“Silent” Genetic Changes May Impact Human Health

New analyses of tens of thousands of people show that genetic changes previously believed meaningless, or “silent,” may in fact play an important but overlooked role in human diseases, including breast cancer.

These silent genetic changes were first discovered when researchers in the 1960s cracked the DNA code. DNA gives cells instructions for making proteins in strings of 3-letter segments, called codons; each 3-letter codon corresponds to a particular amino acid in the protein.

But with 64 possible codons and only 20 amino acids, most amino acids are encoded by several different codons. That redundancy means some DNA mutations will not change the amino acid sequence of the protein. 

Geneticists have generally ignored these synonymous DNA mutations. Yet recent studies have shown that synonymous mutations can influence the amount of protein that is produced; so-called “optimal” codons are faster for cells to process and lead to increased protein production. 

Testing the idea that synonymous mutations are not meaningless requires massive amounts of genetic data, which has only recently become available as more people have their genomes sequenced.

Synonymous mutations under selective pressure

In the new study, Ryan Dhindsa, PhD, and David Goldstein, PhD, at Columbia University’s Institute for Genomic Medicine and colleagues tapped into databases containing nearly 200,000 human genomes and found the first clear evidence that natural selection favors synonymous mutations that improve optimality.

“We found that synonymous mutations that reduce codon optimality appear far less frequently in the population than synonymous mutations that increase optimality,” Dhindsa says. “That shows synonymous mutations are under selective pressure, and we already know that regions of the genome under selective pressure are generally important for human health.”

Silent mutations in BRCA1

A closer gene-by-gene analysis confirmed that genes that are more intolerant to changes in synonymous codons include those associated with cancer, as well as those that cause disease when their expression levels change. 

In BRCA1, for example, a gene well-known for causing breast and ovarian cancer, the study found that mutations that reduce codon optimality may impact the levels of the encoded protein and possibly play an important role in the disease. 

For other researchers who wish to examine the role of silent codons in other genes, Dhindsa created intolerance scores that assess the importance of synonymous codons in each gene.

“These scores will help us locate other potential genes in which synonymous variants that change codon optimality may also cause disease,” Dhindsa says.