Backup transcription factor binding sites protect human genes from mutations in the promoter

This study was designed to test the idea that human gene promoters have evolved to be resistant to the effects of mutations in their primary function, the control of gene expression. It is proposed that the transcription factor/transcription factor binding site (TF/TFBS) pair having the greatest effect on control of a gene is the one with the highest abundance in the promoter. Other pairs would have the same effect on gene expression and would predominate in the event of a mutation in the most abundant pair. It is expected that the overall promoter architecture proposed here will be highly resistant to mutagenic change that would otherwise affect expression of the gene. The idea was tested beginning with a database of 42 human genes highly specific for expression in brain. For each gene, information was accumulated about its expression level and about the TFBS occupancy of the five most abundant TF/TFBS pairs. Expression level was then plotted against TFBS occupancy separately for each of the five pairs, and the plots were compared with each other. The plots were found to be similar, and the results were interpreted to indicate that the TFBS occupancy ranks evolved to yield the same effect on gene expression level with multiple ranks able to function in the event of mutation in another. A similar analysis was conducted with a database of 31 human liver specific genes, and the overall result was found to be the same. Backup TFBS occupancy ranks were interpreted to be present in both brain and liver specific genes. Finally, the TFBSs in the brain specific and liver specific gene populations were compared with each other with the goal of identifying any brain selective or liver selective TFBSs. Of the 89 TFBSs in the pooled population, 58 were found only in brain specific but not liver specific genes, 8 only in liver specific but not brain specific genes and 23 were found in both brain and liver specific genes. The results were interpreted to emphasize the large number of TFBS in brain specific but not liver specific genes.