PgmNr D1473: Competitive binding of transcription factors drives dominance in regulatory genetic pathways.

Authors:
A. H. Porter 1 ; N. A. Johnson 1 ; A. Y. Tulchinsky 2


Institutes
1) Univ Massachusetts, Amherst, MA; 2) SUNY New Paltz, New Paltz, NY.


Keyword: computational models

Abstract:

We report a new mechanism for allelic dominance in regulatory genetic interactions and its sensitivity to genetic background.  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 (–ΔG) and TF concentration.  Transcription and gene expression proceed at the regulated cis site while the trans-acting TF is in the bound state.  In diploids, individuals may be heterozygous at the cis-site promoter, at the TF’s coding region, or at the TF’s own promoter, which determines allele-specific TF concentration.  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 concentration is also dominant.  Cis-site heterozygotes have additive and therefore codominant phenotypes.  While this dominance is inevitable at the molecular level, it may be difficult to detect in the phenotype under some biophysical conditions, more so when TF concentration is high. In three-locus linear pathways of loci A->B->C where A and B are TF’s, dominance propagates down the pathway: locus A can show dominance with respect to expression at locus C.  This dominance is attenuated at the phenotypic level such that only low-expression A alleles appear recessive, especially when TF concentration is high at the B locus.  Two types of genetic background effects occur.  In the proximal background of the two-locus interaction, where a TF is heterozygous in both its promoter and coding sites, their effects on competitive binding interact to increase, decrease or even reverse dominance of the other; heterozygosity in the cis-site promoter has no effect.  In more distant interactions of three-locus pathways, locus A’s dominance with respect to C-locus expression can be modified by allelic variation at locus B, especially at its coding site.  Many empirical findings of dominance in TF and cis-site interactions in the literature can be explained by this simple mechanism of competitive binding.