‘Silent’ gene mutations can be harmful, not neutral – Futurity

Most “silent” genetic mutations are highly harmful, not neutral, new research using yeast in the lab shows.

In the early 1960s, Marshall Nirenberg and several other scientists deciphered the genetic code of life and determined the rules by which information in DNA molecules is translated into proteins, the working parts of 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, for which Nirenberg later shared a Nobel Prize with two others.

Occasionally, some letter misspellings occur in the genetic code, known as point mutations. Point mutations that alter the resulting protein sequences are called non-synonymous mutations while those that do not alter the protein sequences are called silent or synonymous mutations.

Between a quarter and a third of point mutations in protein-coding DNA sequences are synonymous. Since the genetic code has been cracked, it has been widely believed that these mutations are neutral, or nearly so.

The new research, published in Naturerefutes that assumption.

Synonym mutations

The strong non-neutrality of most synonymous mutations — if found to be true for other genes and in other organisms — would have major implications for the study of human disease mechanisms, population and conservation biology, and evolutionary biology, according to the study authors.

“Since the genetic code was resolved in the 1960s, synonymous mutations have been widely believed to be benign. We are now showing that this belief is false,” said senior author Jianzhi “George” Zhang, a professor in the University of Michigan’s Department of Ecology and Evolutionary Biology.

“Since many biological conclusions are based on the assumption that synonymous mutations are neutral, their invalidity has broad implications. For example, synonymous mutations are generally ignored in the study of disease-causing mutations, but they may be an undervalued and general mechanism.”

Over the past decade, anecdotal evidence has suggested that some synonymous mutations are non-neutral. Zhang and his colleagues wanted to know whether such cases are the exception or the rule.

They chose to answer this question in budding yeast (Saccharomyces cerevisiae) because the organism’s short generation time (about 80 minutes) and small size allowed them to measure the effects of a large number of synonymous mutations relatively quickly, accurately and easily.

They used CRISPR/Cas9 genome editing to construct more than 8,000 mutated yeast strains, each carrying a synonymous, non-synonymous, or nonsense mutation in one of the 21 genes the researchers targeted.

They then quantified the “fitness” of each mutant strain by measuring how fast it reproduced relative to the non-mutant strain. Darwinian fitness, simply put, refers to the number of offspring an individual has. In this case, measuring the reproduction rates of the yeast strains showed whether the mutations were beneficial, deleterious or neutral.

To their surprise, the researchers found that 75.9% of the synonymous mutations were significantly harmful, while 1.3% were significantly beneficial.

Time to investigate

“The previous anecdotes of non-neutral synonymous mutations proved to be the tip of the iceberg,” said lead author Xukang Shen, a graduate student research assistant in Zhang’s lab.

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

Zhang says that based on the anecdotal reports, the researchers knew in advance that some synonymous mutations would likely turn out to be non-neutral.

“But we were shocked by the sheer number of such mutations,” he says. “Our results imply that synonymous mutations are almost as important as non-synonymous mutations in disease causation and require greater effort in predicting and identifying pathogenic synonymous mutations.”

The researchers say that while there is no specific reason why their results would be limited to yeast, confirmations in different organisms are needed 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

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