Mutation and Types of Mutations

Every time a cell copies its DNA, there is a tiny chance of a mistake. Most are caught and repaired, but a few slip through. A permanent change in the DNA sequence like this is called a mutation. Mutations sound harmful, and some are, but the full picture is more interesting: most mutations have no effect at all, a few are harmful, and a rare few are helpful. Those rare helpful ones are the raw material of evolution, and the harmful ones underlie diseases like sickle cell anemia and cancer.

For a microbiology student, mutations matter for one more reason that shows up daily in the clinic: they are a major way bacteria become resistant to antibiotics. This article explains what a mutation is, the different types (from a single changed base to large changes in whole chromosomes), and what each type does to the protein and the cell.

A mutation is a change in the nucleotide sequence of a gene. This gives rise to a new genetic trait or a changed genotype. A cell or an organism that shows the effect of a mutation is called a mutant.

A mutant differs from its parental strain in its genotype (nucleotide sequences of the genome). In addition, the mutant’s observable properties may change relative to its parent, called the phenotype. The effect of mutations in an organism leads to changes, some good, some bad, but mostly neutral.

How mutations are classified

Mutations can be grouped in three different ways, and it helps to keep these separate, because a single mutation can be described by all three at once.

1. By cause: spontaneous or induced. Spontaneous mutations arise naturally from errors during DNA copying. Their rate is remarkably low, between 10⁻⁸ and 10⁻¹¹ errors per base pair, because DNA polymerase proofreads its work. Induced mutations are caused by an outside agent, such as ionizing radiation, carcinogens, chemicals called mutagens, or infection by some viruses.
2. By where they occur: germline or somatic. Germline mutations occur in eggs or sperm and can be passed to offspring. Somatic mutations occur in body cells and are not inherited.
3. By how they change the DNA: this is the most detailed grouping and the one usually meant by "types of mutations." It splits into small-scale changes (point mutations and frameshift mutations, affecting one or a few bases) and large-scale changes (chromosomal mutations, affecting large segments).

The sections below follow this third grouping, from the smallest change to the largest.

Types of Mutations

At the molecular level, there are several ways in which changes in the purine-pyrimidine base sequence of a gene can occur, resulting in a mutation. Two common types are point mutations and frameshift mutations.

Figure: Mutation (Courtesy: National Human Genome Research Institute)

Point Mutations

Point mutations occur as a result of substituting one nucleotide for another in the specific nucleotide sequence of a gene.

1. The substitution of one purine (A or G) base for another purine or one pyrimidine (C or T) base for another pyrimidine is called the transition type of point mutation.
2. A transversion replaces a purine with a pyrimidine or vice versa.

This base-pair substitution may result in one of three kinds of effects.

1. Silent mutation: altered codon corresponds to the same amino acid
2. Missense mutation: altered codon corresponds to a different amino acid
3. Nonsense mutation: altered codon corresponds to a stop signal.

Silent Mutation

The altered codon still specifies the same amino acid, because the new codon is a synonym for the original one. The protein is unchanged. Silent mutations are almost always in the third base of the codon, the flexible "wobble" position. For example, a change in the mRNA from UAC to UAU has no effect, because both code for tyrosine.

A related term is a neutral mutation. This is slightly different: a neutral mutation may change the amino acid, but the change does not affect how the protein works, so the cell is unharmed. Every silent mutation is neutral, but not every neutral mutation is silent.

Missense Mutation

In the missense mutation, the altered gene triplet produces a codon in the mRNA, specifying a different amino acid than the one present in the normal protein. Altered proteins formed after missense mutation may be functionally inactive, less active, or more active than normal ones. The amino acid substitution may not affect its function. Changes in the first or second base of the codon more often lead to significant changes in the polypeptide.

A good example of a missense mutation in humans is the disease sickle cell anemia. The sixth amino acid of normal hemoglobin A is glutamic acid(GAG). A single base substitution in the codon of this amino acid, the substitution of U in place of A, changes the amino acid to valine (GUG), forming characteristic hemoglobin S of sickle cell anemia.

Figure: Point mutation (Courtesy: National Human Genome Research Institute)

For instance, a single base change from GGU to GCU results in an amino acid change within the polypeptide from Glycine to Alanine at a specific site.

Nonsense Mutation

A nonsense mutation is the substitution of a single base pair that leads to the formation of an altered gene triplet which produces a chain-terminating codon in mRNA. For example, a single base change from UAC to UAA changes a tyrosine codon (UAC) into a stop codon (UAA), ending the protein early at that point.

Unless the nonsense mutation is very near the end of the gene, the result is the premature termination of protein during translation, forming an incomplete or shortened polypeptide that is most likely nonfunctional.

Frameshift Mutations

Frameshift mutations result from adding or deleting one or more nucleotides (the number of added or deleted base pairs is not divisible by three) in a gene.

