The Genetic Code Is Triplet

KEY CONCEPTS
-The genetic code is read in triplet nucleotides called codons.
-The triplets are nonoverlapping and are read from a fixed starting point.
-Mutations that insert or delete individual bases cause a shift in the triplet sets after the site of mutation; these are frameshift mutations.
-Combinations of mutations that together insert or delete three bases (or multiples of three) insert or delete amino acids, but do not change the reading of the triplets beyond the last site of mutation.

Each protein-coding gene encodes a particular polypeptide chain (or chains). The concept that each polypeptide consists of a particular series of amino acids dates from Sanger’s characterization of insulin in the 1950s. The discovery that a gene consists of DNA presents us with the issue of how a sequence of nucleotides in DNA is used to construct a sequence of amino acids in protein.
The sequence of nucleotides in DNA is important not because of its structure per se, but because it encodes the sequence of amino acids that constitutes the corresponding polypeptide. The relationship between a sequence of DNA and the sequence of the corresponding polypeptide is called the genetic code.
The structure and/or enzymatic activity of each protein follows from its primary sequence of amino acids and its overall conformation, which is determined by interactions between the amino acids. By determining the sequence of amino acids in each protein, the gene is able to carry all the information needed to specify an active polypeptide chain. In this way, the thousands of genes found in the genome of a complex organism are able to direct the synthesis of many thousands of polypeptide types in a cell.
Together, the various proteins of a cell undertake the catalytic and structural activities that are responsible for establishing its phenotype. Of course, in addition to sequences that encode proteins, DNA also contains certain control sequences that are recognized by regulator molecules, usually proteins. Here, the function of the DNA is determined by its sequence directly, not via any intermediary molecule. Both types of sequence—genes expressed as proteins and sequences recognized by proteins— constitute genetic information.
The coding region of a gene is deciphered by a complex apparatus that interprets the nucleic acid sequence; this apparatus is essential if the information carried in DNA is to have meaning. The initial step in the interpretation of the genetic code is to copy DNA into RNA. In any particular region it is usually the case that only one of the two strands of DNA encodes a functional RNA, so we write the genetic code as a sequence of bases (rather than base pairs).
(Recent evidence suggests that both strands are transcribed in some regions, but in most cases it is not clear that both resulting transcripts have functional importance.)
A coding sequence is read in groups of three nucleotides, each group representing one amino acid. Each trinucleotide sequence is called a codon. A gene includes a series of codons that is read sequentially from a starting point at one end to a termination point at the other end. Written in the conventional 5′ to 3′ direction, the nucleotide sequence of the DNA strand that encodes a polypeptide corresponds to the amino acid sequence of the polypeptide written in the direction from N-terminus to C-terminus.
A coding sequence is read in nonoverlapping triplets from a fixed starting point:
-Nonoverlapping implies that each codon consists of three nucleotides and that successive codons are represented by successive trinucleotides. An individual nucleotide is part of only one codon.
-The use of a fixed starting point means that assembly of a polypeptide must begin at one end and work to the other, so that different parts of the coding sequence cannot be read independently.
The nature of the code predicts that two types of mutations, base substitution and base insertion/deletion, will have different effects. If a particular sequence is read sequentially, such as
UUU AAA GGG CCC (codons)
aa1 aa2 aa3 aa4 (amino acids; the number reflects different types of amino acids, not position)
a nucleotide substitution, or point mutation, will affect only one amino acid. For example, the substitution of an A by some other base (X) causes aa2 to be replaced by aa5
UUU AAX GGG CCC
aa1 aa5 aa3 aa4
because only the second codon has been changed.
However, a mutation that inserts or deletes a single nucleotide will change the triplet sets for the entire subsequent sequence. A change of this sort is called a frameshift. An insertion might take the following form:
UUU AAX AGG GCC C
aa1 aa5 aa6 aa7
Because the new sequence of triplets is completely different from the old one, the entire amino acid sequence of the polypeptide is altered downstream from the site of mutation, so the function of the protein is likely to be lost completely.
Frameshift mutations are induced by the acridines, compounds that bind to DNA and distort the structure of the double helix, causing additional bases to be incorporated or omitted during
replication. Each mutagenic event in the presence of an acridine results in the addition or removal of a single base pair.

If an acridine mutant is produced by, say, the addition of a nucleotide, it should revert to wild type by deletion of the nucleotide. However, reversion also can be caused by deletion of a different base at a site close to the first. Combinations of such mutations provided revealing evidence about the nature of the genetic code, as is discussed in a moment.
FIGURE 1. illustrates the properties of frameshift mutations. An insertion or deletion changes the entire polypeptide sequence following the site of mutation. However, the combination of an insertion and a deletion of the same number of nucleotides causes the code to be read incorrectly only between the two sites of mutation; reading in the original frame resumes after the second site.

FIGURE 1.Frameshift mutations show that the genetic code is read in triplets from a fixed starting point.
In a 1961 experiment by Francis Crick, Leslie Barnett, Sydney Brenner, and R. J. Watts-Tobin, genetic analysis of acridine mutations in the rII region of the phage T4 showed that all the mutations could be classified into one of two sets, described as (+) and (−). Either type of mutation by itself causes a frameshift: the (+) type by virtue of a base addition, and the (−) type by virtue of a base deletion. Double mutant combinations of the types (+ +) and (− −) continue to show mutant behavior. However, combinations of the types (+ −) and (− +) suppress one another so that one mutation is described as a frameshift suppressor of the other. (In the context of this work, “suppressor” is used in an unusual sense because the second mutation is in the same gene as the first; in fact, these are second-site reversions.)
These results show that the genetic code must be read as a sequence that is fixed by the starting point. Therefore, a single nucleotide addition and deletion compensate for each other, whereas double additions or double deletions remain mutant.
However, these observations do not suggest how many nucleotides make up each codon.
When triple mutants are constructed, only (+ + +) and (− − −) combinations show the wild-type phenotype, whereas other combinations remain mutant. If we take three single nucleotide
additions or three deletions to correspond respectively to the addition or omission overall of a single amino acid, this implies that the code is read in triplets. An incorrect amino acid sequence is found between the two outside sites of mutation and the sequence on either side remains wild type, as indicated in Figure 1.

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