The 6-letter genetic code

A collaborative project by The Scripps Research Institute, Centre National de la Recherche Scientifique and Henan Normal University has seen a stable expansion of the genetic alphabet. Their paper has now been published in PNAS detailing the creation of a semisynthetic organism with a 6-letter genetic code.

 

 

Our genetic code consists of 4 bases: A, T, C, G. These letters are able to form two base pairs which make DNA as we currently know it. In order to create a 6-letter genetic code, additional synthetic nucleotides, X and Y, were added which join to form an unnatural base pair (UBP). Expanding the genetic code created the opportunity to engineer a semisynthetic organism able to store more information.

Abstract: All natural organisms store genetic information in a four-letter, two-base-pair genetic alphabet. The expansion of the genetic alphabet with two synthetic unnatural nucleotides that selectively pair to form an unnatural base pair (UBP) would increase the information storage potential of DNA, and semisynthetic organisms (SSOs) that stably harbor this expanded alphabet would thereby have the potential to store and retrieve increased information. Toward this goal, we previously reported that Escherichia coli grown in the presence of the unnatural nucleoside triphosphates dNaMTP and d5SICSTP, and provided with the means to import them via expression of a plasmid-borne nucleoside triphosphate transporter, replicates DNA containing a single dNaM-d5SICS UBP. Although this represented an important proof-of-concept, the nascent SSO grew poorly and, more problematically, required growth under controlled conditions and even then was unable to indefinitely store the unnatural information, which is clearly a prerequisite for true semisynthetic life. Here, to fortify and vivify the nascent SSO, we engineered the transporter, used a more chemically optimized UBP, and harnessed the power of the bacterial immune response by using Cas9 to eliminate DNA that had lost the UBP. The optimized SSO grows robustly, constitutively imports the unnatural triphosphates, and is able to indefinitely retain multiple UBPs in virtually any sequence context. This SSO is thus a form of life that can stably store genetic information using a six-letter, three-base-pair alphabet.”

The full article is available here: http://tinyurl.com/gsdrec9

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