The combination of the words "neutral" and "mutations" may seem like an error or fallacy. How can something be mutated - altered at the genetic level - and its effects be neutral? Well, not only are neutral mutations not a fallacy, they are quite common, representing the most commonly occurring forms of mutations. The relatively resilient nature of the genetic material of both us, as humans, and the many forms of life around us, makes this possible. It's important to understand the forms that neutral mutations can come in, and how these are exhibited at both the genetic level and in the lives of varied organisms.
What is the definition of a neutral mutation?
A neutral mutation is defined as any mutation that occurs within an organism's genome, that either has no effect at all or has an effect that is neither better nor worse than the effect that the natural, wild-type gene would confer.
We can see from this definition that, under the category of neutral mutations, there is a subcategory. That is if neutral mutations can be drawn as one big Venn diagram, encased in the circle representing them are another type of mutation. These are called silent mutations, and they are mutations with no effect at all on the organism.
All silent mutations are neutral mutations, but not all neutral mutations are silent mutations.
Fig. 1: Neutral vs silent mutations. StudySmarter original.
In summary, neutral mutations neither increase nor decrease the fitness - that is, the capacity of an organism to produce live offspring - of an organism, alter its survivability, nor confer upon it any competitive advantage or disadvantage.
Neutral mutations may change some things about an organism.
Such as the amino acid that is exhibited at a certain spot in a certain protein, but these changes made are neutral - they don't affect the above factors.
Silent mutations, quite literally change nothing about the way an organism presents itself, even in terms of the amino acids that make up its proteins. Silent mutations are silent in their effect - presumably, the only way to know they are occurring or have occurred is to look at the genes.
Neutral genetic mutations
Let us look at what is happening on the level of the genome when neutral mutations occur. Non-silent neutral mutations occur when some error in DNA replication leads to a change in the amino acid sequence that comprises a protein. This occurs when DNA polymerase causes this error, often due to its inherent fallibility as a copying machine
In humans, after copying about 100 - 1000 nucleotides, DNA polymerase tends to have at least one error, where an incorrect nucleotide (adenosine, cytosine, thymine, or guanine) is planted in the place of another.
Errors in DNA polymerase replication can also occur because of mutagens present in the environment, that either alter the existing genetic code or interfere with the ability of DNA polymerase to properly replicate.
Mutagen - an agent that predisposes to (or directly causes) genetic mutations. X-rays are an example of mutagens.
It may seem to be a rather small-scale concern, that of neutral mutations leading to amino acid changes. However, we must not underestimate what these proteins can be - proteins decide everything from the skin, eye, and hair color of humans and animals; to plant flower colors and seed shapes, to bacterial antibiotic resistance and infectivity, to ion channels, receptors, and organelles at the cellular level; and so much more. Essentially the proteins exhibited by living organisms decide, to a very large extent, how they look, act, interact, survive, and reproduce.
The errors in replication that lead to these non-normal, non-wild-type proteins; arise from alterations in amino acid coding sequences, which in turn arise from alterations in DNA sequences. These DNA alterations can be missense, nonsense, or frameshift, while silent mutations are distinguished by the fact that they alter DNA but do not alter amino acids or proteins.
Missense mutations
Missense mutations occur when the nucleotide (or nucleotides) that are altered or replaced lead to the production of different amino acids than were originally intended.
Three sequential nucleotides together are termed a codon.
Each codon represents and eventually is translated into a single amino acid, and sometimes (but not always, this exception occurs in silent mutations) altering one of these nucleotides leads to an alternate amino acid.
While this can be very rarely beneficial, and sometimes deleterious, this is often neutral; especially if the two amino acids have similar properties (both acidic, both basic, both hydrophobic, etc.) and are not in a very important region of the protein such as the receptor where it makes interactions.
Nonsense mutations
Nonsense mutations are seen when an alteration in a strand of DNA leads to a premature STOP codon. Just as different combinations of three nucleotides can code for the translation of a specific amino acid; three specific codons encode a message that tells the ribosomes to STOP producing a certain protein. These three include - TGA, TAA, and TAG.
