Faculty & Research
Center for Genomics & Bioinformatics
Daphnia Genomics Consortium
Indiana Molecular Biology Institute
School of Informatics
- Contact Information
- Contact Michael Lynch by milynch [at] indiana [dot] edu
- By telephone: 812-855-7384/6-0115(lab)
- JH 324C / JH 327 (lab)
- Evolution, Ecology & Behavior
- Research Areas
- Chromatin, Chromosomes, and Genome Integrity
- Eukaryotic Cell Biology, Cytoskeleton and Signaling
- Genomics and Bioinformatics
Ph.D., University of Minnesota, 1977
Member, US National Academy of Sciences, 2009
Fellow, American Academy of Arts and Sciences, 2002
Our research is focused on mechanisms of evolution at the gene, genomic, cellular, and phenotypic levels, with special attention being given to the roles of mutation, random genetic drift, and recombination. For these purposes, we are currently utilizing several model systems, the microcrustacean Daphnia, the nematode Caenorhabditis, the ciliate Paramecium and its bacterial endosymbionts, the unicellular alga Chlamydomonas, the diatom Phaeodactylum, and numerous bacterial species. In addition, comparative analyses of completely sequenced genomes are being performed to shed light on issues concerning the origins of genomic and gene-structural complexity. Most of our empirical work is integrated with the development and use of mathematical theory in an effort to develop a formal understanding of the constraints on the evolutionary process. Evolution is a population-level process, and the underlying philosophy of our research is that "nothing in evolution makes sense except in the light of population genetics."
The Evolution of Genome Complexity. Despite the common view that a causal link exists between complexity at the genomic and organismal levels, little thought has gone into the mechanisms that are responsible for the origin of the fundamental features of the eukaryotic genome. Using population-genetic principles as a guide to understanding the evolution of duplicate genes, introns, mobile-genetic elements, and regulatory-region complexity, our work is advancing the hypothesis that much of eukaryotic genome complexity initially evolved as a passive indirect response to reduced population size (relative to the situation in prokaryotes). One of the primary goals of our work on gene duplication is to explain the shortcomings of the classical model, which postulates that the usual fate of a duplicated genes is either conversion to a nonfunctional pseudogene or acquisition of a new function. We believe that duplicate genes are frequently preserved through a partitioning of functions of ancestral genes (subfunctionalization), rather than by the evolution of new functions.
Our empirical work on the evolutionary fates of duplicate genes is now focused on the genomes of species within the Paramecium aurelia complex, which arose as a cryptic species raidation following an ancient polyploidization event. Sequencing the complete genomes of the members of this lineage is revealing the degree to which specific members of duplicate-gene pairs are lost/preserved in parallel or divergently resolved in sister taxa, and work on subcellular localization is helping reveal the functional fates of duplicates.
Our work on intron evolution is focused on the hypothesis that newly arisen introns are typically mildly deleterious. A major goal is to understand how introns eventually came to be integrated into fundamental aspects of gene-transcript processing. Empirical work in this area is being pursued with populations of Daphnia, which have revealed an unprecedented level of intron gain (to the extent that presence/absence polymorphisms, as well as parallel intron gains, can be found within populations). We hope that this work will eventually yield an answer to the long-term mystery as to the origins of introns.
As an initial foray into microbial evolution, we are studying the evolution of a unique series of endosymbiotic bacterial species inhabiting Paramecium. Known as “killer” bacteria because of their effects on non-killer bearing Paramecium, these microbes are providing us with a novel perspective on the consequences of a reduction in global effective population size on the evolution of genomic architecture in prokayotes. Complete-genome sequencing of several strains has revealed an enormous proliferation of mobile-genetic elements in some lineages, and gene inventories indicate that many biosynthetic pathways have been lost. Future work will focus on the mechanisms that result in the killing properties of the bacteria (which have apparently evolved independently numerous times), and the mechanisms by which the ciliate host cells develop immunity. Current work suggests that some of these bacterial species can be grown outside of their host cells, which will greatly facilitate future functional work.
