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A crucial step towards understanding properties of cellular systems is to map networks of DNA-, RNA-, and protein-protein interactions, or the “interactome network,” of an organism. Of these, the protein interactome network is a molecular determinant of function as proteins carry out their functions by interacting with other proteins. To better understand the mechanistic and genetic basis of human disease, we examined disease mutations in the context of a three-dimensional protein network and found that in-frame mutations are enriched on the interaction interfaces of proteins associated with the corresponding disorders, and that the disease specificity for different mutations of the same gene can be explained by their location within an interface[1,2]. Using this network, we also found that contrary to common belief, truncating mutations can still lead to functional protein products and that the widely accepted “guilt-by-association” principle does not apply to dominant mutations[3]. Thus, three-dimensional networks are extremely valuable in translating a wealth of genomic data into mechanistic insights about disease[2,4]. To study the molecular basis of evolution, we developed a systematic cross-species interactome mapping framework using which we compared protein interactions between two evolutionarily related yeast species. We found significant rewiring of interactions between the two species, far more than what is expected by mere sequence orthology. Our results suggest that interactions even between orthologous proteins may be rewired to accommodate novel functions[5,6].
References:
[1]. J. Das and H. Yu, BMC Syst Biol, 2012, 6, 92.
[2]. X. Wang, X. Wei, B. Thijssen, J. Das, S. M. Lipkin and H. Yu, Nat Biotechnol, 2012, 30, 159-164.
[3]. Y. Guo, X. Wei, J. Das, A. Grimson, S. M. Lipkin, A. G. Clark and H. Yu, Am J Hum Genet, 2013, 93, 78-89.
[4]. M. J. Meyer, J. Das, X. Wang and H. Yu, Bioinformatics, 2013.
[5]. J. Das, T. V. Vo, X. Wei, J. C. Mellor, V. Tong, A. G. Degatano, X. Wang, L. Wang, N. A. Cordero, N. Kruer-Zerhusen, A. Matsuyama, J. A. Pleiss, S. M. Lipkin, M. Yoshida, F. P. Roth and H. Yu, Sci Signal, 2013, 6, ra38.
[6]. J. Das, J. Mohammed and H. Yu, Bioinformatics, 2012, 28, 1873-1878. |