Chapter 3
Mutations and Health
What is a gene mutation and how do mutations occur?
A gene mutation is a permanent change in the DNA sequence that makes up a gene. Mutations range in size from a single DNA building block (DNA base) to a large segment of a chromosome.
Gene mutations occur in two ways: they can be inherited from a parent or acquired during a person's lifetime. Mutations that are passed from parent to child are called hereditary mutations or germline mutations (because they are present in the egg and sperm cells, which are also called germ cells). This type of mutation is present throughout a person's life in virtually every cell in the body.
Mutations that occur only in an egg or sperm cell, or those that occur just after fertilization, are called new (de novo) mutations. De novo mutations may explain genetic disorders in which an affected child has a mutation in every cell, but has no family history of the disorder.
Acquired (or somatic) mutations occur in the DNA of individual cells at some time during a person's life. These changes can be caused by environmental factors such as ultraviolet radiation from the sun, or can occur if a mistake is made as DNA copies itself during cell division. Acquired mutations in somatic cells (cells other than sperm and egg cells) cannot be passed on to the next generation.
Mutations may also occur in a single cell within an early embryo. As all the cells divide during growth and development, the individual will have some cells with the mutation and some cells without the genetic change. This situation is called mosaicism.
Some genetic changes are very rare; others are common in the population. Genetic changes that occur in more than 1 percent of the population are called polymorphisms. They are common enough to be considered a normal variation in the DNA. Polymorphisms are responsible for many of the normal differences between people such as eye color, hair color, and blood type. Although many polymorphisms have no negative effects on a person's health, some of these variations may influence the risk of developing certain disorders.
For more information about mutations:
The National Cancer Institute offers a discussion of hereditary mutations (http://www.cancer.gov/cancertopics/understandingcancer/genetesting/page11) and information about acquired mutations (http://www.cancer.gov/cancertopics/ understandingcancer/genetesting/page12).
The Centre for Genetics Education provides a fact sheet discussing changes to the genetic code (http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/ Changes-to-the-Genetic-Code-FS4).
Additional information about genetic changes is available from the University of Utah fact sheet "What is a Mutation?" (http://learn.genetics.utah.edu/archive/ mutations/index.html)
How can gene mutations affect health and development?
To function correctly, each cell depends on thousands of proteins to do their jobs in the right places at the right times. Sometimes, gene mutations prevent one or more of these proteins from working properly. By changing a gene's instructions for making a protein, a mutation can cause the protein to malfunction or to be missing entirely. When a mutation alters a protein that plays a critical role in the body, it can disrupt normal development or cause a medical condition. A condition caused by mutations in one or more genes is called a genetic disorder.
In some cases, gene mutations are so severe that they prevent an embryo from surviving until birth. These changes occur in genes that are essential for development, and often disrupt the development of an embryo in its earliest stages. Because these mutations have very serious effects, they are incompatible with life.
It is important to note that genes themselves do not cause disease-genetic disorders are caused by mutations that make a gene function improperly. For example, when people say that someone has "the cystic fibrosis gene," they are usually referring to a mutated version of the CFTR gene, which causes the disease. All people, including those without cystic fibrosis, have a version of the CFTR gene.
For more information about mutations and genetic disorders:
The National Cancer Institute provides additional information about how gene mutations can trigger disease:
• Gene Mutations and Disease (http://www.cancer.gov/cancertopics/ understandingcancer/genetesting/page8)
• Altered DNA, Altered Protein (http://www.cancer.gov/cancertopics/ understandingcancer/genetesting/page10)
The Centre for Genetics Education offers a fact sheet about genetic changes that lead to disorders (http://www.genetics.edu.au/Information/Genetics-Fact-Sheets/ Changes-that-make-a-gene-faulty-FS5).
Do all gene mutations affect health and development?
No; only a small percentage of mutations cause genetic disorders-most have no impact on health or development. For example, some mutations alter a gene's DNA base sequence but do not change the function of the protein made by the gene.
Often, gene mutations that could cause a genetic disorder are repaired by certain enzymes before the gene is expressed (makes a protein). Each cell has a number of pathways through which enzymes recognize and repair mistakes in DNA. Because DNA can be damaged or mutated in many ways, DNA repair is an important process by which the body protects itself from disease.
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. For example, a beneficial mutation could result in a protein that protects the organism from a new strain of bacteria.
