Academic Appointments


Honors & Awards


  • Fellow, American Academy of Arts and Sciences (1999)
  • Onsager Prize, American Physical Society (2013)
  • Member, National Academy of Sciences (2015)

Professional Education


  • PhD, Harvard University, Physics (1979)
  • BA, Cornell University, Math and Physics (1975)

Current Research and Scholarly Interests


Evolutionary & ecological dynamics & diversity, microbial, expt'l, & cancer

2023-24 Courses


Stanford Advisees


Graduate and Fellowship Programs


All Publications


  • Spatiotemporal ecological chaos enables gradual evolutionary diversification without niches or tradeoffs. eLife Mahadevan, A., Pearce, M. T., Fisher, D. S. 2023; 12

    Abstract

    Ecological and evolutionary dynamics are intrinsically entwined. On short timescales, ecological interactions determine the fate and impact of new mutants, while on longer timescales evolution shapes the entire community. Here we study the evolution of large numbers of closely related strains with generalized Lotka Volterra interactions but no niche structure. Host-pathogen-like interactions drive the community into a spatiotemporally chaotic state characterized by continual, spatially-local, blooms and busts. Upon the slow serial introduction of new strains, the community diversifies indefinitely, accommodating an arbitrarily large number of strains in spite of the absence of stabilizing niche interactions. The diversifying phase persists - albeit with gradually slowing diversification - in the presence of general, nonspecific, fitness differences between strains, which break the assumption of tradeoffs inherent in much previous work. Building on a dynamical-mean field-theory analysis of the ecological dynamics, an approximate effective model captures the evolution of the diversity and distributions of key properties. This work establishes a potential scenario for understanding how the interplay between evolution and ecology - in particular coevolution of a bacterial and a generalist phage species - could give rise to the extensive fine-scale diversity that is ubiquitous in the microbial world.

    View details for DOI 10.7554/eLife.82734

    View details for PubMedID 37114771

  • Population genetics of polymorphism and divergence in rapidly evolving populations. Genetics Melissa, M. J., Good, B. H., Fisher, D. S., Desai, M. M. 2022

    Abstract

    In rapidly evolving populations, numerous beneficial and deleterious mutations can arise and segregate within a population at the same time. In this regime, evolutionary dynamics cannot be analyzed using traditional population genetic approaches that assume that sites evolve independently. Instead, the dynamics of many loci must be analyzed simultaneously. Recent work has made progress by first analyzing the fitness variation within a population, and then studying how individual lineages interact with this traveling fitness wave. However, these "traveling wave" models have previously been restricted to extreme cases where selection on individual mutations is either much faster or much slower than the typical coalescent timescale Tc. In this work, we show how the traveling wave framework can be extended to intermediate regimes in which the scaled fitness effects of mutations (Tcs) are neither large nor small compared to one. This enables us to describe the dynamics of populations subject to a wide range of fitness effects, and in particular, in cases where it is not immediately clear which mutations are most important in shaping the dynamics and statistics of genetic diversity. We use this approach to derive new expressions for the fixation probabilities and site frequency spectra of mutations as a function of their scaled fitness effects, along with related results for the coalescent timescale Tc and the rate of adaptation or Muller's ratchet. We find that competition between linked mutations can have a dramatic impact on the proportions of neutral and selected polymorphisms, which is not simply summarized by the scaled selection coefficient Tcs. We conclude by discussing the implications of these results for population genetic inferences.

    View details for DOI 10.1093/genetics/iyac053

    View details for PubMedID 35389471

  • Synonymous mutations reveal genome-wide levels of positive selection in healthy tissues. Nature genetics Poon, G. Y., Watson, C. J., Fisher, D. S., Blundell, J. R. 2021; 53 (11): 1597-1605

    Abstract

    Genetic alterations under positive selection in healthy tissues have implications for cancer risk. However, total levels of positive selection across the genome remain unknown. Passenger mutations are influenced by all driver mutations, regardless of type or location in the genome. Therefore, the total number of passengers can be used to estimate the total number of drivers-including unidentified drivers outside of cancer genes that are traditionally missed. Here we analyze the variant allele frequency spectrum of synonymous mutations from healthy blood and esophagus to quantify levels of missing positive selection. In blood, we find that only 30% of passengers can be explained by single-nucleotide variants in driver genes, suggesting high levels of positive selection for mutations elsewhere in the genome. In contrast, more than half of all passengers in the esophagus can be explained by just the two driver genes NOTCH1 and TP53, suggesting little positive selection elsewhere.

