Michael Lynch

Indiana University Bloomington, Bloomington, Indiana, United States

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Publications (178)1519.49 Total impact

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    ABSTRACT: Despite the general assumption that site-specific mutation rates are independent of the local sequence context, a growing body of evidence suggests otherwise. To further examine context-dependent patterns of mutation, we amassed 5645 spontaneous mutations in wild-type and mismatch-repair deficient mutation accumulation lines of the gram-positive model organism Bacillus subtilis. We then analysed > 7500 spontaneous base-substitution mutations across Bacillus subtilis, Escherichia coli, and Mesoplasma florum wild-type and mismatch-repair deficient mutation-accumulation lines, finding a context-dependent mutation pattern that is asymmetric around the origin of replication. Different neighbouring nucleotides can alter site-specific mutation rates by as much as 75-fold, with sites neighbouring G:C base pairs or dimers involving alternating pyrimidine-purine and purine-pyrimidine nucleotides having significantly elevated mutation rates. The influence of context-dependent mutation on genome architecture is strongest in M. florum, consistent with the reduced efficiency of selection in organisms with low effective population size. If not properly accounted for, the disparities arising from patterns of context-dependent mutation can significantly influence interpretations of positive and purifying selection. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution 2015. This work is written by US Government employees and is in the public domain in the US.
    Molecular Biology and Evolution 03/2015; DOI:10.1093/molbev/msv055 · 14.31 Impact Factor
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    ABSTRACT: High levels of genetic diversity exist among natural isolates of the bacterium Pseudomonas fluorescens, and are especially elevated around the replication terminus of the genome, where strain-specific genes are found. In an effort to understand the role of genetic variation in the evolution of Pseudomonas, we analyzed 31,106 base substitutions from 45 mutation accumulation lines of P. fluorescens ATCC948, naturally deficient for mismatch repair, yielding a base-substitution mutation rate of 2.34 × 10(-8) per site per generation (SE: 0.01 × 10(-8)) and a small-insertion-deletion mutation rate of 1.65 × 10(-9) per site per generation (SE: 0.03 × 10(-9)). We find that the spectrum of mutations in prophage regions, which often contain virulence factors and antibiotic resistance, is highly similar to that in the intergenic regions of the host genome. Our results show that the mutation rate varies around the chromosome, with the lowest mutation rate found near the origin of replication. Consistent with observations from other studies, we find that site-specific mutation rates are heavily influenced by the immediately flanking nucleotides, indicating that mutations are context dependent. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.
    Genome Biology and Evolution 12/2014; 7(1). DOI:10.1093/gbe/evu284 · 4.53 Impact Factor
  • Michael Lynch, Kyle Hagner
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    ABSTRACT: Many cellular functions depend on highly specific intermolecular interactions, for example transcription factors and their DNA binding sites, microRNAs and their RNA binding sites, the interfaces between heterodimeric protein molecules, the stems in RNA molecules, and kinases and their response regulators in signal-transduction systems. Despite the need for complementarity between interacting partners, such pairwise systems seem to be capable of high levels of evolutionary divergence, even when subject to strong selection. Such behavior is a consequence of the diminishing advantages of increasing binding affinity between partners, the multiplicity of evolutionary pathways between selectively equivalent alternatives, and the stochastic nature of evolutionary processes. Because mutation pressure toward reduced affinity conflicts with selective pressure for greater interaction, situations can arise in which the expected distribution of the degree of matching between interacting partners is bimodal, even in the face of constant selection. Although biomolecules with larger numbers of interacting partners are subject to increased levels of evolutionary conservation, their more numerous partners need not converge on a single sequence motif or be increasingly constrained in more complex systems. These results suggest that most phylogenetic differences in the sequences of binding interfaces are not the result of adaptive fine tuning but a simple consequence of random genetic drift.