The reading of the genetic code starts from one end of the protein template, mRNA, and is read in consecutive blocks of three bases. Each group of three bases (a codon) specifies one amino acid or a stop signal. There are 64 codons for 20 amino acids, so most amino acids have more than one codon.

Figure: Frameshift mutation (single nucleotide insertion) Courtesy: National Human Genome Research Institute

Frameshift mutations happen in two ways: insertion (adding one or more bases) or deletion (removing one or more bases). Either one, unless it involves a multiple of three bases, shifts the reading frame. Everything downstream is then read in the wrong groups of three, so almost every amino acid after the mutation is wrong. This is why frameshift mutations are usually more damaging than a single base substitution: one changes the whole message from that point on, while the other changes just one amino acid. This generally leads to premature termination or formation of non-functional proteins.

Chromosomal (large-scale) mutations

Not all mutations are small. Larger changes can affect whole segments of a chromosome. These are important in genetic disease and in cancer.

• Deletion: a segment of the chromosome is lost.
• Duplication: a segment is copied, so it appears twice.
• Inversion: a segment breaks off, flips around, and rejoins in reverse order.
• Translocation: a segment moves to a different chromosome.

These large-scale changes usually have bigger effects than point mutations, because they move, lose, or duplicate many genes at once.

Grouping mutations by their effect

Whatever the mechanism, a mutation can also be described by what it does to the organism:

1. A deleterious (harmful) mutation reduces how well the cell or organism works. A lethal mutation is an extreme case that causes death.
2. A neutral mutation has no meaningful effect, good or bad. Most mutations fall here.
3. A beneficial mutation improves survival in a particular environment. These are rare, but they are the raw material of evolution and natural selection.

Why mutations matter: antibiotic resistance and more

For a microbiology student, the most important real-world consequence of mutation is antibiotic resistance. When a population of bacteria is exposed to an antibiotic, a random mutation in one cell can happen to change the drug's target, or switch on a pump that removes the drug. That one cell survives while the others die, and it passes the mutation to its descendants. Over time the whole population becomes resistant. The mutation did not happen because of the antibiotic; it was already there by chance, and the antibiotic simply selected for it.

Mutations also drive other things a health-science student meets: the constant change of influenza and other viruses (which is why the flu vaccine is updated each year), the development of cancer (from mutations in genes that control cell growth), and inherited diseases such as sickle cell anemia and cystic fibrosis. In every case, the same basic event, a change in the DNA sequence, is at the root.

How to Remember

Transition versus transversion. A transition stays within the same type: purine to purine, or pyrimidine to pyrimidine (a small "transit" within the group). A transversion crosses over: purine to pyrimidine or the reverse. "Transversion crosses; transition stays."

Silent, missense, nonsense, in one line. Silent = same amino acid (no change). Missense = wrong amino acid (a "mis-sense"). Nonsense = a stop codon (the message stops making sense). Three names, three outcomes, in increasing severity.

Why frameshift is worse. A point mutation changes one letter; a frameshift changes where every following word begins. Picture the sentence "THE BIG DOG" losing one letter: "THE IGD OG..." Everything after the change turns to nonsense. That is a frameshift.

The wobble link to silent mutations. Silent mutations sit in the third base of the codon, the same flexible position the wobble hypothesis is about. "Third base changes, amino acid stays" connects the two ideas.

Mutation and antibiotic resistance. The antibiotic does not cause the resistance mutation; it selects the cell that already had it. "The drug does not create the survivor, it reveals it."

Key exam facts in one table

Where Students Get Confused

Silent versus neutral mutation. A silent mutation does not change the amino acid at all (same protein). A neutral mutation may change the amino acid, but the change does not affect how the protein works. Every silent mutation is neutral, but not every neutral mutation is silent.

Transition versus transversion. A transition swaps within the same base type (purine for purine, or pyrimidine for pyrimidine). A transversion swaps across types (purine for pyrimidine or the reverse). The names are easy to swap; "transversion crosses over."

Frameshift is usually worse than a point mutation. A point substitution changes at most one amino acid. A frameshift (from an insertion or deletion) changes every codon downstream, so it usually produces a completely wrong, non-functional protein. More bases changed does not always mean worse, but a shifted reading frame almost always is.

The antibiotic does not cause the resistance mutation. A common misunderstanding is that antibiotics make bacteria mutate. The mutation arises randomly, on its own. The antibiotic only selects the already-resistant cell by killing the others. This distinction matters for understanding how resistance spreads.

Mutations are not usually harmful. It is easy to assume every mutation causes disease. In fact most are neutral, some are silent, and only a minority are harmful. A rare few are even beneficial, and those drive evolution.

References and further readings

1. Madigan MT, Bender KS, Buckley DH, Sattley WM, Stahl DA. Brock Biology of Microorganisms. 16th ed. Pearson; 2021.
2. Willey JM, Sherwood LM, Woolverton CJ. Prescott's Microbiology. 11th ed. McGraw-Hill; 2020.
3. National Human Genome Research Institute. Mutation. genome.gov.