite its importance, the effects of background selection are not fully understood. Previous theoretical analyses of this process have taken a backward-time approach based on the structured coalescent. While they provide some insight, these methods are either limited to very small samples or are computationally prohibitive. Here, we present a new forward-time analysis of the trajectories of both neutral and deleterious mutations at a nonrecombining locus. We find that strong purifying selection leads to remarkably rich dynamics: neutral mutations can exhibit sweep-like behavior, and deleterious mutations can reach substantial frequencies even when they are guaranteed to eventually go extinct. Our analysis of these dynamics allows us to calculate analytical expressions for the full site frequency spectrum. We find that whenever background selection is strong enough to lead to a reduction in genetic diversity, it also results in substantial distortions to the site frequency spectrum, which can mimic the effects of population expansions or positive selection. Because these distortions are most pronounced in the low and high frequency ends of the spectrum, they become particularly important in larger samples, but may have small effects in smaller samples. We also apply our forward-time framework to calculate other quantities, such as the ultimate fates of polymorphisms or the fitnesses of their ancestral backgrounds.

    View details for DOI 10.1534/genetics.118.301058

    View details for Web of Science ID 000440014100019

    View details for PubMedID 29844134

    View details for PubMedCentralID PMC6063222

  • Fate of a mutation in a fluctuating environment PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cvijovic, I., Good, B. H., Jerison, E. R., Desai, M. M. 2015; 112 (36): E5021–E5028

    Abstract

    Natural environments are never truly constant, but the evolutionary implications of temporally varying selection pressures remain poorly understood. Here we investigate how the fate of a new mutation in a fluctuating environment depends on the dynamics of environmental variation and on the selective pressures in each condition. We find that even when a mutation experiences many environmental epochs before fixing or going extinct, its fate is not necessarily determined by its time-averaged selective effect. Instead, environmental variability reduces the efficiency of selection across a broad parameter regime, rendering selection unable to distinguish between mutations that are substantially beneficial and substantially deleterious on average. Temporal fluctuations can also dramatically increase fixation probabilities, often making the details of these fluctuations more important than the average selection pressures acting on each new mutation. For example, mutations that result in a trade-off between conditions but are strongly deleterious on average can nevertheless be more likely to fix than mutations that are always neutral or beneficial. These effects can have important implications for patterns of molecular evolution in variable environments, and they suggest that it may often be difficult for populations to maintain specialist traits, even when their loss leads to a decline in time-averaged fitness.

    View details for DOI 10.1073/pnas.1505406112

    View details for Web of Science ID 000360994900009

    View details for PubMedID 26305937

    View details for PubMedCentralID PMC4568713