Missense Mutation

Missense Mutation Definition

A missense mutation is a type of point mutation in which a different amino acid is placed within the produced protein, other than the original. In the process of converting DNA into protein, the language of DNA must be translated into the language of proteins. During this process, a change in the structure of DNA, or a mutation, can change the sequence of amino acids which creates a protein. If it does not change the structure or function of the protein, it may be considered a silent mutation. If it does change the protein, it is considered a missense mutation.

Point mutations

Point mutations

The above image shows various point mutations, and their effects on the resulting amino acid. The DNA is read in units of three, called codons. These codons call for one of 21 amino acids, which the ribosome complex will assemble in order by reading the messenger RNA, or mRNA. If there are 3 spots in a codon, and 4 possible nucleotides to go in that spot, the codons can call for 64 different signals. Since there are only 21 amino acids, many of these codons call for the same amino acid. If a mutation calls for the same amino acid as before the mutation, it is considered silent.

On the other hand, several other codons also call for signals to stop and process the protein. In this case, instead of adding an amino acid, the sequence is ended and the protein is ejected from the ribosome. In this case, the mutation would be a nonsense mutation, because the protein would be incomplete. A missense mutation continues the chain of the protein, but it may also interfere with the functioning of the protein. To this end, there are two basic types of missense mutation.

Types of Missense Mutation

Conservative

In a conservative missense mutation, the amino acid replaced is similar in function and shape to the amino acid being replaced. A conservative missense mutation may result in loss of function, but it may only be minor. In the context of population genetics and ecology, a missense mutation may not necessarily be a negative thing. A slowed or slightly changed function of a protein may actually increase the fitness of an organism. If the product of the protein needs to be regulated, or is currently hindering the fitness of the organism, a change may be beneficial. A conservative missense mutation is typically changes the function of a protein less drastically than the other type of missense mutation.

Non-conservative

In a non-conservative missense mutation, a completely different kind of amino acid is added to the chain. Where a polar amino acid was present, a non-polar amino acid will be added. This type of missense mutation can greatly change the function of a protein, as it will likely change the shape and structure of the protein.

Proteins have various levels of structure, all which depend upon the DNA. If a missense mutation changes an amino acid, it first changes the primary structure, or the basic sequence of amino acids. The secondary structure of proteins consists of patterns and structures formed by interactions between these amino acids. A missense mutation could completely disrupt a form such as an alpha helix or beta sheet. These structures can be crucial to the overall tertiary structure of the protein, or its general shape and size. This structure informs how the protein interacts with other molecules within the environment. A non-conservative missense mutation may completely change these interactions. At the final level of protein structure, quaternary structure, a missense mutation can even prevent a protein from joining a larger protein complex it is intended to be a part of. This can render entire biochemical pathways useless, or give them a completely new use.

Missense Mutation Example

A common and well-known example of a missense mutation is sickle-cell anemia, a blood disease. People with sickle-cell anemia have a missense mutation at a single point in the DNA. This missense mutation calls for a different amino acid, and affects the overall shape of the protein produced. This, in turn, causes the entire shape of blood cells to be different. People with the disease experience symptoms of not being able acquire oxygen efficiently, and experience blood clotting. However, they are partially protected from blood borne parasites which live in blood cells. Malaria is a disease caused by these parasites, and people with sickle-cell anemia have an inherent defense against the parasite. Their sickle-shaped blood cells cannot support the life cycle of the parasite.

The missense mutation which causes all of this is the difference of one nucleotide. It is first translated into mRNA, then into a protein. The missense mutation causes a valine to be placed where a glutamic acid normally goes. This non-conservative missense mutation causes the shape of the protein, hemoglobin, to change. Where normal hemoglobin separates, the mutated hemoglobin forms long chains. These chains, when incorporated into blood cells, change their shape and force them into a sickle. This can be seen in the image below.

Risk Factors for Sickle Cell Anemia

Many other anemias and various genetic diseases are caused by a missense mutation. All proteins are reliant on the sequence of amino acids which makes it up. While mutations may sometimes bring benefits to an organism, they more often disrupt a stable and relied-upon process. In disrupting even a single protein, cells can become functionless, or at least struggle to function.

Quiz

1. Which of the following is a missense mutation?
A. Serine is substituted for Serine
B. Arginine is substituted for Glutamine
C. A STOP signal is substituted for Cysteine

Answer to Question #1
B is correct. The other two answers can both be point mutations, but only B is a missense mutation. Remember that a missense mutation continues the chain of amino acids, but changes the exact amino acid. Answer C would be a nonsense mutation.

2. Which of the following would be the worst mutation?
A. Missense Mutation
B. Nonsense Mutation
C. It depends…
D. XXXX

Answer to Question #2
C is correct. A mutation in itself does not mean that something is bad. In fact, all new adaptations and forms come from some sort of mutation. Therefore, depending on the environment or organisms, a mutation may actually be beneficial. There is nothing inherently “good” or “bad” about them.

3. Sickle-cell anemia, and some other genetic diseases, recur at steady low rates throughout some populations. Why is this?
A. The mutations are partially beneficial
B. Single point mutations are more likely than others
C. Both

Answer to Question #3
C is correct. A point mutation requires only a single nucleotide to be replaced. These small errors can easily be missed by genetic proof-reading proteins. Thus, small levels of mutation in all genes are seen across the population. Like sickle-cell anemia and resistance to malaria, some missense mutations are also beneficial in some ways.

References

  • Hartwell, L. H., Hood, L., Goldberg, M. L., Reynolds, A. E., & Silver, L. M. (2011). Genetics: From Genes to Genomes. Boston: McGraw Hill.
  • Lodish, H., Berk, A., Kaiser, C. A., Krieger, M., Scott, M. P., Bretscher, A., . . . Matsudaira, P. (2008). Molecular Cell Biology (6th ed.). New York: W.H. Freeman and Company.
  • Nelson, D. L., & Cox, M. M. (2008). Principles of Biochemistry. New York: W.H. Freeman and Company.
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