For more information about DNA repair and the health effects of gene mutations:
The University of Utah Genetic Science Learning Center provides information about genetic disorders (http://learn.genetics.utah.edu/content/disorders/whataregd/) that explains why some mutations cause disorders but others do not.
Additional information about DNA repair is available from the NCBI Science Primer. In the chapter called What Is A Cell? (http://www.ncbi.nlm.nih.gov/About/primer/ genetics_cell.html), scroll down to the heading "DNA Repair Mechanisms.”
What kinds of gene mutations are possible?
The DNA sequence of a gene can be altered in a number of ways. Gene mutations have varying effects on health, depending on where they occur and whether they alter the function of essential proteins. The types of mutations include:
Missense mutation (illustration on page 41)
This type of mutation is a change in one DNA base pair that results in the substitution of one amino acid for another in the protein made by a gene.
Nonsense mutation (illustration on page 42)
A nonsense mutation is also a change in one DNA base pair. Instead of substituting one amino acid for another, however, the altered DNA sequence prematurely signals the cell to stop building a protein. This type of mutation results in a shortened protein that may function improperly or not at all.
Insertion (illustration on page 42)
An insertion changes the number of DNA bases in a gene by adding a piece of DNA. As a result, the protein made by the gene may not function properly.
Deletion (illustration on page 43)
A deletion changes the number of DNA bases by removing a piece of DNA. Small deletions may remove one or a few base pairs within a gene, while larger deletions can remove an entire gene or several neighboring genes. The deleted DNA may alter the function of the resulting protein(s).
Duplication (illustration on page 43)
A duplication consists of a piece of DNA that is abnormally copied one or more times. This type of mutation may alter the function of the resulting protein.
Frameshift mutation (illustration on page 44)
This type of mutation occurs when the addition or loss of DNA bases changes a gene's reading frame. A reading frame consists of groups of 3 bases that each code for one amino acid. A frameshift mutation shifts the grouping of these bases and changes the code for amino acids. The resulting protein is usually nonfunctional. Insertions, deletions, and duplications can all be frameshift mutations.
Repeat expansion (illustration on page 44)
Nucleotide repeats are short DNA sequences that are repeated a number of times in a row. For example, a trinucleotide repeat is made up of 3-base-pair sequences, and a tetranucleotide repeat is made up of 4-base-pair sequences. A repeat expansion is a mutation that increases the number of times that the short DNA sequence is repeated. This type of mutation can cause the resulting protein to function improperly.
For more information about the types of gene mutations:
The National Human Genome Research Institute offers a Talking Glossary of Genetic Terms (http://www.genome.gov/Glossary/). This resource includes definitions, diagrams, and detailed audio descriptions of several of the gene mutations listed above.
Illustrations
In this example, the nucleotide adenine is replaced by cytosine in the genetic code, introducing an incorrect amino acid into the protein sequence.
In this example, the nucleotide cytosine is replaced by thymine in the DNA code, signaling the cell to shorten the protein.
In this example, one nucleotide (adenine) is added in the DNA code, changing the amino acid sequence that follows.
In this example, one nucleotide (adenine) is deleted from the DNA code, changing the amino acid sequence that follows.
A section of DNA is accidentally duplicated when a chromosome is copied.
A frameshift mutation changes the amino acid sequence from the site of the mutation.
In this example, a repeated trinucleotide sequence (CAG) adds a series of the amino acid glutamine to the resulting protein.
Can a change in the number of genes affect health and development?
People have two copies of most genes, one copy inherited from each parent. In some cases, however, the number of copies varies-meaning that a person can be born with one, three, or more copies of particular genes. Less commonly, one or more genes may be entirely missing. This type of genetic difference is known as copy number variation (CNV).
Copy number variation results from insertions, deletions, and duplications of large segments of DNA. These segments are big enough to include whole genes. Variation in gene copy number can influence the activity of genes and ultimately affect many body functions.
Researchers were surprised to learn that copy number variation accounts for a significant amount of genetic difference between people. More than 10 percent of human DNA appears to contain these differences in gene copy number. While much of this variation does not affect health or development, some differences likely influence a person's risk of disease and response to certain drugs. Future research will focus on the consequences of copy number variation in different parts of the genome and study the contribution of these variations to many types of disease.
For more information about copy number variation:
The Howard Hughes Medical Institute discusses the results of recent research on copy number variation in the news release, Genetic Variation: We're More Different Than We Thought (http://www.hhmi.org/news/scherer20061123.html).
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