    View details for DOI 10.1038/s41588-021-00957-1

    View details for PubMedID 34737428

  • Fundamental limits on the rate of bacterial growth and their influence on proteomic composition. Cell systems Belliveau, N. M., Chure, G., Hueschen, C. L., Garcia, H. G., Kondev, J., Fisher, D. S., Theriot, J. A., Phillips, R. 2021

    Abstract

    Despite abundant measurements of bacterial growth rate, cell size, and protein content, we lack a rigorous understanding of what sets the scale of these quantities and when protein abundances should (or should not) depend on growth rate. Here, we estimate the basic requirements and physical constraints on steady-state growth by considering key processes in cellular physiology across a collection of Escherichia coli proteomic data covering 4,000 proteins and 36 growth rates. Our analysis suggests that cells are predominantly tuned for the task of cell doubling across a continuum of growth rates; specific processes do not limit growth rate or dictate cell size. We present a model of proteomic regulation as a function of nutrient supply that reconciles observed interdependences between protein synthesis, cell size, and growth rate and propose that a theoretical inability to parallelize ribosomal synthesis places a firm limit on the achievable growth rate. A record of this paper's transparent peer review process is included in the supplemental information.

    View details for DOI 10.1016/j.cels.2021.06.002

    View details for PubMedID 34214468

  • Stabilization of extensive fine-scale diversity by ecologically driven spatiotemporal chaos. Proceedings of the National Academy of Sciences of the United States of America Pearce, M. T., Agarwala, A., Fisher, D. S. 2020

    Abstract

    It has recently become apparent that the diversity of microbial life extends far below the species level to the finest scales of genetic differences. Remarkably, extensive fine-scale diversity can coexist spatially. How is this diversity stable on long timescales, despite selective or ecological differences and other evolutionary processes? Most work has focused on stable coexistence or assumed ecological neutrality. We present an alternative: extensive diversity maintained by ecologically driven spatiotemporal chaos, with no assumptions about niches or other specialist differences between strains. We study generalized Lotka-Volterra models with antisymmetric correlations in the interactions inspired by multiple pathogen strains infecting multiple host strains. Generally, these exhibit chaos with increasingly wild population fluctuations driving extinctions. But the simplest spatial structure, many identical islands with migration between them, stabilizes a diverse chaotic state. Some strains (subspecies) go globally extinct, but many persist for times exponentially long in the number of islands. All persistent strains have episodic local blooms to high abundance, crucial for their persistence as, for many, their average population growth rate is negative. Snapshots of the abundance distribution show a power law at intermediate abundances that is essentially indistinguishable from the neutral theory of ecology. But the dynamics of the large populations are much faster than birth-death fluctuations. We argue that this spatiotemporally chaotic "phase" should exist in a wide range of models, and that even in rapidly mixed systems, longer-lived spores could similarly stabilize a diverse chaotic phase.

    View details for DOI 10.1073/pnas.1915313117

    View details for PubMedID 32518107

  • The evolutionary dynamics and fitness landscape of clonal hematopoiesis. Science (New York, N.Y.) Watson, C. J., Papula, A. L., Poon, G. Y., Wong, W. H., Young, A. L., Druley, T. E., Fisher, D. S., Blundell, J. R. 2020; 367 (6485): 1449–54

    Abstract

    Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance remains largely unknown. Blood sequencing data from ~50,000 individuals reveal how mutation, genetic drift, and fitness shape the genetic diversity of healthy blood (clonal hematopoiesis). We show that positive selection, not drift, is the major force shaping clonal hematopoiesis, provide bounds on the number of hematopoietic stem cells, and quantify the fitness advantages of key pathogenic variants, at single-nucleotide resolution, as well as the distribution of fitness effects (fitness landscape) within commonly mutated driver genes. These data are consistent with clonal hematopoiesis being driven by a continuing risk of mutations and clonal expansions that become increasingly detectable with age.

    View details for DOI 10.1126/science.aay9333

    View details for PubMedID 32217721

  • A model for the interplay between plastic tradeoffs and evolution in changing environments. Proceedings of the National Academy of Sciences of the United States of America Tikhonov, M. n., Kachru, S. n., Fisher, D. S. 2020

    Abstract

    Performance tradeoffs are ubiquitous in both ecological and evolutionary modeling, yet they are usually postulated and built into fitness and ecological landscapes. However, tradeoffs depend on genetic background and evolutionary history and can themselves evolve. We present a simple model capable of capturing the key feedback loop: evolutionary history shapes tradeoff strength, which, in turn, shapes evolutionary future. One consequence of this feedback is that genomes with identical fitness can have different evolutionary properties shaped by prior environmental exposure. Another is that, generically, the best adaptations to one environment may evolve in another. Our simple framework bridges the gap between the phenotypic Fisher's Geometric Model and the genotypic properties, such as modularity and evolvability, and can serve as a rich playground for investigating evolution in multiple or changing environments.

