A major achievement of 20th-century biology was the identification of the fundamental, shared genetic and biochemical properties of all life forms. Now, understanding the nature of biological variation at the population and species levels represents a core question in modern biological research, one that spans disciplines from genetics to biochemistry and genomics. Which cellular processes are most commonly affected to generate diverse phenotypes?
Genetic studies of morphological innovation owe a debt to early studies of homeosis, from William Bateson’s observations of aberrant developmental transformations to Ed Lewis’s elegant characterization of Drosophila HOX genes. Subsequent work in the field of evo-devo has identified numerous examples in which derived aspects of biological systems can be traced directly to subtle changes in transcription factors and cis regulatory elements.
Indeed, from microbes to man, analysis of population variation demonstrates that these elements are free agents, constantly sampling new functional space and shifting their roles in gene regulatory circuits to generate novel outputs. As we move into more quantitative molecular studies with systems-biology approaches, more general questions are “How predominant are specific changes in the periphery of gene expression?” and “How much does variation at the very core processes of gene expression contribute to evolutionary innovation?”
Responding to these challenges, the first meeting on evolution and core processes in gene expression, sponsored by the American Society for Biochemistry and Molecular Biology, was held July 25 28 in Chicago. Speakers from North America, Europe, Israel and Japan shared insights on interdisciplinary topics. The symposium brought together speakers from diverse backgrounds to discuss mechanistic gene expression and evolution, to highlight our current understanding, and to focus on how the field may develop a more global understanding of these processes.
Some of the presentations from microbial research set the scene for how research in higher organisms may develop. Saeed Tavazoie of Columbia University and Eduardo Groisman of Yale University School of Medicine discussed how bacteria can show remarkable “molecular memory” in regulatory systems with precisely tuned outputs. Yet with a few genetic transitions, bacteria can easily shift toward a completely different regulatory paradigm. Their examples focused on transcription factors and signaling molecules.
However, the impact of variation of the core machinery was highlighted by Seth Darst of The Rockefeller University, Robert Landick of the University of Wisconsin and Zach Burton of Michigan State University, who discussed the structure and function of E. coli RNA polymerase. This organism’s well-studied enzyme features a derived structure not observed with other bacterial polymerases, a prominent 188-amino-acid insertion connecting a key element of the active site, the “trigger loop,” to the outside of the protein. The significance of this structural innovation is unknown, but the element frequently is mutated in bacterial populations grown under conditions of nutritional stress, and certain mutations allow bacteria to ignore facultative pause sites, globally changing gene expression. How frequently such alterations in the enzyme might contribute to innovations in gene expression is an important question for future studies.
A similar, but less complete, picture emerges from research presented by Aviv Regev of the Broad Institute and Ian Dworkin of Michigan State University. These speakers described how genetic background has a critical impact on the function of the mammalian immune system and organ development in the fly. At this point, these and similar studies are still cataloging the numerous loci that affect signaling and developmental outputs; we don’t know if the bulk of such modifications occur on the periphery of regulatory networks or might also implicate central nodes, such as the transcription, splicing or translational machinery.
Lawrence Myers of Dartmouth College provided a clue to such a possibility in a discussion of his analysis of the transcriptional mediator complex of Candida albicans, a pathogen in which genes for certain subunits of the mediator have undergone a tremendous expansion. Mutation of these genes affects fungal virulence, indicating that this novelty may be an acquired trait important for growth in certain niches.
Whether human mediator similarly is subject to such evolutionary tampering is unknown, but Jean-Marc Egly at the Institut de Genetique et de Biologie Moléculaire et Cellulaire described how mutations in mediator and some of the other ∼200 factors of the basal machinery lead to very tissue-specific effects in human disease. Such genetic variation is present in the human population, although examples of adaptive modifications are unknown.
One clue relating to animal development concerns the conserved heptapeptide repeat of the RNA polymerase C-terminal domain. Most eukaryotes feature such a repeat domain, which is of variable length in different species. Across eukaryotes, from yeast to Arabidopsis to mice, the composition of the YSPTSPS repeats are relatively invariant, except in Drosophila, where divergent sequences are abundant and conserved. Whether this alternative CTD reflects the special gene regulatory requirements of early rapid development in the long germband syncytial embryo, as discussed by Melissa Harrison of the University of Wisconsin-Madison and Julia Zeitlinger of the Stowers Institute for Medical Research, is unknown.
Jeremy Lynch of the University of Illinois at Chicago noted that the long germband developmental program has been multiply derived, as in Nasonia, and that certain patterns of gene expression appear to be bottlenecks that are more conserved than others; thus, it would be interesting to determine whether alternative CTD of RNA polymerase II are similarly selected in these lineages, perhaps to deal with the unique chromatin challenges of rapid development.
How does the biochemical view of gene expression at the level of Ångstrom and kd connect with evolutionary perspectives? How important are variations in core processes of gene expression, which are highly pleiotropic, in sampling the functional gene expression space explored as populations and species evolve? Quantitative genetics and systems biology are providing the raw material to map this landscape; a challenge for future studies will be to develop tools and systems that can provide us comprehensive answers to central questions of evolutionary gene expression.
David Arnosti (firstname.lastname@example.org) studies transcriptional enhancers and corepressors in Drosophila with colleagues in the Gene Expression in Development and Disease Focus Group at Michigan State University.