Michael Lynch

Indiana University Bloomington, Bloomington, Indiana, United States

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Publications (186)1571.19 Total impact

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    ABSTRACT: Genetic linkage maps are critical for assembling draft genomes to a meaningful chromosome level and for deciphering the genomic underpinnings of biological traits. The estimates of recombination rates derived from genetic maps also play an important role in understanding multiple aspects of genomic evolution such as nucleotide substitution patterns and accumulation of deleterious mutations. In this study, we developed a high-throughput experimental approach that combines fluorescence-activated cell sorting, whole-genome amplification, and short-read sequencing to construct a genetic map using single sperm cells. Furthermore, a computational algorithm was developed to analyze single sperm whole-genome sequencing data for map construction. These methods allowed us to rapidly build a male-specific genetic map for the freshwater microcrustacean Daphnia pulex, which shows significant improvements compared to a previous map. With a total of mapped 1672 haplotype blocks and an average intermarker distance of 0.87 cM, this map spans a total genetic distance of 1451 Kosambi cM and comprises 90% of the resolved regions in the current Daphnia reference assembly. The map also reveals the mistaken mapping of seven scaffolds in the reference assembly onto chromosome II by a previous microsatellite map based on F2 crosses. Our approach can be easily applied to many other organisms and holds great promise for unveiling the intragenomic and intraspecific variation in the recombination rates. Copyright © 2015, The Genetics Society of America.
    Genetics 06/2015; DOI:10.1534/genetics.115.179028 · 4.87 Impact Factor
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    ABSTRACT: Deinococcus bacteria are extremely resistant to radiation, oxidation, and desiccation. Resilience to these factors has been suggested to be due to enhanced damage prevention and repair mechanisms, as well as highly efficient antioxidant protection systems. Here, using mutation-accumulation experiments we find that the GC-rich Deinococcus radiodurans has an overall background genomic mutation rate similar to that of E. coli, but differs in mutation spectrum, with the A/T to G/C mutation rate (based on a total count of 88 A:T→G:C transitions and 82 A:T→C:G transversions) per site per generation higher than that in the other direction (based on a total count of 157 G:C→A:T transitions and 33 G:C→T:A transversions). We propose that this unique spectrum is shaped mainly by the abundant uracil DNA glycosylases (UDG) reducing G:C→T:A transversions, adenine methylation elevating A:T→C:G transversions, and absence of cytosine methylation decreasing G:C→A:T transitions. As opposed to the >100× elevation of the mutation rate in MMR(-) strains of most other organisms, MMR(-) D. radiodurans only exhibits a four-fold elevation, raising the possibility that other DNA repair mechanisms compensate for a relatively low-efficiency DNA mismatch repair pathway. Since D. radiodurans has plentiful insertion sequence (IS) elements in the genome and the activities of IS elements are rarely directly explored, we also estimated the insertion (transposition) rate of the IS elements to be 2.50 × 10(-3) per genome per generation in the wild-type strain; knocking out MMR did not elevate the IS element insertion rate in this organism. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Molecular Biology and Evolution 05/2015; DOI:10.1093/molbev/msv119 · 14.31 Impact Factor
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    ABSTRACT: Spontaneous mutations are ultimately essential for evolutionary change and are also the root cause of many diseases. However, until recently, both biological and technical barriers have prevented detailed analyses of mutation profiles, constraining our understanding of the mutation process to a few model organisms and leaving major gaps in our understanding of the role of genome content and structure on mutation. Here, we present a genome-wide view of the molecular mutation spectrum in Burkholderia cenocepacia, a clinically relevant pathogen with high %GC-content and multiple chromosomes. We find that B. cenocepacia has low genome-wide mutation rates with insertion-deletion mutations biased towards deletions, consistent with the idea that deletion pressure reduces prokaryotic genome sizes. Unlike prior studies of other organisms, mutations in B. cenocepacia are not AT-biased, which suggests that at least some genomes with high %GC-content experience unusual base-substitution mutation pressure. Importantly, we also observe variation in both the rates and spectra of mutations among chromosomes and elevated G:C>T:A transversions in late-replicating regions. Thus, although some patterns of mutation appear to be highly conserved across cellular life, others vary between species and even between chromosomes of the same species, potentially influencing the evolution of nucleotide composition and genome architecture. Copyright © 2015, The Genetics Society of America.
    Genetics 05/2015; DOI:10.1534/genetics.115.176834 · 4.87 Impact Factor
  • Jean-Francois Gout, Michael Lynch
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    ABSTRACT: Whole-Genome Duplications (WGDs) have contributed to gene-repertoire enrichment in many eukaryotic lineages. However, most duplicated genes are eventually lost and it is still unclear why some duplicated genes are evolutionary successful while others quickly turn to pseudogenes. Here, we show that dosage constraints are major factors opposing post-WGD gene loss in several Paramecium species that share a common ancestral WGD. We propose a model where a majority of WGD-derived duplicates preserve their ancestral function and are retained to produce enough of the proteins performing this same ancestral function. Under this model, the expression level of individual duplicated genes can evolve neutrally as long as they maintain a roughly constant summed expression, and this allows random genetic drift towards uneven contributions of the two copies to total expression. Our analysis suggests that once a high level of imbalance is reached, which can require substantial lengths of time, the copy with the lowest expression level contributes a small enough fraction of the total expression that selection no longer opposes its loss. Extension of our analysis to yeast species sharing a common ancestral WGD yields similar results, suggesting that duplicated-gene retention for dosage constraints followed by divergence in expression level and eventual deterministic gene loss might be a universal feature of post-WGD evolution. © The Author 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Molecular Biology and Evolution 04/2015; DOI:10.1093/molbev/msv095 · 14.31 Impact Factor
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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(22). 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; 111(48). 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; 6(9). 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; 6(5). DOI:10.1093/gbe/evu085 · 4.53 Impact Factor

Publication Stats

17k Citations
1,571.19 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
  • 2008
    • The University of Edinburgh
      • Institute of Evolutionary Biology
      Edinburgh, Scotland, United Kingdom
    • University of Windsor
      • Great Lakes Institute for Environmental Research
      Windsor, Ontario, Canada
    • Saint Petersburg State University
      • Faculty of Biology and Soil Science
      Sankt-Peterburg, St.-Petersburg, Russia
  • 2007
    • University of Leipzig
      • Institute of Biology
      Leipzig, Saxony, Germany
  • 2006
    • University of New Mexico
      • Department of Biology
      Albuquerque, New Mexico, United States
  • 2005
    • Georgia Institute of Technology
      Atlanta, Georgia, United States
  • 1992–2004
    • University of Oregon
      • • Center for Ecology and Evolutionary Biology
      • • Department of Biology
      Eugene, OR, United States
  • 2000
    • National Center for Genome Resources
      Santa Fe, New Mexico, United States
  • 1999
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 1995–1997
    • University of Vienna
      Wien, Vienna, Austria
  • 1989–1991
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States