The four nucleotides that comprise DNA are called adenine (A), thymine (T), guanine (G) and cytosine (C). In a molecule of DNA, nucleotides form base pairs with a unique molecular geometry called Watson and Crick geometry, named for the scientists who discovered the double-helix structure of DNA in 1953. These Watson and Crick pairs always form in the same configurations: A-T and C-G. The double-helix structure of DNA is formed when many Watson and Crick base pairs come together. "This is a remarkably effective system for encoding biological information, which is why serious mistakes in transcription and translation are relatively rare," said Wang. The study uses a new version of the standard genetic alphabet, called the Artificially Expanded Genetic Information System (AEGIS), that incorporates two new base pairs. The result: the enzymes that transcribe DNA can't tell the difference between these synthetic base pairs and those found in nature.

 

"In biology, structure determines function," said Wang. This hypothesis, called the tautomer hypothesis, says the standard four nucleotides can form mismatched pairs due to tautomerization, or the tendency of nucleotides to oscillate between several structural variants with the same composition. This phenomenon is thought to be one source of point mutations, or genetic mutations that only impact one base pair in a DNA sequence. Tautomerization of mispairs has been observed in replication and translation processes, but here researchers provide the first direct structural evidence that tautomerization also happens during transcription. The researchers are next interested in testing whether the effect they observed here is consistent in other combinations of synthetic base pairs and cellular enzymes.