A gene pool is the complete set of unique alleles in a species or population. Mutations create variation in the gene pool. Populations with a large gene pool are said to be genetically diverse and very robust. They are able to survive intense times of natural selection against certain phenotypes. During these times of selection, individuals with less favorable phenotypes resulting from deleterious alleles (due to mutations) may be selected against and removed from the population. Concurrently, the more favorable mutations that cause beneficial or advantageous phenotypes tend to accumulate in that population, resulting, over time, in evolution. We will discuss evolution and the genetic effects on evolution in much more detail in a later chapter.
Harmful Mutations
Mutations can result in errors in protein sequence, creating partially or completely non-functional proteins. These can obviously result in harm to the cell and organism. As discussed in the previous lesson, to function correctly and maintain homeostasis, each cell depends on thousands of proteins to all work together to perform the functions of the cell. When a mutation alters a protein that plays a critical role in the cell, the tissue, organ, or organ system may not function properly, resulting in a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder, which will be discussed in the next chapter. However, only a small percentage of mutations cause genetic disorders; most have no impact on health. If a mutation does not change the protein sequence or structure, resulting in the same function, it will have no effect on the cell. Often, these mutations are repaired by the DNA repair system of the cell. Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA (Figure below). Because DNA can be damaged or mutated in many ways, the process of DNA repair is an important way in which the cell protects itself to maintain proper function.
Figure 8.20
DNA repair. Shown is a model of DNA ligase repairing chromosomal damage. is an enzyme that joins broken nucleotides together by catalyzing the formation of a bond between the phosphate group and deoxyribose sugar of adjacent nucleotides in the DNA backbone.
A mutation present in a germ cell can be passed to the next generation. If the zygote contains the mutation, every cell in the resulting organism will have that mutation. If the mutation results in a disease phenotype, the mutation causes what is called a hereditary disease. These will be discussed in the next chapter. On the other hand, a mutation that is present in a somatic cell of an organism will be present (by DNA replication and mitosis) in all descendants of that cell. If the mutation is present in a gene that is not used in that cell type, the mutation may have no effect. On the other hand, the mutation may lead to a serious medical condition such as cancer. Mutations and cancer will be discussed in the next lesson.
Beneficial Mutations
A very small percentage of all mutations actually have a positive effect. These mutations lead to new versions of proteins that help an organism and its future generations better adapt to changes in their environment. The genetic diversity that results from mutations is essential for evolution to occur. Without genetic diversity, each individual of a species would be the same, and no one particular individual would have an advantage over another. Adaptation and evolution would not be possible. Beneficial mutations lead to the survival of the individual best fit to the current environment, which results in evolution. This will be discussed in the evolution chapter.
Mutations and Cancer
During the discussion of the cell cycle, cancer was described as developing due to unregulated cell division. That is, cancer is a disease characterized by a population of cells that grow and divide without respect to normal limits. These cancerous cells invade and destroy adjacent tissues, and they may spread throughout the body.
Nearly all cancers are caused by mutations in the DNA of the abnormal cells. These mutations may be due to the effects of carcinogens, cancer causing agents such as tobacco smoke, radiation, chemicals, or infectious agents. These carcinogens may act as an environmental “trigger,” stimulating the onset of cancer in certain individuals and not others. Do all people who smoke get cancer? No. Complex interactions between carcinogens and an individual’s genome may explain why only some people develop cancer after exposure to an environmental trigger and others do not. Do all cancers need an environmental trigger to develop? No. Cancer causing mutations may also result from errors incorporated into the DNA during replication, or they may be inherited. Inherited mutations are present in all cells of the organism.
Oncogenes and Tumor Suppressor Genes
Mutations found in the DNA of cancer cells typically affect two general classes of genes: oncogenes and tumor suppressor genes. In “normal,” non-cancerous cells, the products of proto-oncogenes promote cell growth and mitosis prior to cell division; thus, proto-oncogenes encode proteins needed for normal cellular functions. Mutations in proto-oncogenes can modify their expression and the function of the gene product, increasing the amount of activity of the product protein. When this happens, they become oncogenes; thus, the cells have a higher chance of dividing excessively and uncontrollably. Cancer-promoting oncogenes are often activated in cancer cells, giving those cells abnormal properties. The products of these genes result in uncontrolled cell growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Proto-oncogenes cannot be removed from the genome, as they are critical for growth, repair and homeostasis. It is only when they become mutated that the signals for growth become excessive.