Finally, to empirically determine the response of genomes to alterations in population effective sizes and mutation rates, we have initiated long-term experiments with highly replicated populations of the bacterium Escherichia coli. Some of the goals of this experiment include testing the mutational-hazard theory of genome evolution, ascertaining the degree to which the pathways taken by evolution are repeatable, understanding how the mutation rate evolves in different population-genetic environments, and determining whether population bottlenecks induce heritable problems in protein folding and challenges for chaperone systems.
The Role of Mutation in Evolution. Although mutations provide the ultimate material upon which natural selection depends, most mutations are deleterious, and in certain settings can lead to a substantial fitness load. We are attempting to quantify rates and phenotypic effects of mutations, with an ultimate goal of evaluating their contribution to both adaptive progress and extinction risk. This work exploits a mutation-accumulation strategy in which lines are propagated as single individuals to minimize the ability of natural selection to influence the fate of newly arisen mutations. Our long-term lines of Daphnia, C. elegans, Paramecium, and Chlamydomonas, in some cases exceeding thousands of generations of divergence, are providing an unprecedented opportunity for studying the mutation process. Molecular analyses of these lines by complete-genome sequencing are yielding the first direct quantitative estimates of the rate and spectrum of mutations at the DNA level, revealing a dramatic scaling of the mutation rate with genome size, an apparently universal mutation pressure towards AT composition, and many other previously unknown mutational features.
This work is now being extended to ~30 bacterial species, ranging widely in genome size and nucleotide composition. In addition, we are starting to pursue studies on transcription error rates and the degree to which these vary among eukaryotic lineages. Our work on mutation extends to the development of population-genetic theory for the evolution of the mutation rate itself, and to obtaining a general understanding of the consequences of somatic mutations for the evolution of multicellularity. Here, we are promoting the idea that the power of random genetic drift imposes a lower bound to the degree to which natural selection can reduce the mutation rate. This drift-barrier hypothesis seems to support a number of previously disconnected observations, including the increase in the mutation rate with reductions in effective population size, and the magnified error rates associated with DNA polymerases and repair enzymes used only infrequently in replication.
The Role of Recombination in Evolution. Sexual recombination provides a powerful means for producing multi-locus genotypes with high fitness, but also has the negative side-effect of breaking apart coadaptive complexes of alleles. A great deal of theory has been developed to help explain the phylogenetic distribution of recombination, but the key biological observations for testing the various hypotheses remain to be developed. To help provide a mechanistic understanding of the causes and consequences of the loss of recombination, we are studying the microcrustacean Daphnia pulex, which consists of both sexual and asexual races of various evolutionary ages. An additional remarkable feature of this system is its "living-fossil" record -- from the sediment cores of lakes, resting eggs from the past 200 years can be hatched and maintained clonally, and DNA can be extracted from remnants of up to 2000 years old. With numerous collaborators, we have initiated a Daphnia Genomics Consortium (http://daphnia.cgb.indiana.edu/ ), the goals of which are to catalogue, map, and characterize the functions of the majority of genes in D. pulex. These tools are now being exploited to understand the molecular mechanisms of phenotypic evolution in the context of natural ecological settings, a luxury that is not available to most model invertebrate systems. Recent tool development includes: sequencing of the complete genome; a high-density genetic map based on ~200 microsatellite loci; complete sequencing of a full-length cDNA library of ~200,000 transcripts; and production of microarrays for functional analysis.
Specific projects now include: the isolation and characterization of the genes responsible for meiosis suppression in obligate asexuals; quantification of the rate of accumulation of deleterious mutations in asexual vs. sexual lineages; estimation of the rate and tempo of allele and genotype turnover in natural populations; and quantification of the influence of recombination on the activity of mobile genetic elements. To this end, we have sequenced 25 complete genomes of obligately asexual lineages of Daphnia and their closely related sexual relatives in an effort to find the molecular signature of recombination suppression. In addition, we are attempting to develop methods for genetic transformation to expand the utility of this system to studies in molecular, cellular, and developmental biology.
Methodology for the Analysis of High-Throughput Genomic Data. The rapid emergence of technological innovations in genome sequencing has resulted in a situation where it is now possible to sequence multiple genomes from natural populations. In anticipation of such data, and the enormous challenges that come with them (most notably, incomplete sampling of parental alleles and errors in sequence reads), we have begun to develop a new generation of maximum-likelihood methods for estimating a broad array of population-genetic parameters, including nucleotide heterozygosity, linkage disequilibrium, and the allele-frequency spectrum. Applications of these methods currently involve the quantification of the above-mentioned parameters in a variety of taxa. Particular emphasis is now being focused on the estimation of patterns of linkage disequilibrium in natural populations, and using this information to estimate effective population sizes, recombination frequencies, and gene-converison tract lengths.
