Distinguishing Homologous From Analogous Proteins

Fitch, W. M. (Dept. Physiological Chem., U. Wisconsin, Madison 53706) 1970. Distinguishing homologous from analogaus proteins. Syst. Zool., 19:99-113.-This work provides a means by which it is possible to determine whether two groups of related proteins have a common ancestor or are of independent origin. A set of 16 random amino acid sequences were shown to be unrelated by this method. A set of 16 real but presumably unrelated proteins gave a similar result. A set of 24 model proteins which was composed of two independently evolving groups, converging toward the same chemical goal, was correctly shown to be convergently related, with the probability that the result was due to chance being <10'. A set of 24 cytochromes composed of 5 fungi and 19 metazoans was shown to be divergently related, with the probability that the result was due to chance being < 10-'. A process was described which leads to the absolute minimum of nucleotide replacements required to account for the divergent descent of a set of genes given a particular topology for the tree depicting their ancestral relations. It was also shown that the convergent processes could realistically lead to amino acid sequences which would produce positive tests for relatedness, not only by a chemical criterion, but by a genetic (nucleotide sequence) criterion as well. Finally, a realistic case is indicated where truly homologous traits, behaving in a perfectly expectable way, may nevertheless lead to a ludicrous phylogeny. The demonstration that two proteins are related has been attempted using two different criteria. One criterion is to show that their chemical structures are very similar. An early example of this approach was the observation of the relatedness of the oxygen carrying proteins, myoglobin and hemoglobin (Watson and Kendrew, 1961). More recent is the relatedness of two enzymes in carbohydrate metabolism, lysozyme and alpha-lactalbumin (Brew, Vanaman and Hill, 1967). The other criterion is to show that underlying genetic structures of the proteins are more alike than one would expect by chance. This is now possible because our knowledge of the genetic code permits us to determine how many nucleotide positions, at the minimum, must differ in the genes encoding the two presumptively homologous proteins. One then compares the answer obtained to the number of differences one would expect for unrelated proteins. An example of this approach is the observation of the relatedness of plant and bacterial ferredoxins (Matsubara, Jukes and Cantor, 1969) for which added evidence has been produced (Fitch, 1970a). But regardless of the approach, the impulse, too powerful to resist, is to conclude that a particular pair of proteins had a common genic ancestor if they meet whichever criterion the observer uses. Now two proteins may appear similar because they descend with divergence from a common ancestral gene (i.e., are homologous in a time-honoured meaning dating back at the least to Darwin's Origin of Species) or because they descend with convergence from separate ancestral genes (i.e., are analogous). And, if a common genic ancestor is to be the conclusion, a genetic criterion should be superior to a chemical criterion. This is because analogous gene products, although they have no common ancestor, do serve similar functions and may well be expected to have similar chemical structures and thereby be confused with homologous gene products. This danger can only be increased by using a chemical, as opposed to a genetic, criterion.