Silencing, Positive Selection and Parallel Evolution: Busy History of Primate Cytochromes c

Abstract

Cytochrome c (cyt c) participates in two crucial cellular processes, energy production and apoptosis, and unsurprisingly is a highly conserved protein. However, previous studies have reported for the primate lineage (i) loss of the paralogous testis isoform, (ii) an acceleration and then a deceleration of the amino acid replacement rate of the cyt c somatic isoform, and (iii) atypical biochemical behavior of human cyt c. To gain insight into the cause of these major evolutionary events, we have retraced the history of cyt c loci among primates. For testis cyt c, all primate sequences examined carry the same nonsense mutation, which suggests that silencing occurred before the primates diversified. For somatic cyt c, maximum parsimony, maximum likelihood, and Bayesian phylogenetic analyses yielded the same tree topology. The evolutionary analyses show that a fast accumulation of non-synonymous mutations (suggesting positive selection) occurred specifically on the anthropoid lineage root and then continued in parallel on the early catarrhini and platyrrhini stems. Analysis of evolutionary changes using the 3D structure suggests they are focused on the respiratory chain rather than on apoptosis or other cyt c functions. In agreement with previous biochemical studies, our results suggest that silencing of the cyt c testis isoform could be linked with the decrease of primate reproduction rate. Finally, the evolution of cyt c in the two sister anthropoid groups leads us to propose that somatic cyt c evolution may be related both to COX evolution and to the convergent brain and body mass enlargement in these two anthropoid clades.

Evolution of the Couple Cytochrome c and Cytochrome c Oxidase in Primates

“…Its existence as a testis-specific isoform (Hüttemann et al, 2003) is satisfying since Cyc c , which has a testis isoform in mammals, appears to bind to COX by first interacting with COX6B (Sampson and Alleyne, 2001; Hüttemann et al, 2003). However, Cyc c testis (Cyct) is lost at the stem of primates (Pierron et al, 2011a) whereas COX6B2 is not. Interestingly, in rodents, which express Cyct, Cox6b2 is the exclusive testes form; humans, which have lost Cyct, express both COX6B isoforms in testes.…”

“…The loss of the testes isoform produces lower fecundity (Narisawa et al, 2002). A detailed recent analysis of the somatic form of Cyt c across primates suggested parallel evolution in both the platyrrhine and catarrhine stems (Pierron et al, 2011a). Examination of the sites of evolutionary changes suggests they are focused on the respiratory chain rather than on other Cyt c functions, such as apoptosis.…”

“…In contrast (but not in contradiction), we suggest that evolution of the Cyt c -COX couple in primates allowed an increase of ROS production in the male germ line. Indeed, we have shown that a Cyt c testis isoform was present in ancestral mammals and it became a pseudogene before primate differentiation (Pierron et al 2011a). Interestingly, when Cyt c testis isoform is silenced in knock-out mice, these mice produce functional but less efficient spermatozoids due to reduced free radical scavenging (Narisawa et al, 2002; Liu et al, 2006).…”

“…One of the notable features is the degree to which changes have taken place at the stem of anthropoid primates or within primate lineages. Cyt c has undergone several periods of accelerated evolution followed by consolidation (purifying selection) in which replacements were concentrated in regions that participate in OxPhos (Baba et al, 1981; Pierron et al, 2011a) and in addition the testes specific isoform that is present in mammals becomes inactivated at the stem of anthropoid primates (Pierron et al, 2011a). For the 13 subunits of COX, 10 have undergone accelerated evolution in anthropoid primates (Grossman et al, 2004).…”

Dolphin genome provides evidence for adaptive evolution of nervous system genes and a molecular rate slowdown

“…Here, we found that CYCS, an electron acceptor of the electron transport chain, has also undergone accelerated evolution on the cetacean lineage. Genes expressed in the mitochondria, especially those of the electron transport chain and CYCS specifically, have experienced accelerated evolution in anthropoid primates as well [10,69]. Examination of the dolphin -anthropoid proteins shows four site differences; half of them are in a region previously suggested to be in the binding site for interaction with complex IV [69], with one of them being identical to the anthropoid site.…”