    Proceedings of the National Academy of Sciences 12/2014; 112(1). DOI:10.1073/pnas.1421641112 · 9.81 Impact Factor
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    ABSTRACT: The origin of the nucleus at the prokaryote-to-eukaryote transition represents one of the most important events in the evolution of cellular organization. The nuclear envelope encircles the chromosomes in interphase and is a selectively permeable barrier between the nucleoplasm and cytoplasm and an organizational scaffold for the nucleus. It remains intact in the ‘closed’ mitosis of some yeasts, but loses its integrity in the ‘open’ mitosis of mammals. Instances of both types of mitosis within two evolutionary clades indicate multiple evolutionary transitions between open and closed mitosis, although the underlying genetic changes that influenced these transitions remain unknown. A survey of the diversity of mitotic nuclei that fall between these extremes is the starting point from which to determine the physiologically relevant characteristics distinguishing open from closed mitosis and to understand how they evolved and why they are retained in present-day organisms. The field is now poised to begin addressing these issues by defining and documenting patterns of mitotic nuclear variation within and among species and mapping them onto a phylogenic tree. Deciphering the evolutionary history of open and closed mitosis will complement cell biological and genetic approaches aimed at deciphering the fundamental organizational principles of the nucleus.
    Current Biology 11/2014; 24. DOI:10.1016/j.cub.2014.10.011 · 9.92 Impact Factor
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    ABSTRACT: All aspects of biological diversification ultimately trace to evolutionary modifications at the cellular level. This central role of cells frames the basic questions as to how cells work and how cells come to be the way they are. Although these two lines of inquiry lie respectively within the traditional provenance of cell biology and evolutionary biology, a comprehensive synthesis of evolutionary and cell-biological thinking is lacking. We define evolutionary cell biology as the fusion of these two eponymous fields with the theoretical and quantitative branches of biochemistry, biophysics, and population genetics. The key goals are to develop a mechanistic understanding of general evolutionary processes, while specifically infusing cell biology with an evolutionary perspective. The full development of this interdisciplinary field has the potential to solve numerous problems in diverse areas of biology, including the degree to which selection, effectively neutral processes, historical contingencies, and/or constraints at the chemical and biophysical levels dictate patterns of variation for intracellular features. These problems can now be examined at both the within- and among-species levels, with single-cell methodologies even allowing quantification of variation within genotypes. Some results from this emerging field have already had a substantial impact on cell biology, and future findings will significantly influence applications in agriculture, medicine, environmental science, and synthetic biology.
    Proceedings of the National Academy of Sciences 11/2014; DOI:10.1073/pnas.1415861111 · 9.81 Impact Factor
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    ABSTRACT: As one of the few known species in an active phase of intron proliferation, the microcrustacean Daphnia pulex is an especially attractive system for interrogating the gain and loss of introns in natural populations. In this study, we used a comparative population-genomic approach to identify and characterize 90 recently gained introns in this species. Molecular clock analyses indicate that these introns arose between 3.9 x 10(5) and 1.45 x 10(4) years ago, with a spike in intron proliferation approximately 5.2 × 10(4) to 1.22 × 10(5) years ago. Parallel gains at homologous positions contribute 47.8% (43/90) of discovered new introns. A disproportionally large number of new introns were found in historically isolated populations in Oregon. Nonetheless, derived, intron-bearing alleles were also identified in a wide range of geographic locations, suggesting intron gain and, to a lesser degree, intron loss, are important sources of genetic variation in natural populations of Daphnia. A majority (55/90 or 61.1%) of the identified neo-introns have associated internal direct repeats with lengths and compositions that are unlikely to occur by chance, suggesting repeated bouts of staggered-DSBs during their evolution. Accordingly, internal, staggered-DSBs may contribute to a passive trend towards increased length and sequence diversity in nascent introns.
    Genome Biology and Evolution 08/2014; DOI:10.1093/gbe/evu174 · 4.53 Impact Factor
  • Takahiro Maruki, Michael Lynch
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    ABSTRACT: Rapidly improving sequencing technologies provide unprecedented opportunities for analyzing genome-wide patterns of polymorphisms. In particular, they have great potential for linkage-disequilibrium analyses on both global and local genetic scales, which will substantially improve our ability to derive evolutionary inferences. However, there are some difficulties with analyzing high-throughput sequencing data, including high error rates associated with base reads and complications from the random sampling of sequenced chromosomes in diploid organisms. To overcome these difficulties, we developed a maximum-likelihood estimator of linkage disequilibrium for use with error-prone sampling data. Computer simulations indicate that the estimator is nearly unbiased with a sampling variance at high coverage asymptotically approaching the value expected when all relevant information is accurately estimated. The estimator does not require phasing of haplotypes and enables the estimation of linkage disequilibrium even when all individual reads cover just single polymorphic sites.
