Learning Goals

By the end of this reading you should be able to:
  • Describe the different types of point mutations
  • Differentiate between different chromosomal mutations
  • Explain how mutations play a role in evolutionary processes
  • Discuss factors that can influence the rate of mutations

Introduction

Figure 1. UV radiation can cause a break in the DNA double-stranded resulting in a mutation

A cell’s DNA is the repository of all the information needed to not only make the cell but to enable it to function. In addition, the chromosome(s) also contain the information to make any cell in the organism. Mutations are variations that occur in the DNA sequence which alter the genetic code and can be passed on through cell division (Fig. 1). It is the genetic variation within cells and within individuals that account in part for the physical differences that we see between individuals and between groups of organisms. Genetic variation is responsible for the diversity of organisms that are on this planet, from single-celled bacteria to the largest animal, the blue whale. This variation is a key factor in the ability of populations to evolve and ultimately adapt to their environments.

Mutations are the ultimate source of genetic variation

Anytime the DNA is replicated, even though it is a highly accurate process, mistakes can occasionally occur. Repair mechanisms are found in both prokaryotic and eukaryotic organisms and many of the mechanisms are conserved. Errors during DNA replication are not the only reason why mutations arise in DNA; they can also occur because of damage to DNA. Thus, mutations may be of two types: induced or spontaneous. Induced mutations are those that result from 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 natural reactions taking place within the body. Whether the damage to the DNA occurs as a result of environmental conditions or errors during DNA replication, cells have evolved a number of mechanisms to detect and repair the damage. It is only in rare cases that mistakes or DNA damage are not corrected, leading to mutations that can be potentially be inherited.

Small Scale Mutations

Small mutations may have a wide range of effects. Point mutations are those mutations that affect a single base pair (Fig. 2). The most common point 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. If the substitution does not alter the amino acid sequence of the resulting protein, then the mutation is considered to be silent. If, however, the substitution results in a different amino acid becoming part of the protein then it is considered to be a missense mutation and is likely to alter the protein’s structure and function. Substitutions can also result in the alteration of the sequence to include a stop codon where one did not exist before (nonsense). This often results in a truncated or unexpressed protein.
Figure 2. Mutations can lead to changes in the protein sequence encoded by the DNA.
Mutations can affect either somatic cells or germ cells. If a mutation occurs in a somatic cell then the mutation will be present in any cells that arise from that cell when it divides, but not in other parts of the body. Therefore, a somatic cell mutation is not inheritable by offspring during sexual reproduction. However if a mutation occurs in a germ cell (cells that produce gametes), then the mutation can be passed on to the next generation, therefore it is inheritable. Thus, mutations in germ cells can have an impact on the genetic diversity of the population in which the organism lives.

Mutations can also be the result of the addition of a base, known as an insertion, or the removal of a base, also known as deletion. These types of mutations can alter the reading frame (3 nucleotides code for 1 amino acid) of the amino acids, and thus the sequence of amino acids that are incorporated into the protein. The number of nucleotides that are inserted or deleted will determine how much of a change, and thereby how damaging the mutation is. If fewer than 3 insertions or deletions occur in a row, then a frameshift mutation can occur.  This alters the reading of the triplet codons during translation of mRNA to proteins and most often results in a non-functional protein. Finally, sometimes a piece of DNA from one chromosome may get translocated to another chromosome or to another region of the same chromosome; this is also known as translocation.

Review Question:

A ___________ occurs when one purine is substituted for different purine.
A ___________ occurs when a purine is substituted for a pyrimidine.
A ___________ mutation occurs when a substitution results in a different amino acid becoming part of the protein being expressed.
A ___________ mutation occurs when a stop codon is the result of a substitution.

Chromosomal Mutations

Most mutations only involve one or a few nucleotides within the DNA sequence. However, some can affect much larger portions of the genome, extending over thousands or millions of nucleotides. Chromosomal mutations are ones that occur when double-stranded breaks in the DNA are incorrectly repaired or errors in DNA replication result in large segments being duplicate or deleted. Changes on this level, either duplications or deletions, result in changes in the copy numbers of genes and ultimately the amount of the products of these genes in a cell. In addition, chromosomal mutations may also include an alteration in the linear order of genes along a chromosome, or interchange of genes between non-homologous chromosomes. These latter types of mutations, while they do not change the number of copies of a gene, can impact chromosome pairing and segregation during meiosis.
Chromosomal mutations.png
Figure 2. Duplications and deletions can alter the number of copies of genes and thus gene dosages.
The most common type of chromosomal abnormalities are the ones in which there are either two copies of a segment of DNA or a segment of DNA is missing completely (Fig. 2). A chromosome in which two copies of a segment occur is said to contain a duplication. When the duplicated segment is large it is also usually harmful and quickly eliminated from the population as individuals with these duplications are often non-functional (the mutation is lethal).

Smaller-scale duplications that include only one or a few genes can be maintained over many generations depending on the genes that are involved. Deletions can occur as a result of an error in replication or from the joining of breaks in a chromosome that eliminates a section. In some cases, deletions can persist in a population because chromosomes occur in homologous pairs in diploid organisms. This means that a copy of the deleted region is still present in one of the homologs and one copy may be enough for survival and reproduction. Some deletions, on the other hand, decrease the chance of survival and/or reproduction even when the homologous chromosome is normal.

Chromosomal Inversions and Translocations

Figure 4. (A) Translocations occur when non-homologous chromosomes swap segments. (B) Inversions occur when segments of a chromosome are excised and then reinserted in the opposite orientation.