    View details for DOI 10.1073/pnas.1915537117

    View details for PubMedID 32245811

  • Rapid adaptation in large populations with very rare sex: Scalings and spontaneous oscillations Pearce, M. T., Fisher, D. S. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2019: 18–40
  • Adaptive walks on high-dimensional fitness landscapes and seascapes with distance-dependent statistics. Theoretical population biology Agarwala, A. n., Fisher, D. S. 2019

    Abstract

    The dynamics of evolution is intimately shaped by epistasis - interactions between genetic elements which cause the fitness-effect of combinations of mutations to be non-additive. Analyzing evolutionary dynamics that involves large numbers of epistatic mutations is intrinsically difficult. A crucial feature is that the fitness landscape in the vicinity of the current genome depends on the evolutionary history. A key step is thus developing models that enable study of the effects of past evolution on future evolution. In this work, we introduce a broad class of high-dimensional random fitness landscapes for which the correlations between fitnesses of genomes are a general function of genetic distance. Their Gaussian character allows for tractable computational as well as analytic understanding. We study the properties of these landscapes focusing on the simplest evolutionary process: random adaptive (uphill) walks. Conventional measures of "ruggedness" are shown to not much affect such adaptive walks. Instead, the long-distance statistics of epistasis cause all properties to be highly conditional on past evolution, determining the statistics of the local landscape (the distribution of fitness-effects of available mutations and combinations of these), as well as the global geometry of evolutionary trajectories. In order to further explore the effects of conditioning on past evolution, we model the effects of slowly changing environments. At long times, such fitness "seascapes" cause a statistical steady state with highly intermittent evolutionary dynamics: populations undergo bursts of rapid adaptation, interspersed with periods in which adaptive mutations are rare and the population waits for more new directions to be opened up by changes in the environment. Finally, we discuss prospects for studying more complex evolutionary dynamics and on broader classes of high-dimensional landscapes and seascapes.

    View details for DOI 10.1016/j.tpb.2019.09.011

    View details for PubMedID 31605706

  • The dynamics of adaptive genetic diversity during the early stages of clonal evolution. Nature ecology & evolution Blundell, J. R., Schwartz, K., Francois, D., Fisher, D. S., Sherlock, G., Levy, S. F. 2018

    Abstract

    The dynamics of genetic diversity in large clonally evolving cell populations are poorly understood, despite having implications for the treatment of cancer and microbial infections. Here, we combine barcode lineage tracking, sequencing of adaptive clones and mathematical modelling of mutational dynamics to understand adaptive diversity changes during experimental evolution of Saccharomyces cerevisiae under nitrogen and carbon limitation. We find that, despite differences in beneficial mutational mechanisms and fitness effects, early adaptive genetic diversity increases predictably, driven by the expansion of many single-mutant lineages. However, a crash in adaptive diversity follows, caused by highly fit double-mutant 'jackpot' clones that are fed from exponentially growing single mutants, a process closely related to the classic Luria-Delbruck experiment. The diversity crash is likely to be a general feature of asexual evolution with clonal interference; however, both its timing and magnitude are stochastic and depend on the population size, the distribution of beneficial fitness effects and patterns of epistasis.

    View details for PubMedID 30598529

  • Hidden Complexity of Yeast Adaptation under Simple Evolutionary Conditions CURRENT BIOLOGY Li, Y., Venkataram, S., Agarwala, A., Dunn, B., Petrov, D. A., Sherlock, G., Fisher, D. S. 2018; 28 (4): 515-+

    Abstract

    Few studies have "quantitatively" probed how adaptive mutations result in increased fitness. Even in simple microbial evolution experiments, with full knowledge of the underlying mutations and specific growth conditions, it is challenging to determine where within a growth-saturation cycle those fitness gains occur. A common implicit assumption is that most benefits derive from an increased exponential growth rate. Here, we instead show that, in batch serial transfer experiments, adaptive mutants' fitness gains can be dominated by benefits that are accrued in one growth cycle, but not realized until the next growth cycle. For thousands of evolved clones (most with only a single mutation), we systematically varied the lengths of fermentation, respiration, and stationary phases to assess how their fitness, as measured by barcode sequencing, depends on these phases of the growth-saturation-dilution cycles. These data revealed that, whereas all adaptive lineages gained similar and modest benefits from fermentation, most of the benefits for the highest fitness mutants came instead from the time spent in respiration. From monoculture and high-resolution pairwise fitness competition experiments for a dozen of these clones, we determined that the benefits "accrued" during respiration are only largely "realized" later as a shorter duration of lag phase in the following growth cycle. These results reveal hidden complexities of the adaptive process even under ostensibly simple evolutionary conditions, in which fitness gains can accrue during time spent in a growth phase with little cell division, and reveal that the memory of those gains can be realized in the subsequent growth cycle.

