Open Access Research article

Molecular evolution of the cytochrome c oxidase subunit 5A gene in primates

Monica Uddin1, Juan C Opazo12, Derek E Wildman134, Chet C Sherwood5, Patrick R Hof6, Morris Goodman17 and Lawrence I Grossman1*

Author Affiliations

1 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit MI 48201, USA

2 Instituto de Ecología y Evolución, Facultad de Ciencias, Universidad Austral de Chile, Casilla 567, Valdivia, Chile

3 Perinatology Research Branch, National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD 20892, USA

4 Department of Obstetrics and Gynecology, Wayne State University School of Medicine and Hutzel Women's Hospital, Detroit, MI 48201, USA

5 Department of Anthropology, The George Washington University, Washington DC 20052, USA

6 Department of Neuroscience, Mount Sinai School of Medicine, New York, NY 10029, USA

7 Department of Anatomy and Cell Biology, Wayne State University School of Medicine, Detroit MI 48201, USA

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BMC Evolutionary Biology 2008, 8:8  doi:10.1186/1471-2148-8-8

Published: 15 January 2008



Many electron transport chain (ETC) genes show accelerated rates of nonsynonymous nucleotide substitutions in anthropoid primate lineages, yet in non-anthropoid lineages the ETC proteins are typically highly conserved. Here, we test the hypothesis that COX5A, the ETC gene that encodes cytochrome c oxidase subunit 5A, shows a pattern of anthropoid-specific adaptive evolution, and investigate the distribution of this protein in catarrhine brains.


In a dataset comprising 29 vertebrate taxa, including representatives from all major groups of primates, there is nearly 100% conservation of the COX5A amino acid sequence among extant, non-anthropoid placental mammals. The most recent common ancestor of these species lived about 100 million years (MY) ago. In contrast, anthropoid primates show markedly elevated rates of nonsynonymous evolution. In particular, branch site tests identify five positively selected codons in anthropoids, and ancestral reconstructions infer that substitutions in these codons occurred predominantly on stem lineages (anthropoid, ape and New World monkey) and on the human terminal branch. Examination of catarrhine brain samples by immunohistochemistry characterizes for the first time COX5A protein distribution in the primate neocortex, and suggests that the protein is most abundant in the mitochondria of large-size projection neurons. Real time quantitative PCR supports previous microarray results showing COX5A is expressed in cerebral cortical tissue at a higher level in human than in chimpanzee or gorilla.


Taken together, these results suggest that both protein structural and gene regulatory changes contributed to COX5A evolution during humankind's ancestry. Furthermore, these findings are consistent with the hypothesis that adaptations in ETC genes contributed to the emergence of the energetically expensive anthropoid neocortex.