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Gene Regulatory Networks (GRNs) consisting of combinations of transcriptionfactors (TFs) and their cis promoters are assumed to be sufficient to directthe development of organisms. Mutations in GRNs are assumed to be the primarydrivers for the evolution of multicellular life. Here it is proven that neitherof these assumptions is correct. They are inconsistent with fundamentalprinciples of combinatorics of bounded encoded networks. It is shown there areinherent complexity and control capacity limits for any gene regulatory networkthat is based solely on protein coding genes such as transcription factors.This result has significant practical consequences for understandingdevelopment, evolution, the Cambrian Explosion, as well as multi-cellulardiseases such as cancer. If the arguments are sound, then genes cannot explainthe development of complex multicellular organisms and genes cannot explain theevolution of complex multicellular life.

Combinatorial Limits of Transcription Factors and Gene Regulatory Networks in Development and Evolution