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The genetic code is the informational key by which a sequence of mRNA nucleotides corresponding to a gene is translated into the sequence of amino acids composing the protein expressed by that gene. That is, the genetic code specifies which amino acids will be used to build a protein. You can think of the code as consisting of a series of sequential, non-overlapping, three-letter “words.” The three “letters” represent three adjacent nucleotide bases in the mRNA polynucleotide. Each three-letter “word” is called a codon, and each codon specifies a particular amino acid. Each codon is complementary to the corresponding triplet of bases in the DNA molecule from which it was transcribed. In short, the genetic code relates codons to their specifically encoded amino acids.

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CHARACTERISTICS OF THE CODE Molecular biologists “broke” the genetic code in the early 1960s. The problem they addressed was perplexing: how could more than 20 “code words” be written with an “alphabet” consisting of only four “letters”? In other words, how could four bases (A, U, G, and C) code for 20 different amino acids?

A triplet code, based on three-letter codons, was considered likely. Since there are only four letters (A, G, C, and U), a one-letter code clearly could not unambiguously encode 20 amino acids; it could encode only four of them. A two-letter code could have only 4 × 4 = 16 unambiguous codons—still not enough. But a triplet code could have 4 × 4 × 4 = 64 codons, more than enough to encode the 20 amino acids.

Marshall W. Nirenberg and J. H. Matthaei, at the U.S. National Institutes of Health, made the first decoding breakthrough in 1961 when they realized that the code would be easier to break if they were working with a very simple, known mRNA sequence rather than with a complex natural mRNA molecule. They set out to synthesize mRNA molecules consisting of just one type of nucleotide base; poly U mRNA, for example, consisted of just uracil nucleotides. Nirenberg and Matthaei’s goal was to then identify, through a translation process conducted in a test tube, the polypeptide that the artificial messenger encoded. Their experiment, which is laid out in Investigating Life: Deciphering the Genetic Code, led to the identification of the first codons. Other scientists soon identified the rest of the code. This was a major achievement, linking the information in DNA (the gene) to its expression in a protein (the phenotype). The understanding that the amino acids for each protein are spelled out via codons not only led to our understanding of the fundamentals of genetics and mutation, but to investigations into the genetic underpinnings of disease, such as the development of resistance in MRSA described in the opening of this chapter.

The complete genetic code is shown in Figure 14.5. Notice that there are many more codons than there are different amino acids in proteins. Proteins are built from just 20 amino acids, but all possible combinations of the four available “letters” (the bases) give 64 (4³) different three-letter codons. Why are there more codons than amino acids? One reason is that there is more than one codon for almost all amino acids. For example, leucine is represented by six different codons (see Figure 14.5). Only methionine and tryptophan are represented by just one codon each. Thus we say that the genetic code is redundant (or degenerate). Also, a few select codons serve functions other than coding for amino acids. AUG, for example, not only codes for methionine but is also the start codon, the initiation signal for translation. Three codons (UAA, UAG, UGA) are stop codons, or termination signals for translation. When the translation machinery reaches one of these codons, translation stops and the polypeptide is released from the translation complex.

Don’t confuse a redundant code with an ambiguous code. If the code were ambiguous, a single codon could specify two (or more) different amino acids, and there would be doubt about which amino acid should be incorporated into a growing polypeptide chain. Redundancy in the code simply means there is more than one clear way to say “Put leucine here.” The genetic code is not ambiguous: a given amino acid may be encoded by more than one codon, but a codon can code for only one amino acid.

THE GENETIC CODE IS (NEARLY) UNIVERSAL The same basic genetic code is used by all the species on our planet. Thus the code must be an ancient one that has been maintained intact throughout the evolution of living organisms. Exceptions are known: for example, the code for *mitochondrial DNA and chloroplast DNA differs slightly from that used by prokaryotes and for the nuclear DNA of eukaryotic cells; and in one group of protists, UAA and UAG code for glutamine rather than for stop codons. The significance of these differences is not yet clear. What is clear is that the exceptions are few.

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A common genetic code provides a common language for evolution. Natural selection acts on phenotypic variations that result from genetic variation. The genetic code probably originated early in the evolution of life. As we saw in Chapter 4, simulation experiments indicate the plausibility of individual nucleotides and nucleotide polymers arising spontaneously on primeval Earth. The common code also has profound implications for genetic engineering, as we will see in Chapter 18, since it means that the code for a human gene is the same as that for a bacterial gene. It is therefore impressive, but not surprising, that a human gene can be expressed in E. coli via laboratory manipulations, since these cells speak the same “molecular language.”

The codons illustrated in the Nirenberg and Matthaei experiment in Investigating Life: Deciphering the Genetic Code are mRNA codons. The base sequence of the DNA strand that is transcribed to produce the mRNA is complementary and antiparallel to these codons. Thus, for example, 3′-AAA-5′ in the template DNA strand corresponds to phenylalanine (which is encoded by the mRNA codon 5′-UUU-3′).

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The non-template strand of DNA has the same sequence as the mRNA (but with T’s instead of U’s), and is often referred to as the “coding strand.” By convention, DNA sequences are usually shown beginning with the 5′ end of the coding sequence.

You might be thinking that in a long DNA molecule with many protein-coding regions, one strand is the coding strand for all the genes and the other strand is the template strand. In fact, some genes are transcribed from one strand and some genes are transcribed from the other. There is strand switching along a long DNA molecule in terms of the roles of the two strands. So while one strand may not be said to be “the” coding strand for all genes in a particular DNA molecule, for a given gene it is correct to say that one strand is coding and its complementary strand is template.