Tradeoffs between transcriptional robustness and dosage sensitivity in development
Sahin Naqvi | Division of Gastroenterology at Boston Children's Hospital
Abstract:
Developmental systems must balance robustness to perturbations with sensitivity to a broad range of regulatory inputs, a tradeoff that underpins both stability and adaptability. Transcription factors (TFs) embody this tension; while development is broadly buffered against quantitative changes in TF dosage, human genetics has revealed exquisite sensitivity, as exemplified by haploinsufficiency and dosage-sensitive disease phenotypes. I will discuss how, by precisely quantifying the effects of craniofacial TF dosage on molecular and cellular phenotypes, we arrived at a model that reconciles dosage sensitivity with robustness. In this model, most SOX9-dependent regulatory elements and genes are robust to quantitative changes in TF dosage, while others act as sensitive effectors, amplifying small changes in dosage into phenotypic diversity or vulnerability. I will discuss the generalizability of this model and some evolutionary implications.