Differences in Promoters of Orthologous Genes

Abstract

Human genetic experiments are often conducted based on the orthologous genes in other mammals such as mouse and rat. The resulting conclusions of such experiments are often limited in their applicability to the human situation. This has raised a question as to why the orthologous genes with closely related or even identical coding regions behave differently in various mammals, and motivated us to study the promoter of these genes. We proposed a functional promoter similarity index (FPSI) based on the number of putative, but statistically significant associations (p ≤ 0.05) between transcription factors and their target orthologous genes. We deduced such association through searching known transcription factor binding sites from promoters of the genes. The FPSI was validated using microarray gene expression data. We did pair-wise study of seven vertebrate genomes (human, chimpanzee, mouse, rat, dog, chicken, and zebrafish). The FPSIs of orthologous genes are generally high between human and chimpanzee, with a mean FPSI of 0.79, but gradually decrease when human is compared to the mouse (0.22), rat (0.2), dog (0.2), chicken (0.13) or zebrafish (0.06). We then performed an analogous analysis for 2128 human cancer-associated genes and the results were similar, but had significantly improved FPSIs between these human genes and their orthologs in mouse, rat, and dog. The differences in the promoter regions of orthologous genes appear to be genome wide and negatively correlated with divergence time of the organisms. Such correlation suggests that the FPSI could be used as a measure of phylogenetic conservation.