Amino Acid Sequence Evidence on the Phylogeny of Primates and Other Eutherians

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Cytochrome c (CYC) oxidase (COX), a multisubunit enzyme that functions in mitochondrial aerobic energy production, catalyzes the transfer of electrons from CYC to oxygen and participates in creating the electrochemical gradient used for ATP synthesis. Modeling three-dimensional structural data on COX and CYC reveals that 57 of the >1,500 COX residues can be implicated in binding CYC. Because of the functional importance of the transfer of electrons to oxygen, it might be expected that natural selection would drastically constrain amino acid replacement rates of CYC and COX. Instead, in anthropoid primates, although not in other mammals, CYC and COX show markedly accelerated amino acid replacement rates, with the COX acceleration being much greater at the positions that bind CYC than at those that do not. Specifically, in the anthropoid lineage descending from the last common ancestor of haplorhines (tarsiers and anthropoids) to that of anthropoids (New World monkeys and catarrhines) and that of catarrhines (Old World monkeys and apes, including humans), a minimum of 27 of the 57 COX amino acid residues that bind CYC were replaced, most frequently from electrostatically charged to noncharged residues. Of the COX charge-bearing residues involved in binding CYC, half (11 of 22) have been replaced with uncharged residues. CYC residues that interact with COX residues also frequently changed, but only two of the CYC changes altered charge. We suggest that reducing the electrostatic interaction between COX and CYC was part of the adaptive evolution underlying the emergence of anthropoid primates. mitochondria ͉ electron transport chain ͉ molecular coevolution C ytochrome c (CYC) and the subunits of CYC oxidase (COX) are mitochondrial-functioning proteins that play a central role in aerobic energy production. By catalyzing the transfer of electrons from CYC to oxygen, COX greatly increases an electrochemical gradient used for ATP synthesis. As a consequence of their critical function, mutations altering the structures of either CYC or COX must face the close scrutiny of natural selection. Among vertebrates, relatively few amino acid replacements have occurred in the structures of CYC and COX. However, against this background of slow rates of CYC and COX evolution, upsurges in COX and CYC amino acid replacement rates occurred during the emergence and evolution of the larger brained primates (members of Anthropoidea) (1-12). Here, by using atomic resolution structural data on bovine COX (13) and horse CYC (14) and an experimentally verified model of the interaction between COX and CYC (15, 16), we identify, among the Ͼ1,500 amino acid residues of COX, 57 residues that are likely to bind CYC during delivery of electrons to oxygen. We then demonstrate that the amino acid replacement rate acceleration in anthropoid lineages is especially pronounced in the subset of COX residues that can bind CYC. We further demonstrate that, among these CYC-binding COX residues, many amino acid replacements were from charge-bearing [electros...

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confidence: 98%

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confidence: 99%

Rapid electrostatic evolution at the binding site for cytochrome c on cytochrome c oxidase in anthropoid primates

Schmidt

Wildman

Uddin

et al. 2005

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“…The origin of the order Cetacea has been the subject of many investigations. Recent molecular evidences suggest that Cetaceans are monophyletic with Artiodactyla (32)(33)(34)(35)(36)(37). Members of the order Artiodactyla surveyed in this study (cow, camel, llama, hippopotamus, and giraffe) do not show any significant variations in their Hoxc8 early enhancer sequences.…”

Section: Discussionmentioning

confidence: 50%

Comparative studies on mammalian Hoxc8 early enhancer sequence reveal a baleen whale-specific deletion of a cis-acting element

Shashikant

Kim

Borbély

et al. 1998

Variations in regulatory regions of developmental control genes have been implicated in the divergence of axial morphologies. To find potentially significant changes in cis-regulatory regions, we compared nucleotide sequences and activities of mammalian Hoxc8 early enhancers. The nucleotide sequence of the early enhancer region is extremely conserved among mammalian clades, with five previously described cis-acting elements, A-E, being invariant. However, a 4-bp deletion within element C of the Hoxc8 early enhancer sequence is observed in baleen whales. When assayed in transgenic mouse embryos, a baleen whale enhancer (unlike other mammalian enhancers) directs expression of the reporter gene to more posterior regions of the neural tube but fails to direct expression to posterior mesoderm. We suggest that regulation of Hoxc8 in baleen whales differs from other mammalian species and may be associated with variation in axial morphology.