    Genetics 08/2014; 197(4):1303-1313. DOI:10.1534/genetics.114.165514 · 4.87 Impact Factor
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    ABSTRACT: The Paramecium aurelia complex is a group of 15 species that share at least three past whole-genome duplications (WGDs). The macronuclear genome sequences of P. biaurelia and P. sexaurelia are presented and compared to the published sequence of P. tetraurelia. Levels of duplicate-gene retention from the recent WGD differ by >10% across species, with P. sexaurelia losing significantly more genes than P. biaurelia or P. tetraurelia. In addition, historically high rates of gene conversion have homogenized WGD paralogs, probably extending paralogs lifetime. The probability of duplicate retention is positively correlated with GC content and expression level; ribosomal proteins, transcription factors, and intracellular signaling proteins are overrepresented among maintained duplicates. Finally, multiple sources of evidence indicate that P. sexaurelia diverged from the two other lineages immediately following, or perhaps concurrent with, the recent WGD, with approximately half of gene losses between P. tetraurelia and P. sexaurelia representing divergent gene resolutions (i.e., silencing of alternative paralogs), as expected for random duplicate loss between these species. Additionally, though P. biaurelia and P. tetraurelia diverged from each other much later, there are still over 100 cases of divergent resolution between these two species. Taken together, these results indicate that divergent resolution of duplicate genes between lineages acts to reinforce reproductive isolation between species in the Paramecium aurelia complex.
    Genome Research 08/2014; 24(10). DOI:10.1101/gr.173740.114 · 13.85 Impact Factor
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    ABSTRACT: Although the analysis of linkage disequilibrium (LD) plays a central role in many areas of population genetics, the sampling variance of LD is known to be very large with high sensitivity to numbers of nucleotide sites and individuals sampled. Here we show that a genome-wide analysis of the distribution of heterozygous sites within a single diploid genome can yield highly informative patterns of LD as a function of physical distance. The proposed statistic, the correlation of zygosity, is closely related to the conventional population-level measure of LD, but is agnostic with respect to allele frequencies and hence likely less prone to outlier artifacts. Application of the method to several vertebrate species leads to the conclusion that > 80% of recombination events are typically resolved by gene-conversion-like processes unaccompanied by crossovers, with the average lengths of conversion patches being on the order of one to several kilobases in length. Thus, contrary to common assumptions, the recombination rate between sites does not scale linearly with distance, often even up to distances of 100 kilobases. In addition, the amount of LD between sites separated by < 200 bp is uniformly much greater than can be explained by the conventional neutral model, possibly because of the nonindependent origin of mutations within this spatial scale. These results raise questions about the application of conventional population-genetic interpretations to LD on short spatial scales, and also about the use of spatial patterns of LD to infer demographic histories.
    Genetics 06/2014; 198(1). DOI:10.1534/genetics.114.166843 · 4.87 Impact Factor
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    ABSTRACT: Paramecium has long been a model eukaryote. The sequence of the Paramecium tetraurelia genome reveals a history of three successive whole-genome duplications (WGDs), and the sequence of Paramecium biaurelia and Paramecium sexaurelia suggests that these WGDs are shared by all members of the aurelia species complex. Here, we present the genome sequence of Paramecium caudatum, a species closely related to the Paramecium aurelia species group. P. caudatum shares only the most ancient of the three WGDs with the aurelia complex. We found that P. caudatum maintains twice as many paralogs from this early event as the P. aurelia species, suggesting that post-WGD gene retention is influenced by subsequent WGDs, and supporting the importance of selection for dosage in gene retention. The availability of P. caudatum as an outgroup allows an expanded analysis of the aurelia intermediate and recent WGD events. Both the GC content and the expression level of pre-duplication genes are significant predictors of duplicate retention. We find widespread asymmetrical evolution among aurelia paralogs, which is likely caused by gradual pseudogenization rather than by neofunctionalization. Finally, cases of divergent resolution of intermediate WGD duplicates between aurelia species implicate this process acts as an on-going reinforcement mechanism of reproductive isolation long after a WGD event.
