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4.10: Mutation Effects - Biology

4.10: Mutation Effects - Biology


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Is this rat hairless?

Yes. Why? The result of a mutation, a change in the DNA sequence. The effects of mutations can vary widely, from being beneficial, to having no effect, to having lethal consequences, and every possibility in between.

Effects of Mutations

The majority of mutations have neither negative nor positive effects on the organism in which they occur. These mutations are called neutral mutations. Examples include silent point mutations. They are neutral because they do not change the amino acids in the proteins they encode.

Many other mutations have no effect on the organism because they are repaired beforeprotein synthesis occurs. Cells have multiple repair mechanisms to fix mutations in DNA. One way DNA can be repaired is illustrated in Figure below. If a cell’s DNA is permanently damaged and cannot be repaired, the cell is likely to be prevented from dividing.

DNA Repair Pathway. This flow chart shows one way that damaged DNA is repaired in E. coli bacteria.

Beneficial Mutations

Some mutations have a positive effect on the organism in which they occur. They are calledbeneficial mutations. They lead to new versions of proteins that help organisms adapt to changes in their environment. Beneficial mutations are essential for evolution to occur. They increase an organism’s changes of surviving or reproducing, so they are likely to become more common over time. There are several well-known examples of beneficial mutations. Here are just two:

  1. Mutations in many bacteria that allow them to survive in the presence of antibiotic drugs. The mutations lead to antibiotic-resistant strains of bacteria.
  2. A unique mutation is found in people in a small town in Italy. The mutation protects them from developing atherosclerosis, which is the dangerous buildup of fatty materials in blood vessels. The individual in which the mutation first appeared has even been identified.

Harmful Mutations

Imagine making a random change in a complicated machine such as a car engine. The chance that the random change would improve the functioning of the car is very small. The change is far more likely to result in a car that does not run well or perhaps does not run at all. By the same token, any random change in a gene's DNA is likely to result in a protein that does not function normally or may not function at all. Such mutations are likely to be harmful. Harmful mutations may cause genetic disorders or cancer.

  • A genetic disorder is a disease caused by a mutation in one or a few genes. A human example is cystic fibrosis. A mutation in a single gene causes the body to produce thick, sticky mucus that clogs the lungs and blocks ducts in digestive organs. You can watch a video about cystic fibrosis and other genetic disorders at this link:http://www.youtube.com/watch?v=8s4he3wLgkM (9:31).
  • Cancer is a disease in which cells grow out of control and form abnormal masses of cells. It is generally caused by mutations in genes that regulate the cell cycle. Because of the mutations, cells with damaged DNA are allowed to divide without limits. Cancer genes can be inherited. You can learn more about hereditary cancer by watching the video at the following link: http://www.youtube.com/watch?v=LWk5FplsKwM (4:29)

Albino Redwoods, Ghosts of the Forest

What happens if a plant does not have chlorophyll? They would lack the part of the leaf that makes them green. So these plants could be referred to as albino. This would have to result from a genetic mutation. Do these plants die because they cannot photosynthesize? Not necessarily. What can these plants tell us about the biochemistry, genetics and physiology of plants?

See Science on the SPOT: Albino Redwoods, Ghosts of the Forest athttp://science.kqed.org/quest/video/science-on-the-spot-albino-redwoods-ghosts-of-the-forest/, Science on the SPOT: Revisiting Albino Redwoods, Biological Mystery athttp://science.kqed.org/quest/video/science-on-the-spot-revisiting-albino-redwoods-biological-mystery/, and Science on the SPOT: Revisiting Albino Redwoods, Cracking the Code at http://science.kqed.org/quest/video/science-on-the-spot-revisiting-albino-redwoods-cracking-the-code/ for more information.

Summary

  • Mutations are essential for evolution to occur because they increase genetic variation and the potential for individuals to differ.
  • The majority of mutations are neutral in their effects on the organisms in which they occur.
  • Beneficial mutations may become more common through natural selection.
  • Harmful mutations may cause genetic disorders or cancer.

Explore More

Explore More I

Use these resources to answer the questions that follow.

  • http://www.hippocampus.org/Biology → Non-Majors Biology → Search: Genetic Disorders
  1. Define genetic disorders.
  2. What are the two primary types of genetic aberrations?
  3. What is a carrier?

Explore More II

  • http://www.hippocampus.org/Biology → Non-Majors Biology → Search: Gene Defects
  1. What are the results of a mutation or defect in a single gene?
  2. Describe the causes and effects of cystic fibrosis, Huntington's Disease, and hemophilia.

