Dominance and interloci interactions in transcriptional activation cascades: Models explaining compensatory mutations and inheritance patterns

Abstract

Mutations in human genes encoding transcription factors are often dominant because one active allele cannot ensure a normal phenotype (haploinsufficiency). In other instances, heterozygous mutations of two genes are required for a phenotype to appear (combined haploinsufficiency). Here, we explore with models (i) the basis of haploinsufficiency and combined haploinsufficiency owing to mutations in transcription activators, and (ii) how the effects of such mutations can be amplified or buffered by subsequent steps in a transcription cascade. We propose that the non-linear (sigmoidal) response of transcription to the concentration of activators can explain haploinsufficiency. We further show that the sigmoidal character of the output of a cascade increases with the number of steps involved, the settings of which will determine the buffering or enhancement of the effects of a decreased concentration of an upstream activator. This exploration provides insights into the bases of compensatory mutations and on interloci interactions underlying oligogenic inheritance patterns.

Recombination initiation maps of individual human genomes

“…Such cooperative interactions could modulate hotspot strength without changing binding specificity and may result in partial dominance (see (44) for discussion). In the case of PRDM9 binding we have clear partial dominance of one allele over the other (fig.…”

Causes and effects of haploinsufficiency

“…cHI has been observed in mice for the homeobox proteins Otx1 and Otx2 (Suda et al, 1999), hoxb-5 andhoxb-6 (Rancourt, Tsuzuki, &Capecchi, 1995), and Otx2 and hepatocyte nuclear factor 3-beta (HNF3B) (Jin et al, 2001). cHI is an example of genetic synergy (digenic/oligogenic inheritance) and may arise when insufficient amounts of TFs act on the same promoters, but also when they are the main regulators of successive steps in a transcription cascade (Bost & Veitia, 2014). Saccharomyces cerevisiae has also been used to screen for cHI.…”

Cis–trans controls and regulatory novelty accompanying allopolyploidization

“…Even for cis–trans relationships that were relatively stable during diploid divergence, it may be inappropriate to simply assume additive inheritance in a polyploid nucleus, because parental species do not necessarily share the same regulatory circuits even when their expression outputs are equivalent (Tsong et al ., ). According to the Hill equation (Chu et al ., ; Bost & Veitia, ), the binding of a transcription factor (TF) to DNA exhibits a nonlinear relationship with the effective concentration of a TF, which is further dependent on the affinity and cooperativity of TF binding (modeled by dissociation constant K and Hill coefficient n , respectively). Upon hybridization, the concentrations of homoeologous TFs may be different from parental values (e.g.…”