In “normal” cells, the products of tumor suppressor genes temporarily discourage cell growth and division to allow cells to finish routine functions, especially DNA repair. Tumor suppressors are generally transcription factors, activated by cellular stress or DNA damage. The function of such genes is to stop the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. However, if the tumor suppressor genes are inactivated, DNA repair cannot occur. Tumor suppressor genes can be inactivated by a mutation that either affects the gene directly or that affects the pathway that activates the gene. The consequence of the lack of DNA repair is that DNA damage accumulates, is not repaired, and inevitably leads to cancer.
Several Mutations to Cause Cancer
Typically, a series of several mutations in these genes that activate oncogenes and inactivate tumor suppressor genes is required to transform a normal cell into a cancer cell (Figure below). Cells have developed a number of control mechanisms to overcome mutations in proto-oncogenes. Therefore, a cell needs multiple mutations to transform into a cancerous cell. A mutation in one proto-oncogene would not cause cancer, as the effects of the mutation would be masked by the normal control of mitosis and the actions of tumor suppressor genes. Similarly, a mutation in one tumor suppressor gene would not cause cancer either, due to the presence of many "backup" genes that duplicate its functions. It is only when enough proto-oncogenes have mutated into oncogenes and enough tumor suppressor genes have been deactivated that the cancerous transformation can begin. Signals for cell growth overwhelm the signals for growth regulation, and the cell quickly spirals out of control. Often, because many of these genes regulate the processes that prevent most damage to the genes themselves, DNA damage accumulates as one ages.
Usually, oncogenes are dominant alleles, as they contain gain-of-function mutations. Meanwhile, mutated tumor suppressors are generally recessive alleles, as they contain loss-of-function mutations. A proto-oncogene needs only a mutation in one copy of the gene to generate an oncogene; a tumor suppressor gene needs a mutation in both copies of the gene to render both products defective. There are instances when, however, one mutated allele of a tumor suppressor gene can render the other copy non-functional. These instances result in what is known as a dominant negative effect.
Figure 8.21
Cancers are caused by a series of mutations. Each
mutation alters the behavior of the cell. In this example, the first mutation inactivates a tumor suppressor gene, the second mutation inactivates a DNA repair gene, the third mutation creates an oncogene, and a fourth mutation inactivates several more tumor suppressor genes, resulting in cancer. It should be noted that it does not necessarily require four or more mutations to lead to cancer.
Lesson Summary
Mutations may be due to environmental factors (mutagens) or may occur spontaneously.
Typical mutagens include chemicals, such as those inhaled by smoking, and radiation, like X-rays, ultraviolet light, and nuclear radiation.
Germline mutations can be passed on to descendants; somatic mutations cannot be transmitted to the next generation.
Chromosomal alterations are large changes in the chromosome structure. There are 5 types of chromosomal alterations: deletions, duplications, insertions, inversions, and translocations.
Point mutations occur at a single site within the DNA; examples of these include silent mutations, missense mutations, and nonsense mutations.
A deletion or insertion in the DNA can alter the reading frame.
Loss-of-function and gain-of-function mutations may result in altered function of the gene product or protein.
Beneficial mutations may accumulate in a population, resulting, over time, in evolution.
Harmful mutations can result in errors in protein sequence, creating partially or completely non-functional proteins.
Nearly all cancers are caused by mutations in the DNA of the abnormal cells.
In non-cancerous cells, proto-oncogenes promote cell growth and mitosis prior to cell division; thus, proto-oncogenes encode proteins needed for normal cellular functions.
In non-cancerous cells, tumor suppressor genes temporarily discourage cell growth and division to allow cells to finish routine functions, especially DNA repair.
Mutations in proto-oncogenes and tumor suppressor genes may lead to cancer.
Usually mutations in multiple genes are necessary to develop cancer.
Review Questions
Define mutation.
What are some common causes of mutations?
List some common types of mutations.
Describe some common chromosomal alterations.
Discuss potential consequences of point mutations, deletions and insertions.
List and describe three common types of point mutations.
What are effect-on-function mutations?
What is a germline mutation? A somatic mutation?
Explain why some mutations are harmful and some beneficial.
Further Reading / Supplemental Links
Campbell, N.A. and Reece, J.B. Biology, Seventh Edition, Benjamin Cummings, San Francisco, CA, 2005.
