Research focus in the Thomas lab has recently shifted to molecular evolution, especially the evolution and function of gene families implicated in environmental interactions and other rapidly changing selective pressures. Work is mostly on nematode and mammalian gene families, with some comparative analyses to other groups.
Gene families are abundant and pervasive in multicellular organisms, where they arise by duplication and diversification of existing genes. The mechanism of duplication and the patterns of diversification that occur subsequent to duplications are poorly understood and probably underlie critical aspects of organismal evolution. Our analysis of positive selection (natural selection to change amino acid sequence) indicates that genes in many families undergo rapid change at specific protein sites. The patterns of these changes often provide strong insight into the function and evolution of the genes. For example, in nematodes and plants, most of the large families of substrate specificity adapter proteins for poly-ubiquitination are under strong positive selection in their substrate-binding domain. This pattern suggests that the adapter substrates have changed over time and that the adapter proteins are selected to maintain substrate binding. A simple explanation is that these proteins function in innate immunity to target foreign proteins for proteolysis. Another example is the rapidly expanded C2H2 (Kruppel-like) zinc finger protein family in mammals, many members of which are under subject to strong positive selection in the nucleotide contacting residues of the zinc fingers. The patterns of family expansion and positive selection suggest that many mammalian zinc finger genes have been selected to increase family complexity (gene number) and to change their regulatory targets (DNA binding specificity). These changes may contribute to the evolutionary plasticity of morphology and development in mammals.
Thomas, J.H. 2005. Global analysis of homologous gene clusters in C. elegans reveals striking regional cluster domains. In press, Genetics.
Choy, R.K.M., J. Kemner, and J.H. Thomas. 2005. Fluoxetine-resistance genes in C. elegans function in the intestine and may regulate lipid metabolism. In press, Genetics.
Efimenko, E., K. Bubb, H.Y. Mak, T. Holzman, G. Ruvkun, M.R. Leroux, J.H. Thomas, and P. Swoboda. 2005. Analysis of xbx genes in C. elegans. Development 132, 1923-1934.
Thomas, J.H., J.L. Kelley, H.M. Robertson, K, Ly, and W.J. Swanson. 2005. Adaptive evolution in the SRZ Chemoreceptor families of C. elegans and C. briggsae. PNAS 102, 4476-4481.
Stewart, M.K., N. Clark, G. Merrihew, E. Galloway, and J.H. Thomas. 2005. High genetic diversity in the chemoreceptor superfamily of C. elegans. Genetics 165, 1985-1996.
Li, J., G. Brown, M.A. Ailion, S. Lee, and J.H. Thomas. 2004. NCR-1 and NCR-2, the C. elegans homologues of the human Niemann-Pick type C1 disease protein, function upstream of DAF-9 in the dauer formation pathways. Development 131, 5741-5752.
McElwee, J.J., E. Schuster, E. Blanc, J.H. Thomas, D. Gems. 2004. Shared transcriptional signature in C. elegans dauer larvae and long-lived daf-2 mutants implicates detoxification system in longevity assurance. J. Biol. Chem. 279, 44533-44543.
Petersen, C.I., T.R. McFarland, S.Z. Stepanovic, P. Yang, D.J. Reiner, K. Hayashi, A.L. George, D.M. Roden, J.H. Thomas, and J.R. Balser. 2004. In vivo identification of genes that modify ether-a-go-go-related gene activity in Caenorhabditis elegans may also affect human cardiac arrhythmia. PNAS 101, 11773-11778.