Scientists for years have known that the genetic code found in all living things contains many layers of complexity. But new research from the University of Rochester cracks the code more deeply, clarifying for example why some genes are inefficiently translated into proteins.
In a study published in the journal Cell, the researchers, co-led by Beth Grayhack, Ph.D., of the UR School of Medicine and Dentistry, discovered the existence and identity of 17 pairs of inefficient codons (DNA nucleotides or bases) within the genetic code.
Scientists have generally considered each piece of the genetic code (or codon) as a single “word” in a language. But the new data suggests some codon combinations act as compound words or phrases whose order and pairing has a significant impact on the translation of genes into proteins.
“Consider the words ‘pancake’ versus ‘cake pan,’ “ said Grayhack, an associate professor of Biochemistry and Biophysics, Pediatrics, and Cancer, in the Center for RNA Biology, at the UR Medical Center. “Switching the word order conveys very different meaning and function. The same is true for the words (codons) in the genetic code. Our work provides proof of this and as a result, it revises the scientific understanding of how the code is read.”
The genetic code, which transmits the directions to make every protein in an organism, consists of 64 triplets of nucleotides. Each triplet is a codon. While the identity of the proteins resulting from the genetic code has been known for 50 years, the code also affects the amount and function of the resulting proteins in ways that scientists do not completely understand. In order to know how gene changes drive diseases, scientists first must learn how to read the genetic code completely and appreciate how changes in the code impact the function of genes.
For instance, the function of a multidrug resistance gene, which plays a central role in how a person responds to chemotherapy and other drugs, is altered by a particular change in one codon.
Prior studies have shown that altering codons affects gene expression and function—but the mechanisms have remained baffling because, until now, the identities of the inhibitory codons or codon pairs were unknown.
In the current study, the research team reasoned that by focusing extensive analysis on a small region in a single gene in yeast, they might identify specific codon combinations that reduced gene expression. Grayhack and Christina Brule, a graduate student in the Grayhack lab, collaborated with Stan Fields, Ph.D. of the University of Washington, and co-author Caitlin Gamble, also in Seattle. Brule led the analysis of a library of more than 35,000 fluorescent protein variants using advanced technology in the URMC Flow Cytometry Core facility, followed by deep sequencing at the University of Washington. The team identified the 17 codon pairs acting in concert with one another to inhibit gene expression and slow the ribosome.
Their findings can be described in terms of roadways, Grayhack said: “Good” codons that efficiently make proteins are like superhighways for gene translation. Until now, the remaining single codons were lumped into a “suboptimal” category, likened to a dirt road. The group’s latest data shows that within the suboptimal category, the inefficiency of the 17 newly discovered codon pairs is analogous to adding a sharp curve in the dirt road.
The discovery paves the way for more investigation into how the codon pairs work to cause inefficient translation and their purpose in gene expression. Grayhack and Brule are collaborating with Dave Mathews, M.D., Ph.D., associate professor of Biochemistry and Biophysics at URMC, and members of his lab, to research the functional importance of codon pairs.
The National Science Foundation and the National Institutes of Health funded the research.
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