The Wobble Hypothesis, proposed by Francis Crick in 1966, explains the degeneracy of the genetic code. The hypothesis attributes this degeneracy to imprecise pairing between the third base of the codon and the first base of the anticodon on tRNA. The wobble position has two main properties: (1) loose bindingThe third position of the codon has looser binding between the cognate tRNA and the codon in the mRNA, and (2) Non-Watson-Crick base pairingsThe third position of the codon can accommodate a variety of non-Watson-Crick base pairings. For example, G may pair with T or U. The wobble hypothesis is important in translating the genetic code because it allows a single tRNA to recognize more than one codon. This means that there are fewer tRNAs (around 40) than codons (61) for amino acids.
Wobble Base Pair
A wobble base pair is a type of non-canonical base pairing that occurs between two nucleotides in RNA molecules, the codon and the anticodon of mRNA and tRNA, respectively that does not follow Watson-Crick base pair rules. The four main wobble base pairs are guanine-uracil (G-U), hypoxanthine-uracil (I-U), hypoxanthine-adenine (I-A), and hypoxanthine-cytosine (I-C)
- Wobble base pairs are fundamental in RNA secondary structure and are critical for the proper translation of the genetic code
- The term “wobble” refers to the flexibility or deviation from the standard Watson-Crick base pairing rules at the third position of the codon, which allows a single tRNA to recognize more than one codon for the same amino acid.
- This phenomenon explains the degeneracy of the genetic code and reduces the number of tRNA molecules required for protein synthesis.
The Wobble Hypothesis
- There are 64 possible codons in the genetic code, each consisting of a 3-nucleotide sequence. Translation requires tRNA molecules, each with an anticodon that complements a specific mRNA codon. Canonical Watson-Crick base pairing is used for stable tRNA-mRNA binding during translation.
- In the standard genetic code, 3 mRNA codons (UAA, UAG, UGA) act as stop codons, terminating translation. This leaves 61 mRNA codons that require tRNA molecules, suggesting a need for 61 types of tRNA.
- Due to the limited number of tRNA species in organisms (usually fewer than 45), some tRNA types can pair with multiple synonymous codons.
- Francis Crick proposed the Wobble Hypothesis in 1966, suggesting that the 5′ base on the anticodon has non-standard base pairing due to spatial flexibility. The “wobble” at the third codon position allows for small conformational adjustments, influencing the overall pairing geometry of tRNA anticodons.
- Crick suggested that the first two bases of the codon form strong and specific Watson-Crick base pairs with the second and third bases of the anticodon, while the third base of the codon can form weaker and less specific base pairs with the first base of the anticodon.
- The first two bases of each codon are primary determinants of specificity. The third base pairing is not very stable and wobbles. For example, CUU, CUG, CUC, CUA codons, which differ only at the third base represent the same amino acid leucine. The first two bases of the codon form strong base pairs with the corresponding bases of the anticodon but the third base forms weak hydrogen bond.
- This allows some tRNA molecules to bind to more than one codon, as long as they differ only at the third position. For example, a tRNA with the anticodon 5′-GmAA-3′ can recognize both UUC and UUU codons for phenylalanine.
The Wobble Rules
Crick also proposed a set of rules that govern the possible wobble base pairs, based on the geometry and hydrogen bonding patterns of the nucleotides involved. The rules are as follows:
- G can pair with U or C (in addition to the canonical C)
- U can pair with A or G (in addition to the canonical A)
- I (inosine, a deaminated form of A) can pair with A, U, or C
- A can pair only with U (the canonical pair)
- C can pair only with G (the canonical pair)
These rules imply that some codons for the same amino acid are more versatile than others in terms of wobble pairing. For instance, codons ending with A or C can be recognized by only one specific tRNA, while codons ending with U or G can be recognized by one or two tRNAs, depending on whether the first base of the anticodon is U, G, or I.
| tRNA 5′ anticodon base | mRNA 3′ codon base (Crick) | mRNA 3′ codon base (Revised) |
|---|---|---|
| A | U | U, C, G, or (A) |
| C | G | G |
| G | C or U | C or U |
| U | A or G | A, G, U, or (C) |
| I | A, C, or U | A, C, or U |
The Significance of Wobble Base Pairing
Wobble base pairing is a common feature of RNA secondary structure and is essential for the accurate and efficient translation of the genetic code. Wobble base pairing has several advantages for the cell:
- It reduces the number of tRNA genes and tRNA molecules needed to translate all 61 sense codons, which saves genetic space and energy.
- It allows for some mutations or errors at the third position of the codon without affecting the protein sequence, which increases the genetic robustness and diversity.
- It enables some tRNA molecules to act as suppressors of nonsense mutations by recognizing stop codons and inserting amino acids instead, which may rescue some defective proteins.
References
- Cleaves, H.J.(. (2014). Wobble Pair. In: Amils, R., et al. Encyclopedia of Astrobiology. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-27833-4_5248-1
- Lehninger Principles of Biochemistry ( 5E 2008 ISBN 9780716771081 ) David L. Nelson, Michael M. Cox
- Genetics: A Conceptual Approach by Benjamin A. Pierce, 3rd edition 2009, WH Freeman and Company
- Genes VIII 2004 by Benjamin Lewin Published by Pearson Prentice Hall Pearson Education, Inc.
