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. 2008 Jan 15:8:8.
doi: 10.1186/1471-2148-8-8.

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

Monica Uddin  1 , Juan C Opazo, Derek E Wildman, Chet C Sherwood, Patrick R Hof, Morris Goodman, Lawrence I Grossman
Affiliations

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

Monica Uddin et al. BMC Evol Biol. .

Abstract

Background: 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.

Results: 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.

Conclusion: 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.

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Figures

Figure 1
Figure 1
Phylogenetic tree depicting the omega ratios and (number of nonsynonymous and synonymous substitutions) for COX5A in each branch of the tree, as estimated by PAML under the free ratio (M1) model. "0" and "*" indicate, respectively, lineages on which the number of nonsynonymous and synonymous changes, as well as dN and dS, were estimated to be effectively 0 (i.e., < 0.00004); and lineages on which the number of synonymous changes was estimated to be 0 (i.e., omega is undefined). The anthropoid, New World monkey and ape stems, indicated in red, depict a classic pattern of positive selection [22]: markedly increased dN relative to dS followed by descendant lineages with a markedly decreased dN relative to ds.
Figure 2
Figure 2
Phylogenetic tree depicting amino acid replacements inferred in COX5Ap within the anthropoid clade determined via maximum parsimony (ACCTRAN and DELTRAN) as implemented in PAUP* [51], and the codon substitution model [52] implemented in PAML 3.15. Non-prosimian outgroup species are not shown. Bold type indicates positively selected amino acids identified via the branch site test using PAML (Table 1). * Amino acid replacements in which the charge has changed, ** amino acid replacements in which the polarity has changed.
Figure 3
Figure 3
COX5A Expression levels as determined by quantitative RT-PCR (solid bars) and microarray signal values (hatched bars). qRT-PCR expression levels are expressed in relative terms, with samples compared to a calibrator amplified from human reference total RNA and represented as species means (± SEM). Samples were tested in triplicate, providing 9 total measurements for human and macaque and three total measurements for chimpanzee and gorilla. Microarray expression levels were as determined in [24].
Figure 4
Figure 4
Immunohistochemical staining of COX5A protein in the dorsolateral prefrontal cortex. The distribution of staining using a monoclonal antibody against COX5Ap in macaque monkey (A), chimpanzee (B), and human (C). Panels D-L show double label immunostaining from macaque monkey. Images in A-I are taken from layer III. Images in J-L are taken from layer I. Scale bar in panel A = 50 μm applies to A-C. Scale bar in D = 25 μm applies to D-L.
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