Complex Patterns of Association between Pleiotropy and Transcription Factor Evolution

Pleiotropy has been claimed to constrain gene evolution but specific mechanisms and extent of these constraints have been difficult to demonstrate. The expansion of molecular data makes it possible to investigate these pleiotropic effects. Few classes of genes have been characterized as intensely as human transcription factors (TFs). We therefore analyzed the evolutionary rates of full TF proteins, along with their DNA binding domains and protein-protein interacting domains (PID) in light of the degree of pleiotropy, measured by the number of TF–TF interactions, or the number of DNA-binding targets. Data were extracted from the ENCODE Chip-Seq dataset, the String v 9.2 database, and the NHGRI GWAS catalog. Evolutionary rates of proteins and domains were calculated using the PAML CodeML package. Our analysis shows that the numbers of TF-TF interactions and DNA binding targets associated with constrained gene evolution; however, the constraint caused by the number of DNA binding targets was restricted to the DNA binding domains, whereas the number of TF-TF interactions constrained the full protein and did so more strongly. Additionally, we found a positive correlation between the number of protein–PIDs and the evolutionary rates of the protein–PIDs. These findings show that not only does pleiotropy associate with constrained protein evolution but the constraint differs by domain function. Finally, we show that GWAS associated TF genes are more highly pleiotropic. The GWAS data illustrates that mutations in highly pleiotropic genes are more likely to be associated with disease phenotypes.