    View details for PubMedID 29429618

    View details for PubMedCentralID PMC5823527

  • Probing the ecological and evolutionary history of a thermophilic cyanobacterial population via statistical properties of its microdiversity. PloS one Rosen, M. J., Davison, M., Fisher, D. S., Bhaya, D. 2018; 13 (11): e0205396

    Abstract

    Despite extensive DNA sequencing data derived from natural microbial communities, it remains a major challenge to identify the key evolutionary and ecological forces that shape microbial populations. We have focused on the extensive microdiversity of the cyanobacterium Synechococcus sp., which is a dominant member of the dense phototrophic biofilms in the hot springs of Yellowstone National Park. From deep amplicon sequencing of many loci and statistical analyses of these data, we showed previously that the population has undergone an unexpectedly high degree of homologous recombination, unlinking synonymous SNP-pair correlations even on intragenic length scales. Here, we analyze the genic amino acid diversity, which provides new evidence of selection and insights into the evolutionary history of the population. Surprisingly, some features of the data, including the spectrum of distances between genic-alleles, appear consistent with primarily asexual neutral drift. Yet the non-synonymous site frequency spectrum has too large an excess of low-frequency polymorphisms to result from negative selection on deleterious mutations given the distribution of coalescent times that we infer. And our previous analyses showed that the population is not asexual. Taken together, these apparently contradictory data suggest that selection, epistasis, and hitchhiking all play essential roles in generating and stabilizing the diversity. We discuss these as well as potential roles of ecological niches at genomic and genic levels. From quantitative properties of the diversity and comparative genomic data, we infer aspects of the history and inter-spring dispersal of the meta-population since it was established in the Yellowstone Caldera. Our investigations illustrate the need for combining multiple types of sequencing data and quantitative statistical analyses to develop an understanding of microdiversity in natural microbial populations.

    View details for PubMedID 30427861

  • Rapid adaptation in large populations with very rare sex: Scalings and spontaneous oscillations. Theoretical population biology Pearce, M. T., Fisher, D. S. 2017

    Abstract

    Genetic exchange in microbes and other facultative sexuals can be rare enough that evolution is almost entirely asexual and populations almost clonal. But the benefits of genetic exchange depend crucially on the diversity of genotypes in a population. How very rare recombination together with the accumulation of new mutations shapes the diversity of large populations and gives rise to faster adaptation is still poorly understood. This paper analyzes a particularly simple model: organisms with two asexual chromosomes that can reassort during rare matings that occur at a rate r. The speed of adaptation for large population sizes, N, is found to depend on the ratio log(Nr)∕log(N). For larger populations, the r needed to yield the same speed decreases as a power of N. Remarkably, the population undergoes spontaneous oscillations alternating between phases when the fittest individuals are created by mutation and when they are created by reassortment, which - in contrast to conventional regimes - decreases the diversity. Between the two phases, the mean fitness jumps rapidly. The oscillatory dynamics and the strong fluctuations this induces have implications for the diversity and coalescent statistics. The results are potentially applicable to large microbial populations, especially viruses that have a small number of chromosomes. Some of the key features may be more broadly applicable for large populations with other types of rare genetic exchange.

    View details for PubMedID 29246459

  • Development of a Comprehensive Genotype-to-Fitness Map of Adaptation-Driving Mutations in Yeast. Cell Venkataram, S., Dunn, B., Li, Y., Agarwala, A., Chang, J., Ebel, E. R., Geiler-Samerotte, K., Hérissant, L., Blundell, J. R., Levy, S. F., Fisher, D. S., Sherlock, G., Petrov, D. A. 2016; 166 (6): 1585-1596 e22

    Abstract

    Adaptive evolution plays a large role in generating the phenotypic diversity observed in nature, yet current methods are impractical for characterizing the molecular basis and fitness effects of large numbers of individual adaptive mutations. Here, we used a DNA barcoding approach to generate the genotype-to-fitness map for adaptation-driving mutations from a Saccharomyces cerevisiae population experimentally evolved by serial transfer under limiting glucose. We isolated and measured the fitness of thousands of independent adaptive clones and sequenced the genomes of hundreds of clones. We found only two major classes of adaptive mutations: self-diploidization and mutations in the nutrient-responsive Ras/PKA and TOR/Sch9 pathways. Our large sample size and precision of measurement allowed us to determine that there are significant differences in fitness between mutations in different genes, between different paralogs, and even between different classes of mutations within the same gene.

    View details for DOI 10.1016/j.cell.2016.08.002

    View details for PubMedID 27594428

    View details for PubMedCentralID PMC5070919

  • Fine-scale diversity and extensive recombination in a quasisexual bacterial population occupying a broad niche SCIENCE Rosen, M. J., Davison, M., Bhaya, D., Fisher, D. S. 2015; 348 (6238): 1019-1023

    Abstract

    Extensive fine-scale genetic diversity is found in many microbial species across varied environments, but for most, the evolutionary scenarios that generate the observed variation remain unclear. Deep sequencing of a thermophilic cyanobacterial population and analysis of the statistics of synonymous single-nucleotide polymorphisms revealed a high rate of homologous recombination and departures from neutral drift consistent with the effects of genetic hitchhiking. A sequenced isolate genome resembled an unlinked random mixture of the allelic diversity at the sampled loci. These observations suggested a quasisexual microbial population that occupies a broad ecological niche, with selection driving frequencies of alleles rather than whole genomes.