    Genetics 05/2014; 197(4). DOI:10.1534/genetics.114.163287 · 4.87 Impact Factor
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    ABSTRACT: Although pooled-population sequencing has become a widely used approach for estimating allele frequencies, most work has proceeded in the absence of a proper statistical framework. We introduce a self-sufficient, closed-form, maximum-likelihood estimator for allele frequencies that accounts for errors associated with sequencing, and a likelihood-ratio test statistic that provides a simple means for evaluating the null hypothesis of monomorphism. Unbiased estimates of allele frequencies < 5/N (where N is the number of individuals sampled) appear to be unachievable, and near-certain identification of a polymorphism requires a minor-allele frequency > 10/N. A framework is provided for testing for significant differences in allele frequencies between populations, taking into account sampling at the levels of individuals within populations and sequences within pooled samples. Analyses that fail to account for the two tiers of sampling suffer from very large false-positive rates, and can become increasingly misleading with increasing depths of sequence coverage. The power to detect significant allele-frequency differences between two populations is very limited unless both the number of sampled individuals and depth of sequencing coverage exceed 100.
    Genome Biology and Evolution 04/2014; DOI:10.1093/gbe/evu085 · 4.53 Impact Factor
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    ABSTRACT: We present the complete genomic sequence of the essential symbiont Polynucleobacter necessarius (Betaproteobacteria), which is a valuable case study for several reasons. First, it is hosted by a ciliated protist, Euplotes; bacterial symbionts of ciliates are still poorly known because of a lack of extensive molecular data. Second, the single species P. necessarius contains both symbiotic and free-living strains, allowing for a comparison between closely related organisms with different ecologies. Third, free-living P. necessarius strains are exceptional by themselves because of their small genome size, reduced metabolic flexibility, and high worldwide abundance in freshwater systems. We provide a comparative analysis of P. necessarius metabolism and explore the peculiar features of a genome reduction that occurred on an already streamlined genome. We compare this unusual system with current hypotheses for genome erosion in symbionts and free-living bacteria, propose modifications to the presently accepted model, and discuss the potential consequences of translesion DNA polymerase loss.
    Proceedings of the National Academy of Sciences 10/2013; DOI:10.1073/pnas.1316687110 · 9.81 Impact Factor
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    ABSTRACT: Accurate transmission and expression of genetic information are crucial for the survival of all living organisms. Recently, the coupling of mutation accumulation experiments and next-generation sequencing has greatly expanded our knowledge of the genomic mutation rate in both prokaryotes and eukaryotes. However, because of their transient nature, transcription errors have proven extremely difficult to quantify, and current estimates of transcription fidelity are derived from artificial constructs applied to just a few organisms. Here we report a unique cDNA library preparation technique that allows error detection in natural transcripts at the transcriptome-wide level. Application of this method to the model organism Caenorhabditis elegans revealed a base misincorporation rate in mRNAs of ∼4 × 10(-6) per site, with a very biased molecular spectrum. Because the proposed method is readily applicable to other organisms, this innovation provides unique opportunities for studying the incidence of transcription errors across the tree of life.
    Proceedings of the National Academy of Sciences 10/2013; DOI:10.1073/pnas.1309843110 · 9.81 Impact Factor
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    ABSTRACT: Despite much theoretical work, the molecular-genetic causes and evolutionary consequences of asexuality remain largely undetermined. Asexual animal species are rare, evolutionarily short-lived, and thought to suffer mutational meltdown as a result of lack of recombination. Whole-genome analysis of 11 sexual and 11 asexual genotypes of Daphnia pulex indicates that current asexual lineages are in fact very young, exhibit no signs of purifying selection against accumulating mutations, and have extremely high rates of gene conversion and deletion. The reconstruction of chromosomal haplotypes in regions containing SNP markers associated with asexuality (chromosomes VIII and IX) indicates that introgression from a sister species, Daphnia pulicaria, underlies the origin of the asexual phenotype. Silent-site divergence of the shared chromosomal haplotypes of asexuals indicates that the spread of asexuality is as recent as 1,250 y, although the origin of the meiosis-suppressing element or elements could be substantially older. In addition, using previous estimates of the gene conversion rate from Daphnia mutation accumulation lines, we are able to age each asexual lineage. Although asexual lineages originate from wide crosses that introduce elevated individual heterozygosities on clone foundation, they also appear to be constrained by the inbreeding-like effect of loss of heterozygosity that accrues as gene conversion and hemizygous deletion expose preexisting recessive deleterious alleles of asexuals, limiting their evolutionary longevity. Our study implies that the buildup of newly introduced deleterious mutations (i.e., Muller's ratchet) may not be the dominant force imperiling nonrecombining populations of D. pulex, as previously proposed.
