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2.9: Mutations

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  • Mutations

    Errors occurring during DNA replication are not the only way by which mutations can arise in DNA. Mutations, variations in the nucleotide sequence of a genome, can also occur because of physical damage to DNA. Such mutations may be of two types: induced or spontaneous. Induced mutations are those that result from an exposure to chemicals, UV rays, x-rays, or some other environmental agent. Spontaneous mutations occur without any exposure to any environmental agent; they are a result of spontaneous biochemical reactions taking place within the cell (including errors of replication).

    Mutations may have a wide range of effects. Some mutations have no effect on gene function; these are known as silent mutations. Point mutations are those mutations that affect a single base pair. The most common nucleotide mutations are substitutions, in which one base is replaced by another. Mutations can also be the result of the addition of a nucleotide, known as an insertion, or the removal of a base, also known as deletion. Sometimes a piece of DNA from one chromosome may be joined to another chromosome or to another region of the same chromosome; this is known as translocation.

    When a mutation occurs in a protein coding region it may have several effects. Nucleotide substitutions may lead to no change in the protein sequence (known as silent mutations), change the amino acid sequence (known as missense mutations), or create a stop codon (known as a nonsense mutation). Insertions and deletions in protein coding sequences lead to frameshift mutations. Missense mutations that lead to conservative changes result in the substitution of similar but not identical amino acids. For example, the acidic amino acid glutamate substituted for the acidic amino acid aspartate would be considered conservative- they have the same charge. In general we do not expect these types of missense mutations to be as severe as a non-conservative amino acid change; such as a glutamate substituted for a valine (changing from charged to hydrophobic). Drawing from our understanding of functional group chemistry we can correctly infer that this type of substitution may lead to severe functional consequences, depending upon location of the mutation.

    Note: Vocabulary Watch

    Note that the preceding paragraph had a lot of potentially new vocabulary - it would be a good idea to learn these terms.

    Mutations can lead to changes in the protein sequence encoded by the DNA.

    Suggested discussion

    Based on your understanding of protein structure, which regions of a protein would you think are more sensitive to substitutions, even conserved amino acid substitutions? Why?

    Suggested discussion

    A insertion mutation that results in the insertion of three nucleotides is often less deleterious than a mutation that results in the insertion of one nucleotide. Why?

    Mutations: Some nomenclature and considerations


    The term mutation simply means a change or alteration. In genetics, a mutation is a change in the genetic material - DNA sequence - of an organism. By extension, a mutant is the organism in which a mutation has occurred. But what is the change compared to? The answer to this question is that it "depends". The comparison can be made with the direct progenitor (cell or organism) or to patterns seen in a population of the organism in question. It mostly depends on the specific context of the discussion. Since genetic studies often look at a population (or key subpopulations) of individuals we begin by describing the term "wild-type". Different forms of a gene, including those associated with "wild type" and respective mutants, in a population are termed alleles.

    Wild Type vs Mutant

    What do we mean by "wild type"? Since the definition can depend on context, this concept is not entirely straightforward. Here are a few examples of definitions you may run into:

    Possible meanings of "wild-type"

    1. An organism having an appearance that is characteristic of the species in a natural breeding population (i.e. a cheetah's spots and tear-like dark streaks that extend from the eyes to the mouth).
    2. The form or forms of a gene most commonly occurring in nature in a given species.
    3. A phenotype, genotype, or gene that predominates in a natural population of organisms or strain of organisms in contrast to that of natural or laboratory mutant forms.
    4. It is also generally safe to say that a completely defective allele (say, an allele with an early stop codon), that cannot encode a functioning version of the gene, is a mutant derivative of the wild-type allele.

    That said, however, it might be the "norm" for an entire species to lack a functioning version of a gene that serves a purpose in a closely related species. In which case a reasonable person might describe this nonfunctioning gene as the wild-type allele- for that species! However, genes that cannot be, and never are, expressed in a species are referred to as psuedogenes.

    The common thread to all of the definitions listed above is based on the "norm" for a set of characteristics with respect to a specific trait compared to the overall population. In the "Pre-DNA sequencing Age" species were classified based on common phenotypes (what they looked like, where they lived, how they behaved, etc.). A "norm" was established for the species in question. For example, Crows display a common set of characteristics, they are large, black birds that live in specific regions, eat certain types of food and behave in a certain characteristic way. If we see one, we know its a crow based on these characteristics. If we saw one with a white head, we would think that either it is a different bird (not a crow) or a mutant, a crow that has some alteration from the norm or wild type.

    In this class we take what is common about those varying definitions and adopt the idea that "wild type" is simply a reference standard against which we can compare members of a population.

    Suggested discussion

    If you were assigning wild type traits to describe a dog, what would they be? What is the difference between a mutant trait and variation of a trait in a population of dogs? Is there a wild type for a dog that we could use as a standard? How would we begin to think about this concept with respect to dogs?

    Mutations can lead to changes in the protein sequence encoded by the DNA that then impact the outward appearance of the organism. Source:

    Mutations are simply changes from the "wild type", reference or parental sequence for an organism. While the term "mutation" has colloquially negative connotations we must remember that change is not inherently "bad". Indeed, mutations (changes in sequences) should not primarily be thought of as "bad" or "good", but rather simply as changes and a source of genetic and phenotypic diversity on which evolution by natural selection can occur. Natural selection ultimately determines the long-term fate of mutations. If the mutation confers a selective advantage to the organism, the mutation may eventually become very common in the population. Conversely, if the mutation is deleterious, natural selection will ensure that the mutation will be lost from the population. If the mutation is neutral, that is it neither provides a selective advantage nor disadvantage, then it may persist in the population.

