Perhaps the cornerstone question in evolution is the nature of the function that relates genotype and phenotype, which is often though of as a fitness landscape. We are interested in describing both the theoretical aspects of evolution on a multidimensional fitness surface, as well in direct observations of epistasis and complex fitness functions in real data. We have managed to combine several aspects of complex fitness functions in our studies of pathogenic mutations in the human genome and related species. We observed many instances in protein and RNA genes, that when a particular mutation is deleterious to one organism, it may be benign in another. Such instances we termed Compensatory Pathogenic Deviations (CPDs), because the same principle can be applied to any genetic change. We have just began to combine genome-wide data, theory and molecular basis of compensatory mutations involving human disease variants. Through our studies, we have managed to show that dramatic changes in fitness, such that when one particular mutation is highly deleterious to one species while being benign in another, is a common phenomenon and in many cases it is related to structural stability aspects of the involved molecules. These observations show, that on a small scale the fitness surfaces in nature are highly epistatic.
Plotnikova OV, Kondrashov FA, Vlasov PK, Ginter EK and Rogaev EI (2007). Conversion and compensatory evolution of the ã-crystallin genes and identification of a cataractogenic mutation that reverses the sequence of the human CRYGD gene to an ancestral state. Am. J. Hum. Genet. 81, 32-43
Kondrashov FA. (2005) Prediction of pathogenic mutations in mitochondrially encoded human tRNAs. Human Molecular Genetics 14, 2415-2419.
Kern AD and Kondrashov FA (2004) Mechanisms and convergence of compensatory evolution in mammalian mitochondrial tRNAs. Nature Genetics 36, 1207-1212.
Kondrashov AS, Sunyaev S and Kondrashov FA. (2002) Dobzhansky-Muller incompatibilities in protein evolution. Proceedings of the National Academy of Sciences USA 99, 14878-14883.
Kondrashov FA and Kondrashov AS. (2001) Multidimensional epistasis and the disadvantage of sex. Proceedings of the National Academy of Sciences USA 98, 12089-12092.