    View details for DOI 10.1126/science.aaa4456

    View details for Web of Science ID 000355276600045

  • Quantitative evolutionary dynamics using high-resolution lineage tracking. Nature Levy, S. F., Blundell, J. R., Venkataram, S., Petrov, D. A., Fisher, D. S., Sherlock, G. 2015; 519 (7542): 181-186

    Abstract

    Evolution of large asexual cell populations underlies ∼30% of deaths worldwide, including those caused by bacteria, fungi, parasites, and cancer. However, the dynamics underlying these evolutionary processes remain poorly understood because they involve many competing beneficial lineages, most of which never rise above extremely low frequencies in the population. To observe these normally hidden evolutionary dynamics, we constructed a sequencing-based ultra high-resolution lineage tracking system in Saccharomyces cerevisiae that allowed us to monitor the relative frequencies of ∼500,000 lineages simultaneously. In contrast to some expectations, we found that the spectrum of fitness effects of beneficial mutations is neither exponential nor monotonic. Early adaptation is a predictable consequence of this spectrum and is strikingly reproducible, but the initial small-effect mutations are soon outcompeted by rarer large-effect mutations that result in variability between replicates. These results suggest that early evolutionary dynamics may be deterministic for a period of time before stochastic effects become important.

    View details for DOI 10.1038/nature14279

    View details for PubMedID 25731169

  • Acceleration of evolutionary spread by long-range dispersal PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Hallatschek, O., Fisher, D. S. 2014; 111 (46): E4911-E4919
  • Rapid evolution of adaptive niche construction in experimental microbial populations EVOLUTION Callahan, B. J., Fukami, T., Fisher, D. S. 2014; 68 (11): 3307-3316

    Abstract

    Many species engage in adaptive niche construction: modification of the local environment that increases the modifying organism's competitive fitness. Adaptive niche construction provides an alternative pathway to higher fitness, shaping the environment rather than conforming to it. Yet, experimental evidence for the evolutionary emergence of adaptive niche construction is lacking, leaving its role in evolution uncertain. Here we report a direct observation of the de novo evolution of adaptive niche construction in populations of the bacteria Pseudomonas fluorescens. In a laboratory experiment, we allowed several bacterial populations to adapt to a novel environment and assessed whether niche construction evolved over time. We found that adaptive niche construction emerged rapidly, within approximately 100 generations, and became ubiquitous after approximately 400 generations. The large fitness effect of this niche construction was dominated by the low fitness of evolved strains in the ancestrally modified environment: evolved niche constructors were highly dependent on their specific environmental modifications. Populations were subjected to frequent resetting of environmental conditions and severe reduction of spatial habitat structure, both of which are thought to make adaptive niche construction difficult to evolve. Our finding that adaptive niche construction nevertheless evolved repeatably suggests that it may play a more important role in evolution than generally thought.

    View details for DOI 10.1111/evo.12512

    View details for Web of Science ID 000344379800018

  • Rapid evolution of adaptive niche construction in experimental microbial populations. Evolution; international journal of organic evolution Callahan, B. J., Fukami, T., Fisher, D. S. 2014; 68 (11): 3307-3316

    Abstract

    Many species engage in adaptive niche construction: modification of the local environment that increases the modifying organism's competitive fitness. Adaptive niche construction provides an alternative pathway to higher fitness, shaping the environment rather than conforming to it. Yet, experimental evidence for the evolutionary emergence of adaptive niche construction is lacking, leaving its role in evolution uncertain. Here we report a direct observation of the de novo evolution of adaptive niche construction in populations of the bacteria Pseudomonas fluorescens. In a laboratory experiment, we allowed several bacterial populations to adapt to a novel environment and assessed whether niche construction evolved over time. We found that adaptive niche construction emerged rapidly, within approximately 100 generations, and became ubiquitous after approximately 400 generations. The large fitness effect of this niche construction was dominated by the low fitness of evolved strains in the ancestrally modified environment: evolved niche constructors were highly dependent on their specific environmental modifications. Populations were subjected to frequent resetting of environmental conditions and severe reduction of spatial habitat structure, both of which are thought to make adaptive niche construction difficult to evolve. Our finding that adaptive niche construction nevertheless evolved repeatably suggests that it may play a more important role in evolution than generally thought.

    View details for DOI 10.1111/evo.12512

    View details for PubMedID 25138718

  • Lineage structure of the human antibody repertoire in response to influenza vaccination. Science translational medicine Jiang, N., He, J., Weinstein, J. A., Penland, L., Sasaki, S., He, X., Dekker, C. L., Zheng, N., Huang, M., Sullivan, M., Wilson, P. C., Greenberg, H. B., Davis, M. M., Fisher, D. S., Quake, S. R. 2013; 5 (171): 171ra19-?