Explore More III

  • http://www.hippocampus.org/Biology → Non-Majors Biology → Search: Chromosomal Abnormalities
  1. What is a chromosomal disorder?
  2. When and how do chromosomal errors occur?
  3. Describe an inversion and translocation.
  4. Describe the causes of Cri-du-chat Syndrome and Down Syndrome.

Review

  1. Why are mutations essential for evolution to occur?
  2. What is a genetic disorder?
  3. What is cancer? What usually causes cancer?

Diversity spectrum analysis identifies mutation-specific effects of cancer driver genes

Mutation-specific effects of cancer driver genes influence drug responses and the success of clinical trials. We reasoned that these effects could unbalance the distribution of each mutation across different cancer types, as a result, the cancer preference can be used to distinguish the effects of the causal mutation. Here, we developed a network-based framework to systematically measure cancer diversity for each driver mutation. We found that half of the driver genes harbor cancer type-specific and pancancer mutations simultaneously, suggesting that the pervasive functional heterogeneity of the mutations from even the same driver gene. We further demonstrated that the specificity of the mutations could influence patient drug responses. Moreover, we observed that diversity was generally increased in advanced tumors. Finally, we scanned potentially novel cancer driver genes based on the diversity spectrum. Diversity spectrum analysis provides a new approach to define driver mutations and optimize off-label clinical trials.


Germ-line mutations vs Somatic mutations

Mutations can spontaneously occur in most cell types at any time. Mutations that occur in the somatic cells (all cells excluding the sperm and egg cells) either during development or in adulthood will not be inherited by the next generation. Mutations in these cells will only be passed on to daughter cells dividing as part of normal cell division that occurs in tissues and organs in the body.

For mutations to be passed on to the organism’s offspring, they must occur in the parental gametes (eggs and sperm, also referred to as the germ-line), as these are the only cells that contribute genetic material to the offspring, and all the cells in the offspring are derived from gametes. Therefore, if the mutation is present in the gametes and passed on the offspring, all the cells in that individual will carry the mutation. Mutations can also occur during the development of sperm and eggs, resulting in a spontaneous mutation being passed on to the next generation.


Mutation effects predicted from sequence co-variation

Many high-throughput experimental technologies have been developed to assess the effects of large numbers of mutations (variation) on phenotypes. However, designing functional assays for these methods is challenging, and systematic testing of all combinations is impossible, so robust methods to predict the effects of genetic variation are needed. Most prediction methods exploit evolutionary sequence conservation but do not consider the interdependencies of residues or bases. We present EVmutation, an unsupervised statistical method for predicting the effects of mutations that explicitly captures residue dependencies between positions. We validate EVmutation by comparing its predictions with outcomes of high-throughput mutagenesis experiments and measurements of human disease mutations and show that it outperforms methods that do not account for epistasis. EVmutation can be used to assess the quantitative effects of mutations in genes of any organism. We provide pre-computed predictions for ∼7,000 human proteins at http://evmutation.org/.

Conflict of interest statement

Competing Financial Interests Statement

The authors declare no competing financial interests.

Figures

Figure 1. Inferring context-dependent effects of mutations…

Figure 1. Inferring context-dependent effects of mutations from sequences

Evolution has generated diverse families of…

Figure 2. Saturation mutagenesis experiments provide a…

Figure 2. Saturation mutagenesis experiments provide a quantitative test of context-dependent predictions

Figure 3. ΔE captures experimental fitness landscapes…

Figure 3. ΔE captures experimental fitness landscapes and identifies deleterious human variants

Figure 4. Improvements of the epistatic model…

Figure 4. Improvements of the epistatic model for functional sites

Figure 5. Computational predictions complement experimental measurements

Figure 5. Computational predictions complement experimental measurements

Various molecular phenotypes (center) such as structure, thermostability,…


Mutations

A change in the sequence of bases in DNA or RNA is called a mutation. Does the word mutation make you think of science fiction and bug-eyed monsters? Think again. Everyone has mutations. In fact, most people have dozens or even hundreds of mutations in their DNA. Mutations are essential for evolution to occur. They are the ultimate source of all new genetic material - new alleles - in a species. Although most mutations have no effect on the organisms in which they occur, some mutations are beneficial. Even harmful mutations rarely cause drastic changes in organisms.

Types of Mutations

There are a variety of types of mutations. Two major categories of mutations are germline mutations and somatic mutations.

  • Germline mutations occur in gametes. These mutations are especially significant because they can be transmitted to offspring and every cell in the offspring will have the mutation.
  • Somatic mutations occur in other cells of the body. These mutations may have little effect on the organism because they are confined to just one cell and its daughter cells. Somatic mutations cannot be passed on to offspring.

Mutations also differ in the way that the genetic material is changed. Mutations may change the structure of a chromosome or just change a single nucleotide.

