Genetic code

Abstract

What is it? As we all learned in high school, the so-called ‘universal’ or standard genetic code is the set of rules that define the correspondence between the ‘20’ amino acids in proteins and groups of ‘three’ bases (codons) in the mRNA. Is the code universal? No. Although most organisms have the same genetic code, researchers began to discover exceptions to the ‘universal’ code in 1979, and today we know of more than 15 alternative codes; each has just a few differences from the standard code, indicating common ancestry from this code. Several of these codes arose independently a number of times in evolution and are present in a variety of taxa. Is the genetic code limited to 20 amino acids? No. The first exception was selenocysteine, encoded by the stop codon UGA in genes with a lenoysteine nsertion equence (SECIS) element. Selenocysteine is used in several proteins and is found in every domain of life. In 2002, a 22nd amino acid – pyrrolysine – was found to be encoded by UAG in the genetic code of some Archaea and possibly Eubacteria species. It is not yet clear if other signals in the mRNA are necessary to specify this amino acid. Can we change the genetic code? Yes. Recent studies have successfully engineered aminoacyl-tRNA synthetases and tRNAs to incorporate several unnatural amino acids in the code of prokaryotes and eukaryotes. In 2003, a strain of E. coli capable of autonomously synthesizing and incorporating an artificial amino acid into proteins was developed. Do codons need to be three bases long? Not necessarily. Studies showed that the E. coli translational machinery is capable of accommodating four and even five base codons. But these seem to be the limits for possible codon sizes: functional two or six base codons have not yet been found, despite efforts to create them. A number of naturally occurring suppressor tRNAs exhibit four-base anticodons, and several studies of artificial genetic code expansion use four base codons to incorporate new amino acids into the code. I heard about a ‘frozen accident’… One of the first proposals, in 1968, for the origin of the code, was Francis Crick's ‘frozen accident’ model. But the discovery of alternative codes showed that the code is not frozen. And similar codons are assigned to similar amino acids, indicating that the code is not an accident. So, how did the code evolve? There are several theories that try to explain the origin of the code. Most can be classified in one of three major groups. Chemical: posits that direct chemical interactions between amino acids and their cognate codons/anticodons influenced codon assignment. Studies of binding of RNA aptamers to amino acids showed that, for at least some amino acids – arginine, tyrosine and isoleucine – such chemical interactions do exist. These theories fail to explain the assignment of codons that do not show direct interactions to their cognate amino acids. Historical: proposes that an initially smaller code grew by incorporation of new amino acids. For example, new amino acids may have captured codons from their metabolic precursors, contributing to the assignment of similar amino acids to similar codons. Selection: suggests that the code was selected to minimize the phenotypic effects of point mutations. The code's organization supports this: nonsynonymous substitutions often lead to replacement of an amino acid by one chemically similar, causing little disruption in the protein. Accumulating evidence for these models suggests that they are not mutually exclusive. Rather, the code probably evolved by an interplay among some or all of them. Direct interactions of short RNA molecules and amino acids may have fixed the assignment of certain codons, while subsequent assignments may have been driven by history and selection. Why study the genetic code? The near universality of the genetic code is one of the major indications that all life on Earth descends from a common ancestor, and the presence of alternative codes can sometimes be used as a marker for phylogenetic relationships. Besides the obvious utility in helping to understand the origins and evolution of life, the study of the genetic code also has several practical applications. For instance, studies of code expansion by incorporation of artificial amino acids are used to help determine protein structure and catalytic mechanisms. These studies may also provide a way to develop proteins with new chemical functionalities not available using the natural amino acids. Where can I find out more?