A report by Wayne State researchers found new evidence of rapid protein evolution, signaling biochemical adaptation and positive selection in the anthropoid primate lineage. The report, (article #09714) published in the April 25-29 issue of the Proceedings of the National Academy of Sciences (PNAS), further elucidates the biochemical mechanisms involved in aerobic energy metabolism, a complex process that coincides with the expansion of the energy-dependent neocortex of the brain during the emergence of higher primates like monkeys, apes, and humans.
The study's corresponding author, Lawrence I. Grossman, Ph.D., professor and director of the Center for Molecular Medicine and Genetics, said the WSU team, which also included Timothy R. Schmidt, Derek E. Wildman, Monica Uddin, Juan C. Opazo, and Morris Goodman, found rapid evolution at the cytochrome c (CYC) binding site on cytochrome c oxidase (COX) in anthropoid primates. CYC is known to interact directly with COX during electron transport by binding to specific sites. Previous research has shown that in vertebrates CYC and COX are largely conserved and have few amino acid replacements. In contrast, the WSU researchers have identified 57 amino acids of COX that may bind CYC during electron transfer. Furthermore, the replacement rate for these residues was significantly accelerated in anthropoids compared to tarsiers, the most closely related non-anthropoid primate.
"With thorough DNA sequencing, we are identifying those positively selected mutations that shaped the genetic basis of being human," Dr. Grossman said.
COX is the enzyme that catalyzes the final step of electron transfer through the respiratory chain, thus playing a vital role in providing energy for aerobic tissue s . Phlyogenetic analyses of gene sequences in different families indicate positively selected evolution of COX in terminal lineages of leading to gorilla, human and chimpanzee.
By parsimony from an interspecies alignment of binding site residues, the scientists discovered 27 changes from the earlier eutherians (placental mammalian ancestors) to humans, of which 59 percent were at electrostatically significant (ES) residue positions. The changes to the ES residues reduced the overall number of charged residues at the CYC binding site. The ES changes occurred only in stem-anthropoids and stem-catarrhines, and few changes occurred in the ape and Old World monkey lineages.
"This reduction in rate of amino acid replacement is consistent with the
hypothesis that the changes in ancestral lineages were advantageous and positively selected and, in descendent lineages, have been maintained by purifying selection," Dr. Grossman said.
Dr. Grossman and his colleagues have developed evidence that cytochrome c and subunits of complex III and COX that interact with it have undergone a period of accelerated evolution suggestive of positive selection at similar times in an ancestor of modern primates. "We believe that this remodeling of the electron transport chain supported the expansion of the energy-consuming enlarged neocortex that was taking place in these primate lineages. We are now seeking to characterize biochemically any modifications in electron transport that resulted. Finally, we are interested in the relation between rapidly evolving genes and human disease," he said.
The full article, "Rapid Electrostatic Evolution at the Binding Site
for Cytochrome c on Cytochrome c Oxidase in Anthropoid Primates," (#09714) is featured in the April 25, 2005 issue of the Proceedings of the National Academy of Sciences. It can be viewed online at This Week in PNAS: http://www.pnas.org/papbyrecent.shtml. (Note: online publication date is April 25-29).
This paper was contributed by Morris Goodman, Ph.D., who was elected into the National Academy of Sciences in 2002. Co-authors are: Timothy R. Schmidt, Derek E. Wildman, Monica Uddin, Juan C. Opazo, Morris Goodman and Lawrence I. Grossman.