Chromosomal Alterations

Chromosomal alterations are mutations that change chromosome structure. They occur when a section of a chromosome breaks off and rejoins incorrectly or does not rejoin at all. Possible ways these mutations can occur are illustrated in the Figure below.

Chromosomal Alterations. Chromosomal alterations are major changes in the genetic material.

Chromosomal alterations are very serious. They often result in the death of the organism in which they occur. If the organism survives, it may be affected in multiple ways.

Point Mutations

A point mutation is a change in a single nucleotide in DNA. This type of mutation is usually less serious than a chromosomal alteration. An example of a point mutation is a mutation that changes the codon UUU to the codon UCU. Point mutations can be silent, missense, or nonsense mutations, as shown in the Table below. The effects of point mutations depend on how they change the genetic code.

Type Description Example Effect
Silent mutated codon codes for the same amino acid CAA (glutamine) &rarr CAG (glutamine) none
Missense mutated codon codes for a different amino acid CAA (glutamine) &rarr CCA (proline) variable
Nonsense mutated codon is a premature stop codon CAA (glutamine) &rarr UAA (stop) usually serious

Frameshift Mutations

A frameshift mutation is a deletion or insertion of one or more nucleotides that changes the reading frame of the base sequence. Deletions remove nucleotides, and insertions add nucleotides. Consider the following sequence of bases in RNA:

Now, assume an insertion occurs in this sequence. Let&rsquos say an A nucleotide is inserted after the start codon AUG:

Even though the rest of the sequence is unchanged, this insertion changes the reading frame and thus all of the codons that follow it. As this example shows, a frameshift mutation can dramatically change how the codons in mRNA are read. This can have a drastic effect on the protein product.


Methylation of DNA and histone H3

Adrian Bird (Institute of Cell and Molecular Biology, Edinburgh, UK) reviewed the in vivo functions of the DNA methyl-binding gene (MBD) family in mice, as revealed by gene knockouts. Whereas the knockout of the MBD protein MECP2 in mice mirrored the human Rett syndrome, the knockout of MBD2 (a component of MECP1, the methyl-DNA-binding chromatin-remodeling complex) resulted in maternal disinterest, an inability to repress a methylated transgene reporter, derepression of the interleukin-4 gene in helper T cells, partial derepression of Xist (a non-coding RNA that is tightly associated with the inactive X chromosome) and a dose-dependent effect on intestinal tumor burden (equivalent to the effect of knocking out the DNA methyltransferase Dnmt1). Wolf Reik (The Babraham Institute, Cambridge, UK) described the use of fluorescence microscopy to show that the erasure of DNA methylation that takes place immediately after fertilization in mouse embryos is highly variable and often grossly impaired in 'cloned' embryos, providing a potential explanation for the low efficiency of cloning.

Thomas Jenuwein (Research Institute of Molecular Pathology, Vienna, Austria) clarified the function of the mouse SUV39H and G9a histone methyltransferases using antibodies directed against histone H3 mono-, di- or tri-methylated at lysine 9. He showed that SUV39H could di- and tri-methylate H3 lysine 9 in vitro and that pericentromeric heterochromatin was tri-methylated. In contrast, G9a appeared incapable of tri-methylation on this residue. Data presented by Jürg Mueller (EMBL) suggested that the histone methyltransferases Trx and Ash1, which methylate lysine 4 of histone H3 in Drosophila, are needed to counteract Polycomb-mediated silencing but are not needed for transcriptional activation per se.

It was clear from this meeting that we have begun to decipher the epigenetic mechanisms that help cells 'remember' which genes should be activated or silenced. Hope was expressed by the organizers that this meeting would be the first of a regular series, perhaps alternating with the bi-annual Gordon Conference in Epigenetics, which takes place in New Hampshire (USA).


Acknowledgements

We dedicate this paper to Brian Charlesworth in honour of his many profound contributions to population genetics. LL thanks BC for many inspiring discussions, stimulating thoughts and a long series of wonderful lab dinners. WGH is supported by USS and looks forward to being joined by BC. We thank Fedya Kondrashov, Mohamed Noor, Allen Orr and Wolfgang Stephan for suggestions that improved this manuscript. Our colleagues at the Institute of Evolutionary Biology and its predecessor departments (ICAPB et al.) in Edinburgh have provided an excellent working environment over many years, for which we are most grateful. The Centre for Systems Biology at Edinburgh is a Centre for Integrative Systems Biology (CISB) funded by BBSRC and EPSRC, reference BB/D019621/1.


Watch the video: The different types of mutations. Biomolecules. MCAT. Khan Academy (May 2022).