Abstract
Modular genetic systems and networks have complex evolutionary histories shaped by selection acting on single genes as well as on their integrated function within the network. However, uncovering molecular coevolution requires the detection of coevolving sites in sequences. Detailed knowledge of the functions of each gene in the system is also necessary to identify the selective agents driving coevolution. Using recently developed computational tools, we investigated the effect of positive selection on the coevolution of ten major genes in the melanocortin system, responsible for multiple physiological functions and human diseases. Substitutions driven by positive selection at the melanocortin-1-receptor (MC1R) induced more coevolutionary changes on the system than positive selection on other genes in the system. Contrarily, selection on the highly pleiotropic POMC gene, which orchestrates the activation of the different melanocortin receptors, had the lowest coevolutionary influence. MC1R and possibly its main function, melanin pigmentation, seems to have influenced the evolution of the melanocortin system more than functions regulated by MC2-5Rs such as energy homeostasis, glucocorticoid-dependent stress and anti-inflammatory responses. Although replication in other regulatory systems is needed, this suggests that single functional aspects of a genetic network or system can be of higher importance than others in shaping coevolution among the genes that integrate it.
Highlights
Characterizing the organization of an organism into autonomous genetic and phenotypic modules has gained strong theoretical and empirical interest [1,2,3,4]
We focused on the 10 major genes of the melanocortin system (POMC, PCSK1, PCSK2, MC1-5R, ASIP, and AGRP), whose sequences were obtained for a total of 138 species representing the main vertebrate lineages (16 birds, 2 snakes, 7 lizards, 1 turtle, 1 monotreme, 3 marsupials, 81 placental mammals, 3 amphibians, 1 coelacanth, 20 teleost fish, 2 sharks, and 1 lamprey species: Supplementary Materials Figure S1)
Similar levels of identity have been observed for other genes such as those associated with the regulation of general vertebrate development [30,31] and it is in line with the conserved functions of the melanocortin system across vertebrates [11,13]
Summary
Characterizing the organization of an organism into autonomous genetic and phenotypic modules has gained strong theoretical and empirical interest [1,2,3,4]. Recently-developed computational tools can complement our understanding of molecular evolution within a genetic system or network by estimating the probability that a nucleotide site coevolved with a site in another gene across a phylogenetic tree [8,9] The use of such tools is a major difference in relation to previous studies, where only the coevolution within a protein or gene sequence (e.g., due to structural constraints) could be considered [10]. The melanocortin system is a key hormonal pathway that exhibits the features of a module It is composed of a set of G protein-coupled membrane receptors (MC1-5R) responsible for the regulation of very distinct functions in vertebrates: from pigmentation to metabolic homeostasis and sexual behavior (Figure 1) [11,12,13,14,15,16,17]. Down-regulation of the MC receptors activity, is triggered by binding the antagonists and inverse agonists: the agouti-signaling protein (ASIP, or ASIP1 the fish orthologue of the mammalian ASIP [17]) and the agouti-related protein (AgRP), in a tissue and melanocortin-receptor dependent manner [22]
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