Biggs, A., Hagins, W.C., Kapicka, C., Lundgren, L., Rillero, P., Tallman, K.G., and Zike, D., Biology: The Dynamics of Life, California Edition, Glencoe Science, Columbus, Oh, 2005.
Nowicki S., Biology, McDougal Littell, Evanston, IL, 2008.
Kimball’s Biology Pages:
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/
How Cancer Starts:
http://www.cancerhelp.org.uk/help/default.asp?page=97
Mutations and evolution:
http://www.nwcreation.net/geneticrecombination.html
http://en.wikipedia.org
Vocabulary
allele
An alternative form of a gene.
beneficial mutation
A mutation that leads to a new version of a protein that helps an organism and its future generations better adapt to changes in their environment.
cancer
A disease characterized by a population of cells that grow and divide without respect to normal limits.
carcinogen
Cancer causing agent, such as tobacco smoke, radiation, chemicals, or infectious agents.
chromosomal alterations
Large changes in chromosome structure.
deamination
A mutation due to the spontaneous deamination of 5-methycytosine.
deletion
Removal of a large chromosomal region, leading to loss of the genes within that region; also the removal of one or more nucleotides from DNA.
depurination
A mutation due to the loss of a purine base (A or G).
DNA ligase
An enzyme that joins broken nucleotides together by catalyzing the formation of a bond between the phosphate group and deoxyribose sugar of adjacent nucleotides in the DNA backbone.
dominant negative mutation
Mutation that results in an altered gene product that acts in a dominant manner to the wild-type gene product.
duplication
Leads to multiple copies of a chromosomal region, increasing the number of the genes located within that region; also know as amplification.
frameshift mutation
Mutations which alter the mRNA reading frame.
gain-of-function mutation
Mutation that results in the gene product or protein having a new and abnormal function.
gene pool
The complete set of unique alleles in a species or population.
genetic disorder
A condition caused by mutations in one or more genes.
germline mutation
Mutation in the DNA within a gamete; can be passed on to descendents.
insertion
Chromosomal alteration involving the addition of material from one chromosome to a nonhomologous chromosome; also a mutation which adds one or more nucleotides into the DNA.
inversion
Chromosomal alteration reversing the orientation of a chromosomal segment.
loss-of-function mutation
Mutation that results in a gene product or protein having less or no function.
missense mutations
Point mutation which codes for a different amino acid.
mutagen
An environmental factor which causes a mutation; includes certain chemicals and radiation.
mutation
A change in the DNA or RNA sequence.
nonsense mutation
Point mutation which codes for a premature stop codon.
oncogene
Cancer promoting gene; the products of these genes result in uncontrolled cell growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments.
point mutations
Exchange one nucleotide for another; known as base substitution mutations.
proto-oncogenes
Genes whose products promote cell growth and mitosis prior to cell division.
silent mutations
Point mutation which codes for the same amino acid.
somatic mutation
A mutation in a body cell, not in a gamete; cannot be transmitted to the next generation.
splice site mutation
Mutation in the coding region of a gene that alters splicing of the mRNA.
tautomerism
A mutation due to the changing of a base by the repositioning of a hydrogen atom.
transition
A purine to purine, or a pyrimidine to pyrimidine change.
translocation
Chromosomal alterations involving the interchange of genetic material between nonhomologous chromosomes.
transversion
A purine is replaced by a pyrimidine, or a pyrimidine is replaced by a purine.
tumor suppressor gene
Gene whose product temporarily discourage cell growth and division to allow cells to finish routine functions, especially DNA repair.
Points to Consider
Now that we have discussed DNA, protein synthesis and mutations, can you think of a mechanism that allows different cell types to have different proteins?
What about during development? Why does a developing embryo need different p
roteins at different times of development?
We have discussed oncogenes and tumor suppressor genes. Can you think of a specific cellular mechanism in which defects in these genes lead to cancer?
Lesson 8.4: Regulation of Gene Expression
Lesson Objectives
Describe general mechanisms of gene expression.
Differentiate between a cis-regulatory element and a trans-acting factor.
Define a transcription factor.
Define an operon.
Describe how the lac operon regulates transcription.
Describe the role of the TATA box.
Express the importance of gene regulation during development.
Describe the role of homeobox genes and gap genes.
Discuss gene regulation in terms of the development of cancer.
Introduction
CK-12 Biology I - Honors Page 36
