UK researchers challenge ‘nearly neutral theory’ of DNA evolution

All organisms have some portion of their DNA that does not code for proteins, but the amounts vary greatly. Bacteria average about 2% non-coding DNA, while in humans the non-coding DNA comes to 98% of the total.

Some have referred to these non-coding regions as “junk” DNA or “bloated” genomes, assuming they have no apparent purpose. A prevailing explanation for the wide variation in its prevalence is called the “nearly neutral theory.” This is the idea that for small population sizes genomes become bloated with "junk" because it is hard for natural selection to purge it.

Nearly neutral theory correctly predicts that many genomic parameters, including germline mutation rates (known as heritable errors), are positively correlated with the effective population size of a species. 

The authors of a recent study at the Milner Centre for Evolution at the University of Bath, UK, wanted to see if the nearly neutral theory could also explain nonheritable errors such as somatic mutations.

To study these nonheritable errors, the authors chose to study translational read through. The study by Alexander Ho and Laurence Hurst appeared in the journal Molecular Biology and Evolution in January 2021. 

How proteins are made

To produce a protein, a sequence of base pairs in the DNA must be copied into a strand of messenger RNA, which is then used as a template for manufacturing the sequence of amino acids that makes up a protein. 

The process of encoding the messenger RNA is called transcription, the first step in gene expression. After being encoded, the RNA guides the assembly and manufacture of amino acid chains into a protein. This is the second step of gene expression known as translation. 

But what about the errors that occur in protein synthesis? Do these show a correlation to effective population size? To find out, the authors compared data from different species on the error rates that occur in a stage of protein synthesis known as translational read-through. 

The stop codon

To signal when to stop adding on the amino acids that form a protein, the messenger RNA contains built in signaling devices called stop codons. However, this termination process is not 100% efficient. 

When the signal from the stop codon fails to stop the protein assembly, it is called translational or stop codon read-through. As this error in translation is fairly common, messenger RNA may contain additional stop codons (ASCs) that act to terminate the translation process. Population geneticists describe the presence of ASCs as a “mitigation strategy.” 

The authors investigated whether the rate of read-through errors and the prevalence of additional stop codons correlated to the effective population size of a species. Previous theory suggested that when population sizes are high, there would be more additional stop codons. 

Contrary to prediction, the authors find that population size is not correlated with the number of additional stop codons.

Additional stop codons are present both in unicellular species (usually of high population size) and in multicellular species when the genes are expressed in unicellular modes. 

However they did find that the presence of a specific primary stop codon, known as TAA, was correlated to population size. 

These results imply,” the authors conclude, “that local phenotypic error rates not local mitigation rates are consistent with a drift barrier/nearly neutral model.” 

––––––––––––––––

Alexander Ho and Laurence Hurst. Effective Population Size Predicts Local Rates but Not Local Mitigation of Read-through Errors, Molecular Biology and Evolution (2021). DOI: https://doi.org/10.1093/molbev/msaa210