Faculty | Ecology & Evolution | University of Chicago

search2.html

Faculty : Students : Administrative Staff : Research Staff

Michael Z. Ludwig, Ph.D.
Research Associate (Associate Professor)
Department of Ecology and Evolution

Office: Zoology 113 | Phone: 773-702-1963 | Fax: 773-702-9740 | email: mludwig(at)uchicago(dot)edu
Subjects: Developmental regulation of gene expression and the genetic basis for evolution of regulatory DNA

Research Interests

My research at the University of Chicago (in collaboration with Martin Kreitman) takes an evolutionary perspective to investigate the structure/function of eukaryotic cis-regulatory modules. Our approach has been to use transgenic analysis to functionally characterize evolved changes in the structure of a well-characterized enhancer controlling embryonic expression of even-skipped pair-rule stripe two in Drosophila. This work has lead us to a paradigm for understanding variation and evolution of eukaryotic regulatory sequences: stabilizing selection can maintain functional conservation of cis - regulatory elements for long periods of evolutionary time despite structural turnover of trans (transcription) -factor binding sites. At the same time, we’ve also documented an instance of rapid functional change in the enhancer function.
The evolution of this enhancer is non-clock-like, with important functional differences between closely related species and functional convergence between distantly related species. Functional divergence is attributable to differences in activation levels rather than spatiotemporal control of gene expression. Our findings have implications for understanding enhancer structure–function, mechanisms of speciation and computational identification of regulatory modules.

Current Projects include:

1. Dynamics of the Drosophila segmentation. Canalization of gene expression during development and evolution. In collaboration with Marty Kreitman, Kevin White, Susan Lott, Cecilia Miles, and Ralf Kittler (University of Chicago).
Functional analysis of genetic mutations that introduce quantitative changes in segmentation gene expression in the spatial or temporal domain.
   Creation of transgenic Drosophila “wildtype” stocks in which some segmentation genes (like even-skipped) have been replaced with a fluorescently tagged (YFP) isoallele. Spatiotemporal measurement of these genes (and also a mitotic marker) in live embryos will improve experimental throughput, measurement accuracy and precision. Embryos are subjected to genetic or environmental perturbations to investigate molecular and developmental mechanisms conferring robust development.
The robustness of segmentation within and between Drosophila species to genetic variation or evolution in embryo shape and size.

2. Construction a model for Diabetes using the fruitfly Drosophila melanogaster.
In collaboration with Marty Kreitman and Greame Bell -http://gbell.bsd.uchicago.edu/index.html   (University of Chicago).
   Recent studies have identified dominant negative mutations in the insulin gene that cause diabetes in mice and man. They are hypothesized to induce beta-cell death through ER stress-mediated apoptosis.
   To test this hypothesis, we are employing the GAL4/UAS driver system to construct stable transgenic Drosophila melanogaster flies in which wildtype and mutant human insulin (Akita) alleles are expressed in the eye. We have shown that mutant insulin (but not wildtype human insulin) expression induces eye degeneration. This fly model of diabetes will allow us to carry out a genome wide screen for modifiers that suppress the mutant insulin phenotype.

Selected Publications

Lott, S.E., Kreitman, M., Palsson A., Alekseeva, E. and M.Z. Ludwig 2007. Canalization of segmentation and its evolution in Drosophila. Proc. Natl. Acad. Sci. U.S.A. 104:10926-31.

Ludwig, M.Z., A. Palsson, C. Bergman, E. Alekseeva, J. Nathan and M. Kreitman 2005. Functional evolution of a cis-regulatory module. PloS Biology 3:588-98.

Lall, S., M.Z. Ludwig and N. H. Patel 2003. Nanos plays a conserved role in axial patterning outside of the diptera. Current Biology, v.13, pp. 224-229.

Ludwig, M. Z. 2002. Functional evolution of noncoding DNA. Current Opinion in Genetics & Development, v.12, pp. 634-639.

Ludwig, M.Z, C. Bergman, N.H. Patel and M. Kreitman 2000. Functional evidence for stabilizing selection in a eukaryotic cis-regulatory element. Nature 403:564-567.

Ludwig, M.Z., N. H.Patel, and M. Kreitman 1998. Functional conservation of even-skipped stripe 2 enhancer in Drosophila. Development 125:949-958.