    Abstract

    The human antibody repertoire is one of the most important defenses against infectious disease, and the development of vaccines has enabled the conferral of targeted protection to specific pathogens. However, there are many challenges to measuring and analyzing the immunoglobulin sequence repertoire, including that each B cell's genome encodes a distinct antibody sequence, that the antibody repertoire changes over time, and the high similarity between antibody sequences. We have addressed these challenges by using high-throughput long read sequencing to perform immunogenomic characterization of expressed human antibody repertoires in the context of influenza vaccination. Informatic analysis of 5 million antibody heavy chain sequences from healthy individuals allowed us to perform global characterizations of isotype distributions, determine the lineage structure of the repertoire, and measure age- and antigen-related mutational activity. Our analysis of the clonal structure and mutational distribution of individuals' repertoires shows that elderly subjects have a decreased number of lineages but an increased prevaccination mutation load in their repertoire and that some of these subjects have an oligoclonal character to their repertoire in which the diversity of the lineages is greatly reduced relative to younger subjects. We have thus shown that global analysis of the immune system's clonal structure provides direct insight into the effects of vaccination and provides a detailed molecular portrait of age-related effects.

    View details for DOI 10.1126/scitranslmed.3004794

    View details for PubMedID 23390249

  • Lineage Structure of the Human Antibody Repertoire in Response to Influenza Vaccination SCIENCE TRANSLATIONAL MEDICINE Jiang, N., He, J., Weinstein, J. A., Penland, L., Sasaki, S., He, X., Dekker, C. L., Zheng, N., Huang, M., Sullivan, M., Wilson, P. C., Greenberg, H. B., Davis, M. M., Fisher, D. S., Quake, S. R. 2013; 5 (171)

    Abstract

    The human antibody repertoire is one of the most important defenses against infectious disease, and the development of vaccines has enabled the conferral of targeted protection to specific pathogens. However, there are many challenges to measuring and analyzing the immunoglobulin sequence repertoire, including that each B cell's genome encodes a distinct antibody sequence, that the antibody repertoire changes over time, and the high similarity between antibody sequences. We have addressed these challenges by using high-throughput long read sequencing to perform immunogenomic characterization of expressed human antibody repertoires in the context of influenza vaccination. Informatic analysis of 5 million antibody heavy chain sequences from healthy individuals allowed us to perform global characterizations of isotype distributions, determine the lineage structure of the repertoire, and measure age- and antigen-related mutational activity. Our analysis of the clonal structure and mutational distribution of individuals' repertoires shows that elderly subjects have a decreased number of lineages but an increased prevaccination mutation load in their repertoire and that some of these subjects have an oligoclonal character to their repertoire in which the diversity of the lineages is greatly reduced relative to younger subjects. We have thus shown that global analysis of the immune system's clonal structure provides direct insight into the effects of vaccination and provides a detailed molecular portrait of age-related effects.

    View details for Web of Science ID 000314810000008

    View details for PubMedID 23390249

  • Genetic Diversity and the Structure of Genealogies in Rapidly Adapting Populations GENETICS Desai, M. M., Walczak, A. M., Fisher, D. S. 2013; 193 (2): 565-585

    Abstract

    Positive selection distorts the structure of genealogies and hence alters patterns of genetic variation within a population. Most analyses of these distortions focus on the signatures of hitchhiking due to hard or soft selective sweeps at a single genetic locus. However, in linked regions of rapidly adapting genomes, multiple beneficial mutations at different loci can segregate simultaneously within the population, an effect known as clonal interference. This leads to a subtle interplay between hitchhiking and interference effects, which leads to a unique signature of rapid adaptation on genetic variation both at the selected sites and at linked neutral loci. Here, we introduce an effective coalescent theory (a "fitness-class coalescent") that describes how positive selection at many perfectly linked sites alters the structure of genealogies. We use this theory to calculate several simple statistics describing genetic variation within a rapidly adapting population and to implement efficient backward-time coalescent simulations, which can be used to predict how clonal interference alters the expected patterns of molecular evolution.

    View details for DOI 10.1534/genetics.112.147157

    View details for Web of Science ID 000314821300020

    View details for PubMedID 23222656

    View details for PubMedCentralID PMC3567745

  • Evolutionary dynamics and statistical physics JOURNAL OF STATISTICAL MECHANICS-THEORY AND EXPERIMENT Fisher, D., Laessig, M., Shraiman, B. 2013
  • Asexual evolution waves: fluctuations and universality JOURNAL OF STATISTICAL MECHANICS-THEORY AND EXPERIMENT Fisher, D. S. 2013
  • Denoising PCR-amplified metagenome data BMC BIOINFORMATICS Rosen, M. J., Callahan, B. J., Fisher, D. S., Holmes, S. P. 2012; 13

    Abstract

    PCR amplification and high-throughput sequencing theoretically enable the characterization of the finest-scale diversity in natural microbial and viral populations, but each of these methods introduces random errors that are difficult to distinguish from genuine biological diversity. Several approaches have been proposed to denoise these data but lack either speed or accuracy.We introduce a new denoising algorithm that we call DADA (Divisive Amplicon Denoising Algorithm). Without training data, DADA infers both the sample genotypes and error parameters that produced a metagenome data set. We demonstrate performance on control data sequenced on Roche's 454 platform, and compare the results to the most accurate denoising software currently available, AmpliconNoise.DADA is more accurate and over an order of magnitude faster than AmpliconNoise. It eliminates the need for training data to establish error parameters, fully utilizes sequence-abundance information, and enables inclusion of context-dependent PCR error rates. It should be readily extensible to other sequencing platforms such as Illumina.

