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Most ‘silent’ genetic mutations are harmful, study says

by Vaishali Sharma

According to a University of Michigan research, point mutations that change the resultant protein sequences are referred to as nonsynonymous mutations, whereas those that do not change the protein sequences are referred to as silent or synonymous mutations.

One-quarter to one-third of protein-coding DNA sequence point mutations are synonymous. Those alterations were often thought to be neutral or nearly so. A recent study utilising the genetic modification of yeast cells reveals that the vast majority of synonymous mutations are extremely detrimental.

They discovered three-letter units in DNA sequences known as codons that designate each of the 20 amino acids that make up proteins, work for which Nirenberg received a Nobel Prize together with two others.

Point mutations are single-letter misspellings in the genetic code that occur on occasion. Nonsynonymous mutations are those that change the resultant protein sequences, whereas silent or synonymous mutations do not change the protein sequences.

One-quarter to one-third of protein-coding DNA sequence point mutations are synonymous. Since the genetic code was deciphered, such alterations have been thought to be neutral or almost so.

However, in a study involving the genetic manipulation of yeast cells in the laboratory and slated for online publication on June 8 in the journal Nature, University of Michigan biologists reveal that most synonymous mutations are extremely detrimental.

According to the research authors, the high non-neutrality of most synonymous mutations, if shown to be true for additional genes and animals, would have major consequences for the study of human disease processes, population and conservation biology, and evolutionary biology.

“Since the genetic code was solved in the 1960s, synonymous mutations have been generally thought to be benign. We now show that this belief is false,” said study senior author Jianzhi “George” Zhang, the Marshall W. Nirenberg Collegiate Professor in the U-M Department of Ecology and Evolutionary Biology.

“Because many biological conclusions rely on the presumption that synonymous mutations are neutral, its invalidation has broad implications. For example, synonymous mutations are generally ignored in the study of disease-causing mutations, but they might be an underappreciated and common mechanism.”

Anecdotal evidence has revealed that certain synonymous mutations are nonneutral in the last decade. Zhang and his colleagues were curious whether such situations were the exception or the rule.

They chose budding yeast (Saccharomyces cerevisiae) to investigate this subject because the organism’s short generation period (approximately 80 minutes) and tiny size allowed researchers to test the impact of a large number of synonymous mutations relatively rapidly, accurately, and easily.

Also Read: A new study reveals that different types of cancer are caused by identical mutations

They employed CRISPR/Cas9 genome editing to create over 8,000 mutant yeast strains, each with a synonymous, nonsynonymous, or nonsense mutation in one of 21 genes selected by the researchers.

They next measured how rapidly each mutant strain reproduced in comparison to the nonmutant strain to determine its “fitness.” Simply expressed, Darwinian fitness refers to the number of children an individual has. In this situation, determining whether the mutations were helpful, detrimental, or neutral was determined by assessing the reproductive rates of the yeast strains.

Surprisingly, the researchers discovered that 75.9% of synonymous mutations were considerably detrimental, whereas 1.3 percent were significantly helpful.

“The previous anecdotes of nonneutral synonymous mutations turned out to be the tip of the iceberg,” said study lead author Xukang Shen, a graduate student research assistant in Zhang’s lab.

“We also studied the mechanisms through which synonymous mutations affect fitness and found that at least one reason is that both synonymous and nonsynonymous mutations alter the gene-expression level, and the extent of this expression effect predicts the fitness effect.”

Zhang said the researchers knew beforehand, based on the anecdotal reports, that some synonymous mutations would likely turn out to be nonneutral.

“But we were shocked by a large number of such mutations,” he said. “Our results imply that synonymous mutations are nearly as important as nonsynonymous mutations in causing disease and call for strengthened effort in predicting and identifying pathogenic synonymous mutations.”

The U-M-led team said that while there is no particular reason why their results would be restricted to yeast, confirmations in diverse organisms are required to verify the generality of their findings.

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