Nonsense mutations are most often deleterious because a premature stop leads to a truncated and often nonfunctional protein. Nonetheless, they can still be neutral, if the remainder of the amino acid sequence following the stop codon is very small and largely irrelevant.
Frameshift mutations
We noted that codons occur in threes, and the genetic code is read in these triplets. Thus, frameshift mutations occur when there are spontaneous additions or deletions of nucleotides in any amount that is not a multiple of three.
For example, if two nucleotides are added; this leads to a frameshift mutation. If one nucleotide is deleted, this leads to a frameshift mutation, and so on.
Frameshift mutations often lead to a series of missense mutations or nonsense mutations.
It's extremely rare for a frameshift mutation to be neutral. Like a nonsense mutation, this would most likely occur if the frameshift happened near the very end of an amino acid sequence, thus not altering the protein very much. Most often, frameshift mutations are deleterious.
Silent mutations
We distinguished this form of mutation early on, depicting how all silent mutations are neutral mutations, but not all neutral mutations are silent mutations.
Most often neutral mutations are missense mutations that do not affect the overall protein activity or structure.
When examining silent neutral mutations we come across a certain important feature of the genetic code. It is degenerate (redundant). In genetics, degeneracy means there are multiple codons (combinations of three nucleotides - A, C, G, and T) that can lead to the same amino acid.
Amino acids have two to five codons that encode their translation. For example, the amino acid proline is translated when any of the following codons: CCT, CCC, CCA, and CCG, are read. Glutamate is translated from from two possible codons - GAA and GAG.
Neutral mutation rate
Neutral mutations occur at higher rates than the two other main forms of mutations - beneficial mutations and deleterious (harmful) mutations.
Natural selection should theoretically, not play a factor in the inheritance of neutral mutations because they neither confer fitness - and hence would be selected for in a population, nor reduce fitness - and hence would be selected against.
Nonetheless, we have seen that although most mutations are neutral and have totally randomized chances of being inherited, many other neutral mutations are linked (sometimes called genetic hitchhiking) to other mutations that do have some effect, whether positive or negative. Thus, these neutral mutations will occur at the same rates (randomly) but may be more or less persistent in a population due to the effects of gene linkage and natural selection.
Neutral mutations in animals
Here we explore the various neutral mutations that can occur in animals such as pigs, flies and dogs.
Fruit flies
Example: Coloration
Most fruit flies naturally have light tan bodies, however, there exist mutant phenotypes with brighter coloring; nearing yellow, or darker coloring; nearing black. These mutations do not appear to reduce or increase fitness, thus they are non-silent, non-neutral mutations.
Dogs
Example: Size and appearance
Dogs have the broadest range of size of any mammal, and this is due to their inherent genetic capacity, and selection; typically by humans. Individual mutations that occur in a dog or dog family were consistently inbred to produce multiple dogs with a pronounced version of this feature (whether it be teacup size or corkscrew fur), which leads to the extreme degree of variation we see in pet dogs today.
Neutral mutation practice examples
We can work through a set of examples of neutral mutations to determine what specific designation they should be given - missense, nonsense, silent, or frameshift.
Remember that U (uracil) is to RNA what T (thymine) is to DNA!
Q: What form of mutation occurs when this code:
is improperly replicated as this code:
A: A missense mutation. The original strand codes:
and the mutant strand codes:
While this could be a neutral mutation, potentially, it could not be a silent mutation.
Q: What form of mutation occurs when this code:
is improperly replicated as this code:
A: A missense mutation. The original strand codes:
and the mutant strand codes:
The amino acid sequence did not change, even though the DNA sequence did, thus this is a silent mutation.
Neutral Mutations - Key takeaways
- Neutral mutations are more common than both beneficial and deleterious mutations
- Neutral mutations are theoretically not selected for or against, although gene linkage can change this
- Neutral mutations can be silent - which means there is no difference in the amino acid sequence although an alteration has occurred in the genetic code.
- Silent mutations are due to the degeneracy or redundancy of the genetic code.
- Neutral mutations are often missense mutations, but can rarely be nonsense or frameshift mutations as well.
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