Genetic Code

1.0What is a Genetic Code?

The concept of the genetic code was initially proposed by George Gamow, suggesting a fundamental relationship between nucleotide sequences and the amino acids they encode. The actual deciphering of the genetic code was achieved through the groundbreaking work of Marshall Nirenberg, Heinrich Matthaei, and Har Gobind Khorana. Their research illuminated how sequences of amino acids in proteins are determined by the sequences of nucleotides in DNA or its RNA transcript.

Proteins are composed of 20 different amino acids, each specified by the genetic information encoded in DNA. During transcription, the genetic instructions in DNA are transcribed to mRNA, transferring the information through complementary nitrogenous base pairing. Each amino acid is represented by a specific sequence of nucleotides on the mRNA, known as a codon. Thus, a codon is a triplet of nucleotides on mRNA that specifies a particular amino acid. The entirety of these codons, comprising the mRNA molecule, forms the genetic code, which encompasses all necessary information for polypeptide chain synthesis.

Triplet Codon

The central challenge in understanding the genetic code involved determining the precise number of nucleotides within a codon required to specify each of the 20 different amino acids. Messenger RNA (mRNA) is composed of four types of nitrogenous bases: adenine (A), uracil (U), guanine (G), and cytosine (C). The complexity arose in figuring out how combinations of these four bases could encode 20 distinct amino acids.

A singlet code, where each codon is composed of a single nitrogen base, would produce only four possible codons (A, U, G, C). This arrangement is inadequate because it allows for only four amino acids to be specified, far less than the 20 needed.

Calculation: 4¹ =4 codons

A doublet code, with codons made up of two nitrogen bases, increases the number of possible codons to 16 (by considering all possible base pairs).

Calculation: 4²=16 codons

However, 16 codons are still insufficient to represent all 20 amino acids.

Recognizing these limitations, George Gamow, in 1954, proposed the concept of a triplet code. In this model, each codon consists of three nitrogen bases, which significantly expands the coding capacity.

Triplet code calculation: 4³=64 codons

With 64 possible codons, this system is more than adequate to encode all 20 amino acids. This realization was pivotal in understanding the genetic code's structure, providing a sufficient number of codons to not only represent each amino acid but also include start and stop signals necessary for protein synthesis.

2.0Genetic Code Table

3.0Characteristics of Genetic Code 

• Triplet Nature: A codon in genetics consists of three contiguous nitrogen bases on the mRNA, each specifying a single amino acid in a polypeptide chain. For example, an mRNA strand with 90 nitrogen bases would determine a polypeptide chain of 30 amino acids, as the 90 bases form 30 codons, each coding for one amino acid.
• Universality: The genetic code is nearly universal across all forms of life, from viruses and bacteria to unicellular and multicellular organisms. This universality suggests a common evolutionary origin for all life.
• Non-Ambiguity and Specificity: Each codon uniquely specifies only one amino acid, making the genetic code non-ambiguous. However, an exception exists with the GUG codon, which can code for both valine and, in some cases, methionine, highlighting a rare instance of ambiguity.
• Non-Overlapping: Each nitrogen base is part of only one codon, ensuring that codons do not overlap within the genetic sequence. 

• Commaless: Codons are sequenced continuously without any punctuation between them. This arrangement means that adding or deleting a nucleotide can shift the reading frame, altering the amino acid sequence synthesized thereafter. For instance, a mutation in the middle of a sequence specifying 50 amino acids could result in the correct synthesis of the first 25 amino acids, but the remaining sequence would be altered.

• Degeneracy: With 64 possible codons and only 20 amino acids, most amino acids are encoded by more than one codon, a feature known as degeneracy of genetic code. This characteristic was discovered by Baurnfield and Nirenberg.

There are three amino acids encoded by six different codons: serine, leucine, arginine. Only two amino acids are specified by a single codon; one of these is the amino-acid methionine, specified by the codon AUG, which also specifies the start of translation; the other is tryptophan, specified by the codon UGG. The degeneracy of the genetic code is what accounts for the existence of silent mutations.

Degeneracy results because a triplet code designates 20 amino acids and a stop codon. Because there are four bases, triplet codons are required to produce at least 21 different codes. For example, if there were two bases per codon, then only 16 amino acids could be coded for (4²=16). Because at least 21 codes are required, then 4³ gives 64 possible codons, meaning that some degeneracy must exist.

4.0Wobble Hypothesis

According to this hypothesis, the base in the first position of anticodon on tRNA is usually an abnormal base, like inosine, pseudouridine, tyrosine, etc. These abnormal bases are able to pair with more than one type of nitrogenous base in the third position of the codon on mRNA.

 eg. Inosine (I) can pair with A, C, or U. This base is called a Wobble base or fluctuating base. Wobble occurs at position 1 of the anticodon and position 3 of the codon.

 The wobble hypothesis states that the third position (3') of the codon on mRNA and the first position (5') of the anticodon on tRNA are bound less tightly than the other pair and therefore, offer unusual base combinations.

 A single amino acid may be specified by many codons, i.e. called degeneracy. Degeneracy is due to the last base in a codon, which is known as a wobble base. Thus the first two codons are more important in determining the amino acid and the one differs without affecting the coding known as the Wobble hypothesis. 

Thus according to this, in codon-anticodon pairing, the third base of the tRNA anticodon does not have to pair with a complementary codon. It is called a wobble base and this position is called the wobble position. The actual base pairing occurs in the first two positions only. 

5.0Types of Genetic Code

1. Chain Initiation Codons

• Protein synthesis begins with the help of initiation codons, primarily AUG and, under certain conditions, GUG.
• In eukaryotes, the AUG codon codes for the amino acid methionine. In prokaryotes, AUG codes for a modified form of methionine, known as N-formylmethionine, which is used to start protein synthesis.
• Occasionally, the GUG codon can also act as a start codon. Although GUG normally codes for the amino acid valine, when positioned at the start of an mRNA sequence, it can code for methionine, indicating its role in initiating protein synthesis under specific circumstances.

2. Chain Termination Codons

• The termination of polypeptide chain synthesis is signaled by three specific codons, known as stop or nonsense codons. These codons do not specify any amino acid and serve to halt the translation process. The three stop codons are:
• • UAA (Ochre)
  • UAG (Amber)
  • UGA (Opal)
• These stop codons are essential for indicating the end of a protein-coding sequence, ensuring that the polypeptide chain is released from the ribosome at the correct point.

3. Implications

• With three codons designated as stop codons, 61 of the total 64 codons are left as sense codons. These sense codons are responsible for specifying the 20 standard amino acids used in protein synthesis.