Evolving Gene-Regulatory Networks

(Guy Coe) #1

From the first paper cited:


" Because GRN topology is encoded directly in cis -regulatory sequence at its nodes, evolutionary changes in this sequence have great potency to alter developmental GRN structure and function. But there are many kinds of cis -regulatory change that affect function in different ways, ranging from loss of function, to quantitative change in function, to qualitative gain of function resulting in redeployment of gene expression."
So, what brings on "evolutionary changes in GRN cis-regulatory sequences?"
From the second paper cited:

“There are similarities between the developmental networks that build organ systems, called gene regulatory networks (GRNs), and the cellular networks that control behavior. One link is explicit: the development of the brain and specific neuronal subpopulations are encoded in the genome by GRNs.”
So, it would seem that altering GRN sequences could potentially also have an immediate effect on social behaviors?
From the third paper cited:

“Throughout evolution, regulatory networks need to expand and adapt to accommodate novel genes and gene functions. However, the molecular details explaining how gene networks evolve remain largely unknown. Recent studies demonstrate that changes in transcription factors contribute to the evolution of regulatory networks. In particular, duplication of transcription factors followed by specific mutations in their DNA-binding or interaction domains propels the divergence and emergence of new networks. The innate promiscuity and modularity of regulatory networks contributes to their evolvability: duplicated promiscuous regulators and their target promoters can acquire mutations that lead to gradual increases in specificity, allowing neofunctionalization or subfunctionalization.”
So, what kinds of things can effect GRN “adaptation” or "evolvability?"
From a fourth paper:

“The rewiring of gene regulatory networks can generate phenotypic novelty. It remains an open question, however, how the large number of connections needed to form a novel network arise over evolutionary time. Here, we address this question using the network controlled by the fungal transcription regulator Ndt80. This conserved protein has undergone a dramatic switch in function—from an ancestral role regulating sporulation to a derived role regulating biofilm formation. This switch in function corresponded to a large-scale rewiring of the genes regulated by Ndt80. However, we demonstrate that the Ndt80-target gene connections were undergoing extensive rewiring prior to the switch in Ndt80’s regulatory function. We propose that extensive drift in the Ndt80 regulon allowed for the exploration of alternative network structures without a loss of ancestral function, thereby facilitating the formation of a network with a new function.”
So, when a protein switches function, novel things happen. What leads to such changes in protein function? A slightly altered folding pattern might, for example.
These are just the first few footfalls down a path headed through, yes, fantastical territory, but which are at least analogous to known scientific findings, to the best of my knowledge. Obviously, I’m not going to be mistaken for a careful scientist by saying so, and please excuse my almost certain ignorance of what even seems possible, scientifically.
Cheers!

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Coe's Epigenetic/Enzymatic Implicated Fall
(Guy Coe) #2

Again with the analogies:
A fifth paper:


(Psychoactive, hallucinogenic effects of ingested substances) " For centuries, Central American cultures considered Psilocybe mushrooms to be divine and used them for spiritual purposes. More recently, they have been called magic mushrooms and used for their hallucinogenic effects. These mushroom drugs may soon also be in use as pharmaceuticals that treat the existential anxiety of advanced-stage cancer patients, depression, and nicotine addiction. Their effects stem from tryptamines, which are chemical derivatives of the amino acid L-tryptophan and structural relatives of the neurotransmitters serotonin and melatonin. Among these, psilocybin is the primary chemical mushroom component. Psilocybin is an inactive precursor that is rapidly activated when consumed: splitting off a phosphate group results in the actual active ingredient, psilocin."
From an article:
https://cen.acs.org/articles/95/web/2017/08/Magic-mushroomenzyme-mystery-solved.html
“During their study, Hoffmeister and coworkers sequenced the genomes of two mushroom species to identify the genes that govern fungal enzymatic production of psilocybin. They further used engineered bacteria and fungi to confirm the gene activity and exact order of synthetic steps. This process includes a newly discovered enzyme that decarboxylates tryptophan, an enzyme that adds a hydroxyl group, an enzyme that catalyzes phosphorylation, and an enzyme that mediates two sequential amine methylation steps. With that knowledge in hand, the team designed a one-pot reaction using three of the enzymes to prepare psilocybin from 4-hydroxy-L-tryptophan.”

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