U.S., Swedish scientists examine differences in amino acid evolution

An international group of scientists has tested the nearly neutral theory of evolution, proposed in 1973 by Japanese geneticist Tomoko Ohta. He predicted that natural selection will have a different evolutionary effect on species depending on the organism's population size.

A smaller population, according to Ohta, will be less able to purge mutations that are slightly deleterious. In contrast, a larger effective population size will have fewer deleterious mutations.

The scientists tested the nearly neutral theory of evolution with respect to amino acid frequencies in different species. They found that the theory was able to identify to subtle differences in natural selection preferences.

Their research appears in a preprint article on bioRxiv, posted Feb. 3. The authors are from Stanford University, the University of Arizona, and Uppsala University in Sweden.

Investigating amino acids

Amino acids are the building blocks of proteins. Their frequencies are measured in terms of their number of codons, the three nucleotides that make up a DNA or RNA molecule. The researchers studied whether amino acid frequencies are selected to help the quality of a protein in the course of evolution.

The researchers examined whether differences in organism population size could predict the selection of amino acid frequencies. They also looked at whether differences in population size affected amino acid flux. In both cases, they found that the nearly neutral theory could be successfully applied to biochemistry.

The team used two methods of testing the nearly neutral theory. The first measured net amino acid fluxes, that is the gains of an amino acid minus losses of an amino acid in an evolutionary trajectory. In this approach the researchers studied differences in amino acid fluxes between rodents and hominids.

The second approach used a new metric, the Codon Adaptation Index of Species, or CAIS, "to quantify how the effectiveness of selection influences outcomes across a broader range of vertebrate species, i.e. we ask whether this metric predicts amino acid frequencies," the researchers write.

The scientists looked at which amino acids are preferred in two evolutionary groups that branched off, humans and chimpanzees, and mice and rats.

As the authors note, each of the two methods has "distinct assumptions and biases."

"Where both methods agree, we have greater confidence that we have detected a real evolutionary trend, namely the greater effectiveness of subtle forms of selection in high [nearly neutral effective population size] species on amino acid frequencies," they write.

Results and future research

Both methods in general agreed on "which amino acids are preferred in vertebrates," the researchers conclude, and they note that the outcome metric had "better statistical resolution."

Specifically, they write, "The most striking preferences are between pairs of biochemically similar amino acids, with selection preferring arginine over lysine and valine over isoleucine. More preferred amino acids tend to have more benign effects when expressed as part of random peptides in E. coli."

The authors found that amino acid frequency differences "depend on the effectiveness of selection on the species as a whole," as measured by CAIS. Previously, the researchers note, these frequency differences were attributed to metabolism differences, availability in the environment and environment and body temperature.

"There are many metrics one can use to order the 20 amino acids," they said. "Here we provide two more, which to our knowledge uniquely capture the subtle preferences of selection. We compare our new metrics to disorder propensity, size, metabolic cost, tendency to benign effects in E. coli, and trends with respect to domain age. ... Much can be learned about proteins and their evolution, through these comparisons, and finding points of overlap or lack thereof."

Regarding further research along these lines, the authors suggest the two methods that they developed could be used to examine other traits than amino acid frequencies and in a greater range of species.

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Hanon McShea et al. "The effectiveness of selection in a species affects the direction of amino acid frequency evolution." bioRxiv, Feb. 3, 2023.

https://doi.org/10.1101/2023.02.01.526552