Most “Silent” Mutations Are Actually Harmful

Synonymous mutations have long been thought to have relatively no impact.

A new study finds that most “silent” mutations are harmful rather than neutral.

Marshall Nirenberg, a University of Michigan alumni, and a small group of researchers cracked the genetic code of life in the early 1960s, figuring out the rule by which information stored in

Occasionally, single-letter misspellings in the genetic code, known as point mutations, occur. Nonsynonymous mutations are point modifications that alter the protein sequences that result from them, while silent or synonymous mutations do not change the protein sequences.

One-quarter to one-third of protein-coding DNA sequence point mutations are synonymous. They have often been thought to be neutral or almost neutral mutations ever since the genetic code was deciphered.

But in a study recently published Nature that involved the genetic manipulation of yeast cells in the laboratory, University of Michigan biologists show that most synonymous mutations are strongly harmful.

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 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…

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