    Proceedings of the National Academy of Sciences 08/2013; DOI:10.1073/pnas.1313388110 · 9.81 Impact Factor
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    ABSTRACT: The molecular mechanisms leading to asexuality remain little understood despite their substantial bearing on why sexual reproduction is dominant in nature. Here, we examine the role of hybridization in the origin and spread of obligate asexuality in Daphnia pulex, arguably the best-documented case of contagious asexuality. Obligately parthenogenetic (OP) clones of D. pulex have traditionally been separated into 'hybrid' (Ldh SF) and 'nonhybrid' (Ldh SS) forms because the lactase dehydrogenase (Ldh) locus distinguishes the cyclically parthenogenetic (CP) lake dwelling Daphnia pulicaria (Ldh FF) from its ephemeral pond dwelling sister species D. pulex (Ldh SS). The results of our population genetic analyses based on microsatellite loci suggest that both Ldh SS and SF OP individuals can originate from the crossing of CP female F1 (D. pulex × D. pulicaria) and backcross with males from OP lineages carrying genes that suppress meiosis specifically in female offspring. In previous studies, a suite of diagnostic markers was found to be associated with OP in Ldh SS D. pulex lineages. Our association mapping supports a similar genetic mechanism for the spread of obligate parthenogenesis in Ldh SF OP individuals. Interestingly, our study shows that CP D. pulicaria carry many of the diagnostic microsatellite alleles associated with obligate parthenogenesis. We argue that the assemblage of mutations that suppress meiosis and underlie obligate parthenogenesis in D. pulex originated due to a unique historical hybridization and introgression event between D. pulex and D. pulicaria.
    Molecular Ecology 07/2013; DOI:10.1111/mec.12407 · 5.84 Impact Factor

Publication Stats

17k Citations
1,519.49 Total Impact Points


  • 2001–2015
    • Indiana University Bloomington
      • Department of Biology
      Bloomington, Indiana, United States
  • 2013
    • University of Münster
      • Institute for Evolution and Biodiversity
      Münster, North Rhine-Westphalia, Germany
  • 2012
    • Reed College
      Portland, Oregon, United States
  • 2011
    • Yale University
      New Haven, Connecticut, United States
  • 2010
    • University of New Hampshire
      • Hubbard Center for Genome Studies
      Durham, New Hampshire, United States
    • Max Planck Institute for Developmental Biology
      • Department of Molecular Biology
      Tübingen, Baden-Württemberg, Germany
    • University of Texas at Arlington
      • Department of Biology
      Arlington, TX, United States
    • Max Planck Institute for Evolutionary Biology
      • Department of Evolutionary Genetics
      Plön, Schleswig-Holstein, Germany
  • 2008
    • University of Windsor
      • Great Lakes Institute for Environmental Research
      Windsor, Ontario, Canada
  • 2003–2008
    • The University of Edinburgh
      • • Institute of Evolutionary Biology
      • • Institute of Cell Biology
      Edinburgh, Scotland, United Kingdom
  • 2007
    • University of Leipzig
      • Institute of Biology
      Leipzig, Saxony, Germany
  • 2006
    • University of New Mexico
      • Department of Biology
      Albuquerque, New Mexico, United States
  • 2005
    • University of Florida
      Gainesville, Florida, United States
    • Benaroya Research Institute
      Seattle, Washington, United States
    • Georgia Institute of Technology
      Atlanta, Georgia, United States
  • 1990–2004
    • University of Oregon
      • • Center for Ecology and Evolutionary Biology
      • • Department of Biology
      Eugene, OR, United States
  • 2000
    • University of Miami
      • Department of Biology
      Coral Gables, FL, United States
    • National Center for Genome Resources
      Santa Fe, New Mexico, United States
  • 1999
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 1997
    • University of Vienna
      Wien, Vienna, Austria
  • 1989–1991
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States