“…[23] Now s(p) has the form of an upright bowl resting on the point s(p)dp, ,u(1 + 3S)-Y2. [28] Not only does the overdominance effect go away, but also no mutants can slip between the old allele and the optimum.…”

Section: Two Models With a Continuum Of Possible Allelesmentioning

confidence: 99%

“…Anomaly 2. Goodman et al (23) report, in the lineage leading to humans, two periods of accelerated substitution rates: (i) the period from 500 to 300 million years ago, during the rise of the jawed fishes and the tetrapods; and (ii) the period between 90 and 40 million years ago, which includes the rise of the primates. The proteins they track include globins, cytochrome c, carbonic anhydrases, fibrinopeptides, and a crystallin.…”

Section: For Nearly Neutral Theory Population Size Mattersmentioning

confidence: 99%

Molecular clock rates at loci under stabilizing selection.

Foley

1987

Under stabilizing selection in a finite population, X, the rate of aflelic substitutions at a locus is approximately A ,I(1 + S)-'½, where iA is the mutation rate. S, the stringency of selection upon new mutants, is defined by SNVm/Vs, where N is the population size and Vm/Vs is a measure of the average fitness decrease experienced by new mutants. The approximation holds both for a "lonely" locus, which is the sole provider of genetic variation for the character under selection, and for an "embedded" locus, which is not. In both cases I use the Crow and Kimura model of a continuum of alleles with Gaussian selection and mutation. Monte Carlo simulations corroborate the substitution rate formula. Some molecular evolution data suggest the potential utility and limitations of the formula for estimating population size, mutation, and selection parameters. This work agrees with the rest of nearly neutral theory in emphasizing the important role of population size for substitution rates.Under a strictly neutral theory of molecular evolution, allelic substitutions would occur at an expected rate of X = 2Nguu(1/2N) = g, [1] where X is the substitution rate, ,u is the mutation rate, N is the population size, and u(1/2N) is the substitution probability. Under a less strict, effectively neutral theory, one could expect [2] where p is the rate of appearance of neutral mutants, and p > p (1). But this model, which corresponds to Kimura's original proposal, depends on the deleterious mutants being so bad that they have no chance of becoming fixed. Meanwhile, new neutral alleles must have substitution probability 1/2N for Eq. 2 to work exactly. Thus, Ohta (2), Kimura (3), and others (4-7) have developed more sophisticated nearly neutral models in which new mutants can assume any of a continuum of selection coefficients. The effectively neutral mutation rate might then be defined, as in ref. 3, by the rate of mutations to alleles with a selection coefficient less than 1/2N. Kimura (3), for example, showed that Eq. 2 holds approximately when selection coefficients are distributed according to a Gamma density.Most students of natural selection agree that at the phenotypic level, stabilizing selection rules. In this paper, I obtain an approximation for X, when the locus of interest is at equilibrium under stabilizing selection. The present work builds on the work of Kimura (8) in which the nearly neutral theory was first extended to this important special case.I show that the approximation is fairly robust to deviations from the assumptions of the model that engenders it. Monte Carlo simulations using a variant of the pseudosamplingvariable method of Kimura and Takahata (9) also corroborate the analytic results. The substitution rate formula can be used, with some discretion, to investigate DNA sequencedivergence data. Two Models with a Continuum of Possible AllelesCrow and Kimura (10) introduced a model for the study of quantitative characters under stabilizing selection that has since been put to considerable use (11,12)....