Natural and artificial variations of the standard genetic code.

The nearly universal standard genetic code is one of the strongest indications for the common ancestry of all extant life. Yet new code variants representing different combinations of codon reassignments have been and continue to be discovered with regular frequency. Recently, many man-made codes have been generated that direct the incorporation of unnatural amino acids, allowing for biocontainment and viral resistance. However, evolutionary and synthetic biologists often seem to be unaware of the developments in the other camp's field. Here we attempt to bridge this gulf and provide an updated overview of different codon reassignments and genetic code variants reported to occur naturally in organisms and their organelles, both now containing over 50 examples. We review the highly expanded range of departures from the standard genetic code, highlighting previously unanticipated code forms and their molecular underpinnings. To account for cases when a codon has a different meaning depending on its context, such as in variants with no dedicated termination codons discovered over the past decade in protists, we introduce the concept of codon homonymy. Considering this new appreciation for the prevalence of genetic code diversity, we also revisit the questions of how and why genetic codes get altered in evolution. Finally, we summarize the current status of artificially redesigned genetic codes, which are increasingly deviating from natural code alterations, opening up completely novel translational possibilities.

Copyright © 2025 Elsevier Inc. All rights reserved.