A New Mechanism for Mendelian Dominance in Regulatory Genetic Pathways: Competitive Binding by Transcription Factors

We report a new mechanism for allelic dominance in regulatory genetic interactions that we call binding dominance. We investigated a biophysical model of gene regulation, where the fractional occupancy of a transcription factor (TF) on the cis-regulated promoter site it binds to is determined by binding energy (-G) and TF dosage. Transcription and gene expression proceed when the TF is bound to the promoter. In diploids, individuals may be heterozygous at the cis-site, at the TF's coding region, or at the TF's own promoter, which determines allele-specific dosage. We find that when the TF's coding region is heterozygous, TF alleles compete for occupancy at the cis-sites and the tighter-binding TF is dominant in proportion to the difference in binding strength. When the TF's own promoter is heterozygous, the TF produced at the higher dosage is also dominant. Cis-site heterozygotes have additive expression and therefore codominant phenotypes. Binding dominance propagates to affect the expression of downstream loci and it is sensitive in both magnitude and direction to genetic background, but its detectability often attenuates. While binding dominance is inevitable at the molecular level, it is difficult to detect in the phenotype under some biophysical conditions, more so when TF dosage is high and allele-specific binding affinities are similar. A body of empirical research on the biophysics of TF binding demonstrates the plausibility of this mechanism of dominance, but studies of gene expression under competitive binding in heterozygotes in a diversity of genetic backgrounds are needed.