Supplementary Material for: Correlated Evolution of Gonadotropin-Releasing Hormone and Gonadotropin-Inhibitory Hormone and Their Receptors in Mammals

<b><i>Background:</i></b> Evolutionary rate variation in genes (proteins) is manifested both within the species (genome) and between the species (genomes). However, the interdependent components of a biological system in form of a gene or a protein are expected to evolve in a correlated manner under a common functional constraint. <b><i>Methods:</i></b> The phylogenetic analysis and correlation analysis of gonadotropin-releasing hormone (GnRH) and gonadotropin-inhibitory hormone (GnIH) and their receptors (GnRHR and GnIHR) was conducted along with other control neuropeptides. <b><i>Results:</i></b> Both neuropeptides and their receptors regulating the reproductive neuroendocrine axis in vertebrates exhibited a correlated evolution under a common physiological constraint to regulate the release of gonadotropin. This result supports a coordinated substitution of amino acids in the GnRH and the GnIH neuropeptides along with their receptors in terms of similar evolutionary rates and distances with similar nucleotide composition of genes. <b><i>Conclusion:</i></b> This is the first demonstration of the correlated evolution of two components of an endocrine system regulating the release of gonadotropin which are acting in concert for successful reproduction.