  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 (-{\Delta}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.
