Exploring the differences in evolutionary rates between monogenic and polygenic disease genes in human.

Comparative analyses on disease and nondisease (ND) genes have greatly facilitated the understanding of human diseases. However, most studies have grouped all the disease genes together and have performed comparative analyses with other ND genes. Thus, the molecular mechanism of disease on which disease genes can be separated into monogenic and polygenic diseases (MDs and PDs) has been ignored in earlier studies. Here, we report a comprehensive study of PD and MD genes with respect to ND genes. Our work shows that MD genes are more conserved than PD genes and that ND genes are themselves more conserved than both classes of disease genes. By separating the ND genes into housekeeping and other genes, it was found that housekeeping genes are the most conserved among all categories of genes, whereas other ND genes show an evolutionary rate intermediate between MD and PD genes. Although PD genes have a higher number of interacting partners than MD and ND genes, the reasons for their higher evolutionary rate require explanation. We provide evidences that the faster evolutionary rate of PD genes is influenced by 1) the predominance of date hubs in protein-protein interaction network, 2) the higher number of disorder residues, 3) the lower expression level, and 4) the involvement with more regulatory processes. Logistic regression analysis suggests that the relative importance of the four individual factors in determining the evolutionary rate variation among the four classes of proteins is in the order of mRNA expression level > presence of party/date hubs > disorder > involvement of proteins in core/regulatory processes.