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20.1: Mutations and Mutants

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.

Mutations may have a wide range of effects. Some mutations are not expressed; these are known as silent mutationsPoint 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. These can be of two types, either transitions or transversions. Transition substitution refers to a purine or pyrimidine being replaced by a base of the same kind; for example, a purine such as adenine may be replaced by the purine guanine. Transversion substitution refers to a purine being replaced by a pyrimidine, or vice versa; for example, cytosine, a pyrimidine, is replaced by adenine, a purine. 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 get translocated to another chromosome or to another region of the same chromosome; this is known as translocation.  

As we will visit later, when a mutation occurs in a protein coding region it may have several effects. Transition or transversion mutants may lead to no change in the protein sequence (known as silent mutations), change the amino acid sequence (known as missense mutations), or create what is known as a stop codon (known as a nonsense mutation). Insertions and deletions in protein coding sequences lead to what are known as frameshift mutations. Missense mutations that lead to conservative changes results in the substitution of similar but not identical amino acids. For example, the acidic amino acid glutamate being substituted for the acidic amino acid aspartate would be considered conservative. 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. 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.

Figure 1. 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

Mutation

Etymologically speaking, 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".

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. The normal, as opposed to the mutant, gene or allele.

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?

Figure 2. 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 neither 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 will be selected and 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 or disadvantage, then it may persist in the population. Different forms of a gene, including those associated with "wild type" and respective mutants, in a population are termed alleles

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 the either the entire gene, a portion of the gene, or by a point mutation in a critical region of the gene that renders the gene product non-functional. 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-coding regions of DNA. These mutations can have a variety of outcomes including altered regulation of gene expression, changes in replication rates or structural properties of DNA and other non-protein associated factors.

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 other mutations that may arise. 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. If, by contrast, a mutation in DNA repair occurs in germ cells (sex cells), the mutation will be passed on to the next generation, as in the case of diseases like hemophilia and xeroderma pigmentosa. In the case of xeroderma pigmentoas individuals with compromised DNA repair processes become very sensitive to UV radiation. In severe cases these individuals may get severe sun burns 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 DNA errors are both detected and corrected, rom proof reading by the various DNA-dependent DNA polymerases, to more complex 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 adapt? Whether mutations are retained by evolution in a population depends largely on whether the mutation provides selective advantage, 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. For most populations this becomes a numbers game. If the mutation rate is 10-6 then a population of 107 cells would have 10 mutants; a population of 108 would have 100 mutants, etc.

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 part of the ribosome. The mutation results in a different final 3D structure of the ribosome protein. While the wildtype 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 bacteria is now resistant to streptomycin. 
Source: Bis2A Team original image

Suggested discussion

Based on our example, if you were to grow up a culture of E. coli to population density of 109 cells/ml; would you expect the entire population to be identical? How many mutants would you expect to see in 1 ml of culture?

An example: Lactate dehydrogenase

Lactate Dehydrogenase (LDH), the enzyme that catalyzes the reduction of pyruvate into lactic acid in fermentation, while virtually every organism has this activity, the corresponding enzyme and therefore gene differs immensely between humans and bacteria. The proteins are clearly related, they perform the same basic function but have a variety of differences, from substrate binding affinities and reaction rates to optimal salt and pH requirements. Each of these attributes have been evolutionarily tuned for each specific organism through multiple rounds of mutation and selection.

Suggested discussion

We can use comparative DNA sequence analysis to generate hypotheses about the evolutionary relationships between three or more organisms. One way to accomplish this is to compare the DNA or protein sequences of proteins found in each of the organisms we wish to compare. Let us, for example, imagine that we were to compare the sequences of LDH from three different organisms, Organism A, Organism B and Organism C. If we compare the LDH protein sequence from Organism A to that from Organism B we find a single amino acid difference. If we now look at Organism C, we find 2 amino acid differences between its LDH protein and the one in Organism A and one amino acid difference when the enzyme from Organism C is compared to the one in Organism B. Both organisms B and C share a common change compared to organism A.  

 

Schematic depicting the primary structures of LDH proteins from Organism A, Organism B, and Organism C. The letters in the center of the proteins line diagram represent amino acids at a unique position and the proposed differences in each sequence. The N and C termini are also noted H2N and COOH, respectively.
Attribution: Marc T. Facciotti (original work)

Question: Is Organism C more closely related to Organism A or B? The simplest explanation is that Organism A is the earliest form, a mutation occurred giving rise to Organism B. Over time a second mutation arose in the B lineage to give rise to the enzyme found in Organism C. This is the simplest explanation, however we can not rule out other possibilities. Can you think of other ways the different forms of the LDH enzyme arose these three organisms?

 

GLOSSARY

 

induced mutation:

mutation that results from exposure to chemicals or environmental agents

mutation:

variation in the nucleotide sequence of a genome

mismatch repair:

type of repair mechanism in which mismatched bases are removed after replication

nucleotide excision repair:

type of DNA repair mechanism in which the wrong base, along with a few nucleotides upstream or downstream, are removed

proofreading:

function of DNA pol in which it reads the newly added base before adding the next one

point mutation:

mutation that affects a single base

silent mutation:

mutation that is not expressed

spontaneous mutation:

mutation that takes place in the cells as a result of chemical reactions taking place naturally without exposure to any external agent

transition substitution:

when a purine is replaced with a purine or a pyrimidine is replaced with another pyrimidine

transversion substitution:

when a purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine