Hybrid Incompatibility Arises in a Sequence-Based Bioenergetic Model of Transcription Factor Binding

Abstract

Postzygotic isolation between incipient species results from the accumulation of incompatibilities that arise as a consequence of genetic divergence. When phenotypes are determined by regulatory interactions, hybrid incompatibility can evolve even as a consequence of parallel adaptation in parental populations because interacting genes can produce the same phenotype through incompatible allelic combinations. We explore the evolutionary conditions that promote and constrain hybrid incompatibility in regulatory networks using a bioenergetic model (combining thermodynamics and kinetics) of transcriptional regulation, considering the bioenergetic basis of molecular interactions between transcription factors (TFs) and their binding sites. The bioenergetic parameters consider the free energy of formation of the bond between the TF and its binding site and the availability of TFs in the intracellular environment. Together these determine fractional occupancy of the TF on the promoter site, the degree of subsequent gene expression and in diploids, and the degree of dominance among allelic interactions. This results in a sigmoid genotype-phenotype map and fitness landscape, with the details of the shape determining the degree of bioenergetic evolutionary constraint on hybrid incompatibility. Using individual-based simulations, we subjected two allopatric populations to parallel directional or stabilizing selection. Misregulation of hybrid gene expression occurred under either type of selection, although it evolved faster under directional selection. Under directional selection, the extent of hybrid incompatibility increased with the slope of the genotype-phenotype map near the derived parental expression level. Under stabilizing selection, hybrid incompatibility arose from compensatory mutations and was greater when the bioenergetic properties of the interaction caused the space of nearly neutral genotypes around the stable expression level to be wide. F 2 's showed higher hybrid incompatibility than F 1 's to the extent that the bioenergetic properties favored dominant regulatory interactions. The present model is a mechanistically explicit case of the Bateson-Dobzhansky-Muller model, connecting environmental selective pressure to hybrid incompatibility through the molecular mechanism of regulatory divergence. The bioenergetic parameters that determine expression represent measurable properties of transcriptional regulation, providing a predictive framework for empirical studies of how phenotypic evolution results in epistatic incompatibility at the molecular level in hybrids. P OSTZYGOTIC hybrid incompatibility (HI), an important component of reproductive isolation (Coyne and Orr 2004), is usually not due to failure of a single gene, but arises from incompatibilities between interacting genes, as described by the Bateson-Dobzhansky-Muller (BDM) model (Bateson 1909;Dobzhansky 1937;Muller 1942). Recent studies of the genes underlying HI show that this BDM model is well supported and that some form of selection p...

Neighboring genes for DNA-binding proteins rescue male sterility in Drosophila hybrids

“…It is unlikely that either Taf1 or agt was involved in the origin of reproductive isolation between D. simulans and D. mauritiana. Recent experimental evidence (62) and theory (63)(64)(65)(66)(67) imply that certain allele combinations causing partial reproductive incompatibility can be found segregating in natural populations, which suggests that, on an evolutionary timescale, reproductive isolation can evolve very rapidly from standing genetic variation for deleterious allelic mutations causing partial reproductive isolation, even in sympatric populations (68,69).…”

Hybrid Incompatibility Despite Pleiotropic Constraint in a Sequence-Based Bioenergetic Model of Transcription Factor Binding

“…Our shorthand follows a distinction made by evolutionary geneticists when offering alternative explanations, pleiotropy vs. linkage disequilibrium, for correlations between evolving traits (e.g., Hartl and Clark 2007). We characterize the one-domain TF as being mechanistically pleiotropic, while the two-domain TF serves as a control for the potential effects of maximal linkage disequilibrium between otherwise mechanistically independent regulatory sites.We obtain a simple quantitative model of compensatory evolution by applying a bioenergetic, information-based model of transcriptional regulation (Von Hippel and Berg 1986;Gerland et al 2002;Mustonen et al 2008;Tulchinsky et al 2014). We give an overview here and refer the reader to Tulchinsky et al (2014) occupancy-the probability that a TF is associated with its cis-regulatory site at any given moment.…”

“…We treat the phenotype, P, as proportional to the level of expression. We calculate the diploid phenotype as the sum of expression from each of the four allele-specific u9 values, scaled following Tulchinsky et al (2014) so that the maximum phenotype P max = 1.0 for a double homozygote with no mismatches (m = 0).Fitness is a function of an organism's deviation from the optimal phenotypic value at each trait. The total organismal fitness is the product of the marginal fitnesses at each trait and these marginal fitnesses are…”

“…Each mutation changed one bit of information. We varied the mutation rate experimentally as described below.We studied the effects on F 2 hybrid misregulation of the G-P map and marginal fitness landscapes by varying the E diff and DG 1 parameters, using the range of values in Tulchinsky et al (2014). As binding to the genetic background increases with decreasing values of E diff , TF availability at the target binding sites declines rapidly following an exponential function.…”

“…Theoretical studies Porter 2000, 2007;Palmer and Feldman 2009) of the molecular basis of evolving regulatory interactions demonstrate that misregulation in hybrids readily arises as a byproduct of adaptation. Tulchinsky et al (2014) show that the degree of this hybrid incompatibility is determined in large part by the bioenergetic [thermodynamic plus kinetic (Morowitz 1978)] details of the molecular interactions between coevolving transcription factors and the sites to which they bind. BDM incompatibilities between species often express themselves in traits other than those involved in adaptation to divergent environments, although the traits may share a genetic basis (Schluter 2009).…”