    View details for DOI 10.1186/1471-2105-13-283

    View details for Web of Science ID 000314687600001

    View details for PubMedID 23113967

    View details for PubMedCentralID PMC3563472

  • The Balance Between Mutators and Nonmutators in Asexual Populations GENETICS Desai, M. M., Fisher, D. S. 2011; 188 (4): 997-1014

    Abstract

    Mutator alleles, which elevate an individual's mutation rate from 10 to 10,000-fold, have been found at high frequencies in many natural and experimental populations. Mutators are continually produced from nonmutators, often due to mutations in mismatch-repair genes. These mutators gradually accumulate deleterious mutations, limiting their spread. However, they can occasionally hitchhike to high frequencies with beneficial mutations. We study the interplay between these effects. We first analyze the dynamics of the balance between the production of mutator alleles and their elimination due to deleterious mutations. We find that when deleterious mutation rates are high in mutators, there will often be many "young," recently produced mutators in the population, and the fact that deleterious mutations only gradually eliminate individuals from a population is important. We then consider how this mutator-nonmutator balance can be disrupted by beneficial mutations and analyze the circumstances in which fixation of mutator alleles is likely. We find that dynamics is crucial: even in situations where selection on average acts against mutators, so they cannot stably invade, the mutators can still occasionally generate beneficial mutations and hence be important to the evolution of the population.

    View details for DOI 10.1534/genetics.111.128116

    View details for Web of Science ID 000293700000020

    View details for PubMedID 21652523

    View details for PubMedCentralID PMC3176104

  • Determinism and stochasticity during maturation of the zebrafish antibody repertoire PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Jiang, N., Weinstein, J. A., Penland, L., White, R. A., Fisher, D. S., Quake, S. R. 2011; 108 (13): 5348-5353

    Abstract

    It is thought that the adaptive immune system of immature organisms follows a more deterministic program of antibody creation than is found in adults. We used high-throughput sequencing to characterize the diversifying antibody repertoire in zebrafish over five developmental time points. We found that the immune system begins in a highly stereotyped state with preferential use of a small number of V (variable) D (diverse) J (joining) gene segment combinations, but that this stereotypy decreases dramatically as the zebrafish mature, with many of the top VDJ combinations observed in 2-wk-old zebrafish virtually disappearing by 1 mo. However, we discovered that, in the primary repertoire, there are strong correlations in VDJ use that increase with zebrafish maturity, suggesting that VDJ recombination involves a level of deterministic programming that is unexpected. This stereotypy is masked by the complex diversification processes of antibody maturation; the variation and lack of correlation in full repertoires between individuals appears to be derived from randomness in clonal expansion during the affinity maturation process. These data provide a window into the mechanisms of VDJ recombination and diversity creation and allow us to better understand how the adaptive immune system achieves diversity.

    View details for DOI 10.1073/pnas.1014277108

    View details for Web of Science ID 000288894800043

    View details for PubMedID 21393572

    View details for PubMedCentralID PMC3069157

  • Leading the dog of selection by its mutational nose PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Fisher, D. S. 2011; 108 (7): 2633-2634

    View details for DOI 10.1073/pnas.1100339108

    View details for Web of Science ID 000287377000004

    View details for PubMedID 21289281

    View details for PubMedCentralID PMC3041133

  • The Rate of Fitness-Valley Crossing in Sexual Populations GENETICS Weissman, D. B., Feldman, M. W., Fisher, D. S. 2010; 186 (4): 1389-1410

    Abstract

    Biological traits result in part from interactions between different genetic loci. This can lead to sign epistasis, in which a beneficial adaptation involves a combination of individually deleterious or neutral mutations; in this case, a population must cross a "fitness valley" to adapt. Recombination can assist this process by combining mutations from different individuals or retard it by breaking up the adaptive combination. Here, we analyze the simplest fitness valley, in which an adaptation requires one mutation at each of two loci to provide a fitness benefit. We present a theoretical analysis of the effect of recombination on the valley-crossing process across the full spectrum of possible parameter regimes. We find that low recombination rates can speed up valley crossing relative to the asexual case, while higher recombination rates slow down valley crossing, with the transition between the two regimes occurring when the recombination rate between the loci is approximately equal to the selective advantage provided by the adaptation. In large populations, if the recombination rate is high and selection against single mutants is substantial, the time to cross the valley grows exponentially with population size, effectively meaning that the population cannot acquire the adaptation. Recombination at the optimal (low) rate can reduce the valley-crossing time by up to several orders of magnitude relative to that in an asexual population.

