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

2017-18 Courses


Stanford Advisees


Graduate and Fellowship Programs


All Publications


  • 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
  • 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

    View details for DOI 10.1111/evo.12512

    View details for Web of Science ID 000344379800018

  • 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)

    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

  • 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

  • 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

  • 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

  • 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