    Consequences of Mutations

    For an individual, the consequence of mutations may mean little or it may mean life or death. Some deleterious mutations are null or knock-out mutations which result in a loss of function of the gene product. These mutations can arise by a deletion of either the entire gene, a portion of the gene, by a point mutation in a critical region of the gene that renders the gene product non-functional, through a nonsense mutation early in the coding sequence, or through a frame-shift mutation. These types of mutations are also referred to as loss-of-function mutations. Alternatively, mutations may lead to a modification of an existing function (i.e. the mutation may change the catalytic efficiency of an enzyme, a change in substrate specificity, or a change in structure). In rare cases a mutation may create a new or enhanced function for a gene product; this is often referred to as a gain-of-function mutation. Lastly, mutations may occur in non-protein-coding regions of DNA. If these mutations occur in regions of the gene that are non-coding, but still important for gene expression (such as a promoter), they can also strongly affect gene function.

    Suggested discussion

    In the discussion above what types of scenarios would allow such a gain-of-function mutant the ability to out compete a wild type individual within the population? How do you think mutations relate to evolution?

    Mutations and cancer

    Mutations can affect either somatic cells or germ cells. Sometimes mutations occur in DNA repair genes, in effect compromising the cell's ability to fix damage, and possibly increasing mutation rate. If, as a result of mutations in DNA repair genes, many mutations accumulate in a somatic cell, they may lead to problems such as the uncontrolled cell division observed in cancer. Cancers, including forms of pancreatic cancer, colon cancer, and colorectal cancer have been associated with mutations like these in DNA repair genes. Similarly, defects in repair can be passed through the generations (due to their recessive nature). Although the frequency of such mutations in the general population is low, occasionally individuals unknowingly heterozygous for the repair defect do have children who inherit both defective alleles. In the case of XP homozygous individuals with compromised DNA repair processes become very sensitive to UV radiation. In severe cases these individuals may get severe sunburns with just minutes of exposure to the sun. Nearly half of all children with this condition develop their first skin cancers by age 10.

    Consequences of errors in replication, transcription and translation

    Something key to think about:

    Cells have evolved a variety of ways to make sure errors of replication are both detected and corrected, from proofreading by the various DNA-dependent DNA polymerases, to more complex mismatch repair systems. Why did so many different mechanisms evolve to repair errors in DNA? By contrast, similar proof-reading mechanisms did NOT evolve for errors in transcription or translation. Why might this be? What would be the consequences of an error in transcription? Would such an error effect the offspring? Would it be lethal to the cell? What about translation? Ask the same questions about the process of translation. What would happen if the wrong amino acid was accidentally put into the growing polypeptide during the translation of a protein? Contrast this with DNA replication.

    Mutations as instruments of change

    Mutations are how populations can adapt to changing environmental pressures.

    Mutations are randomly created in the genome of every organism, and this in turn creates genetic diversity and a plethora of different alleles per gene per organism in every population on the planet. If mutations did not occur, and chromosomes were replicated and transmitted with 100% fidelity, how would cells and organisms evolve? Whether mutations are retained in a population depends largely on whether the mutation provides selective advantage (meaning, increases the frequency of reproduction of that allele), poses some selective cost or is at the very least, not harmful. Indeed, mutations that appear neutral may persist in the population for many generations and only be meaningful when a population is challenged with a new environmental challenge. At this point the apparently previously neutral mutations may provide a selective advantage.

    Example: Antibiotic resistance

    The bacterium E. coli is sensitive to an antibiotic called streptomycin, which inhibits protein synthesis by binding to the ribosome. The ribosomal protein L12 can be mutated such that streptomycin no longer binds to the ribosome and inhibits protein synthesis. Wild type and L12 mutants grow equally well and the mutation appears to be neutral in the absence of the antibiotic. In the presence of the antibiotic wild type cells die and L12 mutants survive. This example shows how genetic diversity is important for the population to survive. If mutations did not randomly occur, when the population is challenged by an environmental event, such as the exposure to streptomycin, the entire population would die.

    Uncorrected errors in DNA replication lead to mutation. In this example, an uncorrected error was passed onto a bacterial daughter cell. This error is in a gene that encodes for an important ribosomal protein. The mutation results in a different final 3D structure of the ribosome protein. While the wild-type ribosome can bind to streptomycin (an antibiotic that will kill the bacterial cell by inhibiting the ribosome function) the mutant ribosome cannot bind to streptomycin. This bacterium is now resistant to streptomycin and will of course outgrow bacteria carrying the wild-type sequence, in the presence of the drug.
    Source: Intelligent Design Center (yes, really)


    Let's say there are 10 different base positions that could change (in any way) to result in a new allele of L12 that confers streptomycin resistance (i.e., there are lots of ways to change the shape of this site, slightly). Let's also say you are infected by a single, wild-type bacterium, that sets up life in your gut. Knowing that the error rate of replication is one in 10-10 bases replicated, and ignoring any possible mutagenic effect of the environment, how many rounds of replication would have to occur before we expect to find a strep resistant bacterium? Please note that this is actually a very tricky question. For people who enjoy probability (like many geneticists), we might ask instead- how many rounds of replication would we need experience in order to have a 90% chance of generating one or more resistant mutants?