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Most “silent” genetic mutations are severely harmful, not neutral, according to new research with yeast in the lab.
In the early 1960s, Marshall Nirenberg and several other scientists deciphered the genetic code of life, determining the rules by which information from DNA molecules is translated into proteins, the working parts of cells. living cells.
They identified three-letter units in DNA sequences, known as codons, that specify each of the 20 amino acids that make up proteins, work for which Nirenberg later shared a Nobel Prize with two others.
Occasionally, single-letter misspellings occur in the genetic code, known as point mutations. Spot mutations that alter the resulting protein sequences are called non-synonymous mutations, while those that do not alter protein sequences are called silent or synonymous mutations.
Between one-fourth and one-third of point mutations in DNA sequences encoding proteins are synonymous. Since the genetic code was broken, it has generally been assumed that these mutations were neutral, or nearly so.
The new research, published in Nature, contradicts this assumption.
Synonymous mutations
According to the study’s authors, the strong non-neutrality of most synonymous mutations, if found to be true for other genes and in other organisms, would have important implications for the study of the mechanisms of human disease. population biology and conservation and evolutionary biology.
“Since the genetic code was resolved in the 1960s, it has been generally thought that synonymous mutations were benign. We now show that this belief is false,” says lead author Jianzhi “George” Zhang, a professor in the department. of Ecology and Evolutionary Biology from the University of Michigan.
“Because many biological findings are based on the presumption that synonymous mutations are neutral, their invalidation has broad implications. For example, synonymous mutations are generally ignored in the study of disease-causing mutations, but they could be a common and underappreciated mechanism “.
Over the past decade, anecdotal evidence has suggested that some synonymous mutations are not neutral. Zhang and his colleagues wanted to know if these cases were the exception or the rule.
They chose to address this issue in yeast germ (Saccharomyces cerevisiae) because the body’s short generation time (about 80 minutes) and small size allowed them to measure the effects of a large number of synonymous mutations with relative speed, accuracy and convenience.
They used CRISPR / Cas9 genome editing to construct more than 8,000 mutant yeast strains, each with a synonymous, non-synonymous, or meaningless mutation in one of the 21 genes targeted by the researchers.
They then quantified the “fitness” of each mutant strain by measuring how quickly it reproduced relative to the non-mutant strain. Darwinian fitness, in a nutshell, refers to the number of offspring an individual has. In this case, the measurement of the reproductive rates of the yeast strains showed whether the mutations were beneficial, harmful or neutral.
To their surprise, the researchers found that 75.9% of synonymous mutations were significantly harmful, while 1.3% were significantly beneficial.
Time to research
“Previous anecdotes of non-neutral synonymous mutations turned out to be the tip of the iceberg,” says lead author Xukang Shen, a research assistant for graduate students at Zhang’s lab.
“We also looked at the mechanisms by which synonymous mutations affect physical condition, and we found that at least one of the reasons is that both synonymous and non-synonymous mutations alter the level of gene expression, and the extent of this expression effect predicts the effect of fitness “.
Zhang says researchers knew in advance, based on anecdotal reports, that some synonymous mutations would likely be non-neutral.
“But we were surprised by the large number of these mutations,” he says. “Our results imply that synonymous mutations are almost as important as non-synonymous mutations when it comes to causing disease and call for a strengthened effort to predict and identify pathogenic synonymous mutations.”
Researchers say that while there is no particular reason why their results would be restricted to yeast, confirmations are required in various bodies to verify the generality of their findings.
The other authors of the study are from the University of Michigan and Stanford University. The National Institutes of Health supported the work.
Source: University of Michigan