In addition to duplications and deletions, the order of genes within a chromosome can also be altered through inversions and reciprocal translocations. An inversion occurs when a block of genes within a chromosome is reversed, typically when a segment between two breaks and the segment is flipped in orientation. In larger genomes, these breaks are most likely to occur in noncoding regions rather than within a gene. Small inversions are common in many populations and because they do not delete or duplicate genes and so are less likely to cause problems. The accumulation of inversions over time long periods of time can explain, at least in part, why the order of genes can differ among closely related organisms.

Reciprocal translocations involve the exchange of segments of genes between two nonhomologous chromosomes. This occurs when there are breaks in both chromosomes and the terminal segments are exchanged before the breaks are repaired. As with inversions, reciprocal translocations change only the arrangement of genes and not their number. Thus, most of these types of mutations do not impact the survival of the organism. However, problems can arise during meiosis as the two chromosomes involved may not pair correctly with their homologs and thus not move properly into the daughter cells. This can result in inequality in gene dosages in the resulting cells, with some cells have duplicates and other missing genes.

Review Question:

What types of mutations can result in a change in the order of genes in chromosomes? (multiple answers)
A) point mutations
B) deletions
C) inversions
D) reciprocal translocations

Mutation Rates

There are multiple factors that can impact the rate at which mutations occur within an organism and within a population. In the absence of environmental conditions that can cause DNA damage (X-rays, ultraviolet radiation, exposure to mutagenic chemicals), most mutations are spontaneous and thus they occur randomly. It makes no difference whether a mutation would be beneficial or harmful to an organism, whether a mutation occurs is purely a matter of chance.

The most common type of mutation is the substitution of one nucleotide for another but even these types of mutations are relatively rare. The rate of mutations varies among different organisms as well as among different individuals within a population. Multiple factors can influence the rate of mutation and thus mutations rates can also vary over a large range. For example, RNA viruses and retroviruses store their genetic information in RNA rather than DNA. RNA is a less stable molecule than DNA and thus more susceptible to mutations. This means that mutation rates in these viruses are often higher than in viruses that utilize DNA as their genetic material.

Another factor that influences mutations is the proofreading mechanisms found within different groups of organisms. The efficiency with which errors are detected as well as the types of DNA repair mechanisms impact the rate of heritable mutations, mutations that are not corrected, and pass on to subsequent cells/offspring. Thus organisms that have highly efficient and complex detection and repair mechanisms tend to demonstrate lower rates of mutational changes in their genomes.

Since errors do occur, even if infrequently, during the replication of DNA, the mutation rate can vary between individuals within a population. For example, in male mammals, germ line cells undergo meiosis at a much higher rate than in females. This means that the DNA is replicated during each meiotic division and thus since replication occurs more often, the possibility of mutations also increases. The same holds true for different bacteria. Those that are in favorable environments will divide more often than those in less favorable conditions, meaning that their DNA will be replicated more often and thus there is a higher potential for mutations to occur.

Summary

Most errors in DNA replication that occur are corrected by built-in proofreading and repair mechanisms. However, if the errors are not repaired, they may result in a mutation, a permanent change in the DNA sequence. Single base pair (point) mutations are the most common type and can involve insertion, deletion, or mismatches. Typically, these are detected by the cell and repaired. Mutations can also occur on a large scale in chromosomes. Inversions and reciprocal translocation can alter the sequence of genes within chromosomes while duplications and deletions can impact the gene dosage. Depending on the gene/s that is/are being impacted and the size of mutation, these alterations can be lethal, damaging, neutral, or in rare cases positive. If the mutation occurs in a cell that is a reproductive cell then the mutations can be inherited by the offspring. These mutations can have an impact on the genetic diversity of populations and thus play a role in the evolution of organisms.

End of Section Review Questions:

Types of Mutations: Match the mutation with its consequence
1) Match the mutation with its consequence.
1) silent A) change in one amino acid
2) missense B) an insertion/deletion alters the sequence
3) nonsense C) a stop code is created
4) frameshift D) no change in the resulting protein

Mutation Characteristics
2) Most mutations are? (Multiple Answers)

A) the result of environmental changes
B) random
C) spontaneous
D) favorable

Mutation Rates
3) Which of the following has an impact on the rate at which mutations occur in cells? (Multiple Answers)
A) the type of environmental change
B) the number of times DNA is replicated

C) the efficiency of DNA proofreading and repair mechanisms
D) the type of molecule used to store genetic information

Review: Think about this
4) Why would a mutation that involves a centromere have a greater impact than a mutation that occurs elsewhere on a chromosome?

References

Adapted from Morris et al. How Life Works 2nd edition (2017) Chapter 14 Mutation and DNA Repair.

Image AttributionFigure 1. Image (UV mutation of DNA) courtesy of derivative work: Mouagip (talk) DNA_UV_mutation.gif: NASA/David Herring. This W3C-unspecified vector image was created with Adobe Illustrator [Public domain]

Figure 2. Image (Point mutations) courtesy of CNX OpenStax[CC BY 4.0]

Figure 3. Left image courtesy of National Human Genome Research Institute [Public domain], via Wikimedia Commons. Right image (chromosomal deletion) was originally uploaded by Mirmillon at French Wikipedia. [Public domain], via Wikimedia Commons

Figure 4. Image courtesy of Guy Leonard / CC BY-SA 3.0  modified by D. Jennings 8/2020

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