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

TL;DR

This paper demonstrates fundamental combinatorial limits on gene regulatory networks based on transcription factors, challenging assumptions about their sufficiency in development and evolution, with implications for understanding biological complexity.

Contribution

It proves that gene regulatory networks with transcription factors are inherently limited by combinatorial principles, contradicting common assumptions about their sufficiency in development and evolution.

Findings

Inherent complexity limits of gene regulatory networks.

Gene regulatory networks cannot fully explain development.

Gene regulatory networks cannot solely account for evolution.

Abstract

Gene Regulatory Networks (GRNs) consisting of combinations of transcription factors (TFs) and their cis promoters are assumed to be sufficient to direct the development of organisms. Mutations in GRNs are assumed to be the primary drivers for the evolution of multicellular life. Here it is proven that neither of these assumptions is correct. They are inconsistent with fundamental principles of combinatorics of bounded encoded networks. It is shown there are inherent complexity and control capacity limits for any gene regulatory network that is based solely on protein coding genes such as transcription factors. This result has significant practical consequences for understanding development, evolution, the Cambrian Explosion, as well as multi-cellular diseases such as cancer. If the arguments are sound, then genes cannot explain the development of complex multicellular organisms and genes cannot explain the evolution of complex multicellular life.