Distinguished Professor

Ph.D., University of Minnesota, 1977

Program Affiliation: Evolution, Ecology and Behavior | Molecular Biology & Genetics

Research Groups Affiliation: Evo-Devo | Evolution | Genetics | Genomics & Bioinformatics

Phone: 812-855-7384
Fax: 812-855-6705
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Lynch Lab website
Mike's CV

Our research is focused on mechanisms of evolution at the gene, genomic, 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 yeast Saccharomyces , and the ciliate Paramecium . 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 genomic 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 fates of duplicated genes are 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, rather than by the evolution of new functions. We have developed methods to estimate the rate of origin and loss of duplicate genes, and we are currently studying the features of newly arisen duplicates that have not yet gone to fixation. In addition, we have recently shown that the modular regulatory-region architecture common in eukaryotes can spontaneously emerge in populations of sufficiently small size. These results challenge the popular idea that modularity arises as a direct consequence of selection for morphological complexity, and by extension raise questions about the common assumption that natural selection was responsible for the emergence of multicellularity.

Our work on intron evolution is focused on the hypothesis that newly arisen introns are typically mildly deleterious, and a major goal is to understand how introns eventually came to be integrated into fundamental aspects of gene-transcript processing.  We are currently attempting to learn how the complex intron-splicing machinery, the spliceosome, evolved and diversified among various phylogenetic lineages. In addition, we are attempting to estimate the rate of intron gain and loss in various lineages. We have hypothesized that intron proliferation was facilitated by the evolution of nonsense-mediated decay (NMD), an mRNA surveillance mechanism that uses exon-junction information as an orientation mechanism for identifying aberrant premature stop codons. Empirical work in this area is being pursued with Paramecium , which not only harbors introns excised at the mRNA level, but also contains internal eliminated sequences (IESs) that are spliced out at the DNA level.

The Role of Mutation in Evolution. Although mutations provide the ultimate material upon which natural selection depends, most mutations are deleterious, and in certain population 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, and Paramecium , in some cases exceeding 400 generations of divergence, are providing an unprecedented opportunity for studying the mutation process. Molecular analyses of these lines are yielding the first direct quantitative estimates of the rate and spectrum of mutations at the DNA level, revealing substantially higher estimates than had previously been obtained by indirect phylogenetic comparisons.

We are now embarked on the development of high-throughput techniques, including whole-genomic sequencing of microbial species, to define the molecular spectrum of mutational changes. In addition, we are using microarray analysis to evaluate the effects of spontaneous mutations on transcriptional activities of the full complement of protein-coding genes in C. elegans.

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 the very same coadaptive complexes of genes. 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 this end, we are exploiting 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 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 will then be 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.

Through an NSF FIBR grant, we have assembled a team of diverse investigators in evolution, ecology, genomics, cell biology, parasitiology, and mathematics (including J. Andrews, J. Boore, C. Caceres, J. Colbourne, E. Housworth, T. Little, C. Lively, B. Robison, K. Thomas, and M. Zolan) to use the D. pulex system to improve our understanding of the evolutionary causes and consequences of recombination. Specific projects 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; measurement of the amount of genetic slippage and release of hidden genetic variance following recombination in natural populations; quantification the influence of recombination on the activity of mobile genetic elements; and the development of population-genetic theory for the behavior of various kinds of genetic elements in recombining and nonrecombining backgrounds. One particularly exciting recent discovery, the presence of substantial mitotic recombination is obligately asexual lineages, raises significant challenges for our understanding of the evolutionary genetic consequences of a loss of meiosis.

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.

Force, A., W. Cresko, F. B. Pickett, S. Proulx, C. Amemiya, and M. Lynch. 2005. The origin of gene subfunctions and modular gene regulation. Genetics 170: 433-446.

Paland, S., J. K. Colbourne, and M. Lynch. 2005. Evolutionary history of contagious asexuality in Daphnia pulex. Evolution 59: 800-813.

Lynch, M., D. G. Scofield, and X. Hong. 2005. The evolution of transcription-initiation sites. Mol. Biol. Evol. 22: 1137-1146.

Denver, D. R., K. Morris, J. T. Streelman, S. K. Kim, M. Lynch, and W. K. Thomas. 2005. The transcriptional consequences of mutation and natural selection in Caenorhabditis elegans. Nature Genetics 37: 544-548.

Denver, D. R., K. Morris, M. Lynch, and W. K. Thomas. 2004. High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome. Nature  430: 679-682.

Lynch, M., and J. S. Conery. 2003. The origins of genome complexity.  Science 302: 1401-1404.

Lynch, M., and A. Kewalramani. 2003. Messenger RNA processing and the evolutionary proliferation of introns. Mol. Biol. Evol. 20: 563-571.

Books:

Lynch, M., and J. B. Walsh. 1998. Genetics and Analysis of Quantitative Traits. 980 pp. Sinauer Assocs., Inc., Sunderland, MA.

Lynch, M. 2007. The Origins of Genome Architecture. Sinauer Assocs., Inc., Sunderland, MA (in press).