Download Chapter 12 Gene Mutation

Chapter 12
Gene Mutation
CHAPTER OVERVIEW
A mutation changes the nucleotide sequence of a gene. Germline mutations can be inherited,
whereas a somatic mutation cannot. Many mutagens are chemicals or forms of radiation. The
frequency of spontaneous mutations varies for different genes, but can be estimated from the
observation of new dominant conditions in populations. The human genome is full of pseudogenes
and transposons. A point mutation (single nucleotide substitution) results in a beta globin
polypeptide that causes sickle cell disease. Sickle cell disease has the distinction of being the first
disorder linked to a defect in a single molecule. In many cases, different mutations can cause the
same disorder, and the effect of a particular mutation depends on where in the protein the change
occurs. Genetic anticipation is a term used to describe disorders such as myotonic dystrophy that
appear at an earlier age in progeny as a result of expansions of triplet repeats as mutant alleles are
transmitted from parent to child. Recessive mutations are generally associated with a loss of
function phenotype while dominant mutations may reflect a gain of function. All organisms have a
battery of DNA repair enzymes. DNA repair reduces the mutation rate. Defects in DNA repair can
cause a variety of disorders including cancer. Some mutations are observable at the chromosome
level, and these large alterations are the focus of the next chapter.
CHAPTER OUTLINE
12.1 Mutations Can Alter Proteins Three Examples
1. A mutation is a change in a gene's DNA (genotype), and a mutant is the corresponding expression (phenotype).
2. Mutations include single base changes, deletions, additions, or moved sequences in genes that encode proteins or in
regulatory genes.
3. Learning how a mutation alters a protein can explain how a disease arises.
4. Germline mutations can be inherited, whereas somatic mutations cannot.
The Beta Globin Gene Revisited
1. Sickle cell disease is a recessive disorder most commonly associated with a mutation caused by a single nucleotide
substitution in the beta globin gene on chromosome 11.
2. In sickle cell disease, a mutation causes hemoglobin to crystallize in a low-oxygen environment, bending red blood
cells into sickle shapes that block circulation, causing diverse symptoms.
3. In beta thalassemia, beta globin is absent or scarce, causing too few complete hemoglobin molecules and buildup of
free alpha globin chains and iron.
Disorders of Orderly Collagen
1. Collagens are highly symmetrical proteins found in a variety of tissues, including bone, cartilage, skin, ligaments, and
tendons.
2. Mutations in collagen genes often disrupt the protein’s precise organization.
Early-Onset Alzheimer Disease
1. In one form of Alzheimer’s disease, a mutation in a receptor protein may lead to beta-amyloid buildup.
2. The gene for the protein, called presenilin 1, is found on chromosome 14.
One Disorder or Several?
1. What is classified as a single disease phenotype may, in fact, be caused by a number of mutations.
2. Different mutations of the same gene may alter the signs and symptoms of a disease.
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12.2 Causes of Mutation
Spontaneous Mutation
1. Mutations occur spontaneously when rare tautomers of bases are incorporated into replicating DNA, causing a base
mismatch.
2. Genes spontaneously mutate at different rates.
3. Because bacteria and viruses reproduce frequently, they have higher spontaneous mutation rates.
4. Spontaneous mutations are more likely in or near repetitive or symmetrical DNA sequences.
Induced Mutation
1. Researchers use mutagens, such as chemicals or radiation, to cause mutations in genes, which they study to shed light
on normal gene function.
2. The Ames test is a method of testing the mutagenicity of a substance.
3. Site-directed mutagenesis is a PCR based technique using primers with intentional mismatches to engineer and
amplify specific mutations.
4. Accidental exposure to mutagens may come from nuclear accidents, radiological weapons, medical treatments,
cosmic rays, and radioactive isotopes in rocks.
Natural Exposure to Mutagens
1. Natural environmental mutagens include exposure to ionizing radiation and chemical mutagens.
2. The effects of radiation damage to DNA depend on the function of mutated genes.
3. The risk that exposure to a chemical will cause a mutation can be difficult to predict since people vary in their
susceptibility to certain chemicals.
12.3 Types of Mutations
Point Mutations
1. A point mutation is a change in a single base. In a transition, a purine replaces a purine or a pyrimidine replaces a
pyrimidine. In a transversion, a purine replaces a pyrimidine or vice versa.
2. A missense mutation is a point mutation that changes one amino acid to a different one.
3. A nonsense mutation is a point mutation that changes an amino acid encoding codon to a stop codon, which halts
translation. A stop codon that changes to an amino-acid coding codon, lengthens the protein.
Splice Site Mutations
1. Splice site mutations can drastically affect the protein product.
Deletions and Insertions Can Shift the Reading Frame
1. Inserting or deleting bases in DNA alters the gene's reading frame, causing a frameshift mutation.
2. A tandem duplication repeats a section of a gene.
Pseudogenes and Transposons Revisited
1. Pseudogenes are nonfunctional sequences that are very similar to a nearby functional gene.
2. Although pseudogenes are not expressed, they can disrupt meiotic pairing. Gaucher disease is an example of a
disorder that can result from a crossover between the working gene and its pseudogene.
3. A transposable element is DNA that moves. It can insert into and disrupt transcription of a gene.
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Expanding Repeats
1. Myotonic dystrophy, Fragile X syndrome, and Huntington disease are examples of diseases that are caused by
expanding triplet repeats.
2. Expanded triplet repeat disorders are described as “dominant toxic gain of function” and often disturb brain function.
3. Some triple repeat mutations affect the export or translation of the mRNA.
Copy Number Variants
1. Copy number maps of the human genome have revealed individual variations in the number of copies of genes.
2. Copy number variants (CVNs) may affect gene expression, phenotype and health.
12.4 The Importance of Position
1. Whether a mutation alters the phenotype and how it does so, depends upon where in the protein the change occurs.
Globin Variants
1. Mutations in the globin genes are well studied and diverse.
2. Globin mutations occur in either the alpha or beta globin genes and they can cause anemia, affect oxygen binding, or
be clinically silent.
Susceptibility to Prion Disorders
1. Certain mutations in the prion protein gene predispose individuals to at least two inherited prion disorders.
2. The disorders fatal familial insomnia and Creutzfeldt-Jakob disease both involve mutations in two key parts of the
prion protein (amino acids 129 and 178).
12.5 Factors that Lessen the Effects of Mutation
1. Many mutations in the third codon-position do not alter the specified amino acid.
2. Changes in the second codon position often replace an amino acid with a structurally similar one.
3. The phenotypes of conditional mutations are expressed only in certain environments.
12.6 DNA Repair
Types of DNA Repair
1. Many genes encode enzymes that search for errors in DNA and correct them.
2. UV light dimerizes adjacent pyrimidines, kinking the DNA and disrupting replication.
3. Pyrimidine dimers and other types of DNA damage can be corrected by photoreactivation, excision repair, or
mismatch repair.
DNA Repair Disorders
1. p53 is one of a variety of proteins that can slow down the cell cycle and permit damaged cells to repair their DNA.
2. If damage is too severe, p53 and other proteins can induce cells to undergo apoptosis (cell death).
3. Abnormal repair genes cause disorders such as HNPCC (deficient mismatch repair), and XP (deficient excision
repair).
4. A defect in a cell cycle gene affects DNA repair in the disorder Ataxia Telangiectasis (AT), which is an autosomal
recessive disorder. Heterozygotes with a defective AT gene have an increased risk for cancer.
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