The noted geneticist and evolutionary biologist Theodosius Dobzhansky (1900-1975) published an essay in 1973 in the journal American Biology Teacher, titled ‘Nothing in biology makes sense except in the light of evolution’. The title became wildly popular in scientific circles. It was even engraved in the Jordan Hall of Science of the University of Notre Dame in the US.
Recently, an article in the Journal of Molecular Evolution by Qiuhua Xie and Yuange Duan from China Agricultural University, Beijing, posited that even in evolution’s light it is not easy to make sense of the widespread persistence of A-to-I RNA editing in animals and fungi.
A-to-I RNA editing had not yet been discovered in Dobzhansky’s time.
Cooking a protein
The DNA is basically a book of recipes. Each recipe tells the cells in our bodies how to make specific proteins by combining 20 ingredients, called amino acids, in different ways.
Sometimes a recipe is for a single protein, sometimes it’s for multiple. Either way, each recipe is called a gene. The recipes are written in the gene’s own language, which uses an alphabet consisting of four ‘letters’: A, T, G, and C. For example, the ingredient alanine can be written as GCA, glycine can be written as GGT, and so on.
A cell transcribes the recipe to make a protein from a gene in the DNA to an mRNA. Then the cell moves the mRNA from the nucleus to the ribosome, where the mRNA is ‘read’ to make the protein.
Sometimes, after the cell copies a recipe to the mRNA, it switches particular letters in it — specifically, the ‘A’ in the mRNA language above (standing for adenosine) to ‘I’ (inosine). This conversion is called A-to-I mRNA editing. Proteins in the cell called ADAR are responsible for it.
And when a ribosome reads from this mRNA to make the protein, it reads inosine as though it was guanine. Thus, A-to-I mRNA editing results in a protein with an amino acid coded by, say, AXX to be manufactured as the protein with the amino acid encoded by GXX instead.
This can be dangerous.
Why so complicated?
Some letters in the recipe tell a ribosome where the recipe ends. They’re called stop codons. Two examples are UAG and UGA. When the ADAR proteins act on either of them, the ribosome reads them as UGG instead, which is the instruction to insert the amino acid tryptophan. So instead of stopping at that point, the protein under construction receives tryptophan and the ribosome continues until it hits the next stop codon.
The funky part is that while we know ADAR-mediated A-to-I mRNA editing exists, we have no idea why.
For example, if the goal was for a cell to instruct a ribosome to see UGG instead of UAG, it would have been simpler for the DNA to say UGG to begin with. But the ADAR-mediated way is for some unknown reason more complicated: the DNA says UAG, followed by the ADAR proteins intervening to change it to UGG later.
Making sense
In a January 2024 study, researchers from the Northwest A&F University in Yangling, China, posed this question to a fungus called Fusarium graminearum, which infects wheat and barley crops.
But instead of finding another reminder of the mystery, they found a glimpse of a clue.
When F. graminearum grows on an infected plant, i.e. in its vegetative growth stage, its cells don’t do any A-to-I mRNA editing. But when the fungus enters its sexual stage, more than 26,000 sites transcribed from its DNA into mRNA undergo A-to-I mRNA editing.
Why?
The team focused on 71 F. graminearum genes whose coding sequence was interrupted by a UAG stop codon that the ADAR proteins had scrambled. Since the pre-scrambled mRNA version of all these genes contained a premature stop codon, the team called the genes PSC.
When they deleted any one of the PSC genes from the genome, F. graminearum wasn’t affected in its vegetative growth stage. But when they started deleting PSC genes in its sexual stage, there were observable effects.
This proved A-to-I mRNA editing was essential for the proper function of the PSC genes during sexual development.
They also found that the unedited version of two genes (PSC69 and PSC64) helped the fungus resist environmental stresses during the vegetative growth stage. This meant that mutating the A to a G in the DNA would be disadvantageous during asexual growth. These findings together explained why evolution didn’t replace the A in the DNA sequence of these two genes with a G at the beginning of their lives.
Never so easy
Of the 71 genes the team examined, only two seemed to benefit from A-to-I mRNA editing. But what about the other 26,000 sites in the fungus’s genome? It’s possible that over time, the genes that benefit from A-to-I mRNA editing will increase and mRNA editing by ADARs will become an essential component of the gene-expression pathway. At that point, it’s conceivable that more G-to-A mutations will begin to accumulate in the genome, sheltered by the ADAR-based editing machinery.
King Alfonso X (1221-1284) of Spain reputedly grumbled, “If the Lord Almighty had consulted me before embarking upon his creation, I should have recommended something simpler.”
The Beijing researchers seem to have shared this lament but were more prosaic in their articulation. Explaining the net benefit of A-to-I mRNA editing “is far more difficult than revealing its function,” they wrote in their paper.
D.P. Kasbekar is a retired scientist.
Published – May 19, 2025 05:30 am IST