THE GENETICS OF ADAPTATION: In order to grasp in both specific and general ways the synergy between gene, protein structure, and organismal phenotype, model systems to explore sequence-function relationships are needed.

First, from an analytical (computational) standpoint, a reliable estimate of the evolution of genes linked to phenotype is necessary as it affords a powerful framework upon which hypotheses about gene and gene network evolution can be tested, such as the origin and sequence of mutations, the selective pressure on a gene, functional convergence/ divergence or pleiotropic effects. This requires the simultaneous consideration of phylogenetic, population genetic, biophysical and biochemical knowledge.

Second, from an experimental standpoint, to put presumed adaptive evolution to the test and thus provide a thorough insight into the structure-function relationship of evolving proteins, functional assays are necessary.

I am studying protein coding sequences that appear to be undergoing adaptive evolution/ changes of function along specific branches of the tree of life from a computational and experimental perspective. Those are in particular protein kinases and myostatins.

Myostatin

I am currently developing a model exploring sequence-function relationship based on an important member of the transforming growth factor B (TGF-B) superfamily – myostatin.

This work is being done in David Liberles' Lab, in collaboration with Aasa Tellgren (graduate student, Liberles Lab).

Myostatin is a negative muscle cell growth regulator. I am particularly interested in myostatin evolution in salmonids. Salmonidae are thought to have undergone a second whole genome duplication event at the base of the Salmonidae tree, in addition to the teleost-specific whole genome duplication event, leading to 4 myostatin copies in ancestral salmon relative to 1 in mammals.

Gen(om)e duplication has classically been proposed to relax the selective constraint on both copies, allowing a faster mutation rate and exploration of sequence space.⁴ On this dataset, I can test this hypothesis, and subsequently detect and experimentally explore all three scenarios of neofunctionalization, subfunctionalization, and pseudogenization. It also will allow for a comparative test of computational prediction versus experimental results and help critically evaluating the former. Additionally, I will be able to gain insight into the influence of gene duplication and coupled selective processes on regulating interactions of different functional parts of genes. These results have practical applications for salmon aquaculture and medical research in muscular dystrophy, forming the basis for the development of agents to up- or down-regulate myostatin activity.

Protein Kinases

This projects is conducted in close collaboration with Stefan Rothenburg, currently at the NIH. We are currently conducting complex database searches to identify functional homologues of eIF2alpha kinases. The eIF2 alpha kinase family contains different members, which have arisen through gene duplication, and share sequence and structural features in their catalytic domains. However, they have unique flanking regulatory domains, allowing for their distinct control patterns.

It has been hypothesized that most eIF2 alpha kinases are important for resistance to diverse environmental stresses. In the case of parasitic kinases, the necessity to respond to environmental stress can be induced by the persistence or passing through certain more or less specific arthropod vectors (as is the case in Trypanosoma cruzi), and it is hypothesized that different organismal classes have distinct kinase families and control patterns depending on the kind of environmental stress they are exposed to (e.g. vertebrates vs. lower eukaryotes). We are particularly interested in detecting horizontal transfers and tracing the history of gene duplication.

Further research on this is crucial in understanding general concepts of host-parasite evolution. One of the traditional paradigms of parasitology is that progressive host adaptation is a cul-de-sac of evolution, dooming parasites to extinction should their hosts do so. However, parasitism is an evolutionary old concept and some parasites have survived since the beginning of time by rapidly switching to new hosts. Processes of neo- and subfunctionalization after gene duplication, as well as directed processes of selective pressure might be pivotal in explaining parasite evolution, and will be tested with this particular data.

Recent publications related to this work:

Roth C, Rastogi S, Arvestad L, Dittmar K, Light S, Ekman D, Liberles D. (2006). Evolution after gene duplication: Models, Mechanisms, Sequences, Systems, and Organisms. Journal of Experimental Zoology (Mol Dev Evol) 306B:1-16.

Rothenburg S, Deigendesch N, Dittmar K, Nolte F, Haag F, Lowenhaupt K, Rich A (2005). A PKR-like eukaryotic initiation factor 2a kinase from zebrafish contains Z-binding domains instead of dsRNA binding domains. Proceedings of the National Academy of Sciences 102(5): 1602-1607.

Otto, H., Reche PA, Bazan, F., Dittmar K., Haag, F., Koch-Nolte, F. (2005). In silico characterization of PARP-like poly-(ADP-ribosyl)transferases (pARTs). BMC Genomics 6: 139.