| Evolution, from a biological perspective, means the process of species emergence, development and elimination due to the combined effect of inheritance, variation and natural selection. It is one of the essential characteristics of all creatures. During evolution, closely related species, like flowers and pollinating insects, hosts and parasites, predator and prey, have developed the traits that are related with the other party of the game. This is defined as co-evolution, which appears to be a quite interesting phenomenon in evolution.At the molecular level, mutation on the nucleotide or amino acid sequence is believed to be selectively neutral. Therefore, the function and 'fate' of the gene is decided by mutation and subsequent random drift. However, some genes related to important bio-function appear to evolve in a different pattern. In order to maintain their biological function or co-ordinate smoothly with their up/downstream factors, closely related molecules tend to evolve in a coordinated fashion, which is called molecular co-evolution. Molecular co-evolution demonstrated that closely related genes have experienced similar evolution process. The co-evolving characteristics can be at different level, e.g. genomic, sequence, or expression level. The analysis of these characteristics can promote the understanding of gene functions. Co-evolution analysis has been implemented in some prokaryotic species. In eukaryotic species, due to their different genome structure, molecular phylogenetic analysis based on amino acid sequence appears to be more suitable.Insulin/IGF signaling pathway widely exists in different species ranging from yeast to human. This evolutionarily conserved pathway is related with different functions, such as development, metabolism, blood sugar regulation, etc. Recent research shows that it is also related with longevity. By using quantitative method in comparing phylogenetic trees, we conducted co-evolution analysis upon insulin/IGF related pathways in various eukaryotic species, e.g. human, chimpanzee, mouse, rat, chicken, zebrafish and fugu. The genes concerned include insulin, IGF-I, IR, IGF-IR, IRS, covering the common key genes in the pathway. Through sequence gathering, evolution matrix construction, and evolutionaily related analysis, we come to understand the co-evolving relation between different genes in the pathway. The result shows that some proteins with known interaction have higher correlated coefficient, whereas that of those without interaction is comparatively lower. Genes with no interaction and the negative control group have even significantly lower correlated coefficient. Meanwhile, based on co-evolution analysis, we predicted the functions of duplicated genes in fishes as well as possible IRS orthologous genes in chicken.Based on these researches, we conducted similar co-evolution analysis on three human genes, DUSP18, PP2Ck and LNX. These new genes are clonedand reported by our laboratory and analyzed via yeast two-hybrid. We selected sequences for the three genes and their interacting genes (detected by yeast two-hybrid) from 11 higher animals and calculated their co-evolutionary coefficient. According the tendency we have found in previous study, (i.e. Interacting molecules have higher correlation coefficient.) we ranked those genes according to their coefficient. On the basis of the ranking, we identified some genes with high level of interaction and excluded those with too low coefficient. Moreover, combined with their known functional clues, we predicted some candidate genes for further functional study.
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