Evolutionary Cell Biology. We have recently begun to explore a broad set of issues in cell biology. Remarkably, although we have fairly well-established fields of molecular evolution, genome evolution, and phenotypic evolution, there is no comprehensive field of evolutionary cell biology. Perhaps there is a good reason for this, but one could argue that the resources that link molecular and phenotypic evolution reside at the level of cellular architecture. Thus, we are beginning to explore the potential for linking evolutionary theory with various observations from comparative cell biology. Some current interests include the evolution of multimeric proteins, the evolution of cellular surveillance mechanisms, and the limits to molecular perfection imposed by the barrier of random genetic drift. Time will tell whether this foray into cell biology is a worthwhile venture.
- Lynch, M. 2012. The evolution of multimeric protein assemblages. Mol. Biol. Evol. (in press).
- Eads, B., D. Tsuchiya, M. Lynch, J. Andrews, and M. E. Zolan. 2012. Evolution of REC8 in Daphnia: the spread of a transposon insertion associated with obligate asexuality. Proc. Natl. Acad. Sci. USA 109: 858-863.
- Colbourne, J., et al. 2011. The ecoresponsive genome of Daphnia pulex. Science 331: 555-561.
- Lynch, M. 2010. Scaling expectations for the time to establishment of complex adaptations. Proc. Natl. Acad. Sci. USA 107: 16577-16582.
- Lynch, M. 2010. Evolution of the mutation rate. Trends in Genetics 26: 345-352.
- Catania, F., F. Wurmser, A. A. Potekhin, E. Przyboś, and M. Lynch. 2009. Genetic diversity in the Paramecium aurelia complex. Mol. Biol. Evol. 26: 421-431.
- Ossowski, S., K. Schneeberger, J. Lucas-Lledo, N. Warthmann, R. M. Clark, R. G. Shaw, D. Weigel, and M. Lynch. 2009. The rate and molecular spectrum of spontaneous mutations in Arabidopsis thaliana. Science 327: 92-94.
- Lynch, M. 2009. Rate, molecular spectrum, and consequences of spontaneous mutations in man. Proc. Natl. Acad. Sci. USA 107: 961-968.
- Rho, M., M. Zhou, X. Gao, S. Kim, H. Tang, and M. Lynch. 2009. Parallel mammalian genome contractions following the KT boundary. Genome Biology and Evolution 2009: 2-12.
- Li, W. A. E. Tucker, W. Sung, W. K. Thomas, M. Lynch. 2009. Extensive, recent intron gains in Daphnia populations. Science 326: 1260-1262.
- Lynch, M. 2008. Estimation of nucleotide diversity, disequilibrium coefficients, and mutation rates from high-coverage genome-sequencing projects. Mol. Biol. Evol. 25: 2421-2431.
- Lynch, M., A. Seyfert, B. Eads, and E. Williams. 2008. Localization of the genetic determinants of meiosis suppression in Daphnia pulex. Genetics 180: 317-327.
- Lynch, M. 2007. The frailty of adaptive hypotheses for the origins of organismal complexity. Proc. Natl. Acad. Sci. USA 104 (Suppl.): 8597-8604.
- Lynch, M. 2007. The Origins of Genome Architecture. Sinauer Assocs., Inc., Sunderland, MA.
- Lynch, M. 2006. The origins of eukaryotic gene structure. Mol. Biol. Evol. 23: 450-468.
- Paland, S., and M. Lynch. 2006. Transitions to asexuality result in excess amino-acid substitutions. Science 311: 990-902.
- Lynch, M., B. Koskella, and S. Schaack. 2006. Mutation pressure and the evolution of organelle genome architecture. Science 311: 1727-1730.
- Lynch, M., and J. B. Walsh. 1998. Genetics and Analysis of Quantitative Traits. 980 pp. Sinauer Assocs., Inc., Sunderland, MA.