    View details for DOI 10.1534/genetics.110.123240

    View details for Web of Science ID 000285297000025

    View details for PubMedID 20923976

    View details for PubMedCentralID PMC2998319

  • Rate of Adaptation in Large Sexual Populations GENETICS Neher, R. A., Shraiman, B. I., Fisher, D. S. 2010; 184 (2): 467-481

    Abstract

    Adaptation often involves the acquisition of a large number of genomic changes that arise as mutations in single individuals. In asexual populations, combinations of mutations can fix only when they arise in the same lineage, but for populations in which genetic information is exchanged, beneficial mutations can arise in different individuals and be combined later. In large populations, when the product of the population size N and the total beneficial mutation rate U(b) is large, many new beneficial alleles can be segregating in the population simultaneously. We calculate the rate of adaptation, v, in several models of such sexual populations and show that v is linear in NU(b) only in sufficiently small populations. In large populations, v increases much more slowly as log NU(b). The prefactor of this logarithm, however, increases as the square of the recombination rate. This acceleration of adaptation by recombination implies a strong evolutionary advantage of sex.

    View details for DOI 10.1534/genetics.109.109009

    View details for Web of Science ID 000281884500014

    View details for PubMedID 19948891

  • The rate at which asexual populations cross fitness valleys THEORETICAL POPULATION BIOLOGY Weissman, D. B., Desai, M. M., Fisher, D. S., Feldman, M. W. 2009; 75 (4): 286-300

    Abstract

    Complex traits often involve interactions between different genetic loci. This can lead to sign epistasis, whereby mutations that are individually deleterious or neutral combine to confer a fitness benefit. In order to acquire the beneficial genotype, an asexual population must cross a fitness valley or plateau by first acquiring the deleterious or neutral intermediates. Here, we present a complete, intuitive theoretical description of the valley-crossing process across the full spectrum of possible parameter regimes. We calculate the rate at which a population crosses a fitness valley or plateau of arbitrary width, as a function of the mutation rates, the population size, and the fitnesses of the intermediates. We find that when intermediates are close to neutral, a large population can cross even wide fitness valleys remarkably quickly, so that valley-crossing dynamics may be common even when mutations that directly increase fitness are also possible. Thus the evolutionary dynamics of large populations can be sensitive to the structure of an extended region of the fitness landscape - the population may not take directly uphill paths in favor of paths across valleys and plateaus that lead eventually to fitter genotypes. In smaller populations, we find that below a threshold size, which depends on the width of the fitness valley and the strength of selection against intermediate genotypes, valley-crossing is much less likely and hence the evolutionary dynamics are less influenced by distant regions of the fitness landscape.

    View details for DOI 10.1016/j.tpb.2009.02.006

    View details for Web of Science ID 000266833500009

    View details for PubMedID 19285994

    View details for PubMedCentralID PMC2992471

  • High-Throughput Sequencing of the Zebrafish Antibody Repertoire SCIENCE Weinstein, J. A., Jiang, N., White, R. A., Fisher, D. S., Quake, S. R. 2009; 324 (5928): 807-810

    Abstract

    Despite tremendous progress in understanding the nature of the immune system, the full diversity of an organism's antibody repertoire is unknown. We used high-throughput sequencing of the variable domain of the antibody heavy chain from 14 zebrafish to analyze VDJ usage and antibody sequence. Zebrafish were found to use between 50 and 86% of all possible VDJ combinations and shared a similar frequency distribution, with some correlation of VDJ patterns between individuals. Zebrafish antibodies retained a few thousand unique heavy chains that also exhibited a shared frequency distribution. We found evidence of convergence, in which different individuals made the same antibody. This approach provides insight into the breadth of the expressed antibody repertoire and immunological diversity at the level of an individual organism.

    View details for DOI 10.1126/science.1170020

    View details for Web of Science ID 000265832400053

    View details for PubMedID 19423829

    View details for PubMedCentralID PMC3086368

  • Ordered phosphorylation governs oscillation of a three-protein circadian clock SCIENCE Rust, M. J., Markson, J. S., Lane, W. S., Fisher, D. S., O'Shea, E. K. 2007; 318 (5851): 809-812

    Abstract

    The simple circadian oscillator found in cyanobacteria can be reconstituted in vitro using three proteins-KaiA, KaiB, and KaiC. The total phosphorylation level of KaiC oscillates with a circadian period, but the mechanism underlying its sustained oscillation remains unclear. We have shown that four forms of KaiC differing in their phosphorylation state appear in an ordered pattern arising from the intrinsic autokinase and autophosphatase rates of KaiC and their modulation by KaiA. Kinetic and biochemical data indicate that one of these phosphoforms inhibits the activity of KaiA through interaction with KaiB, providing the crucial feedback that sustains oscillation. A mathematical model constrained by experimental data quantitatively reproduces the circadian period and the distinctive dynamics of the four phosphoforms.

    View details for DOI 10.1126/science.1148596

    View details for Web of Science ID 000250583900044

    View details for PubMedID 17916691

    View details for PubMedCentralID PMC2427396