Human Genetics: Concepts and Applications (Lewis), 9th Edition

Chapter 12: Gene Mutation

Chapter Outline

CHAPTER OVERVIEW

1. Mutation refers to a change in the DNA sequence (genotype).
2. Mutations include single base changes, deletions, additions, or moved sequences in genes that encode proteins or in regulatory genes.
3. The term mutant refers to the phenotypic expression of a mutation.
4. Germline mutations can be inherited, whereas somatic mutations cannot.

1. Learning how a mutation alters a protein can explain how a disease arises.

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.

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.

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.

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.

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.

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.

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.

1. Splice site mutations can drastically affect the protein product.

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.

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.

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.

1. Copy number maps of the human genome have revealed individual variations in the number of copies of genes.
2. Copy number variants (CNVs) may affect gene expression, phenotype and health.

1. Whether a mutation alters the phenotype and how it does so, depends upon where in the protein the change occurs.

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.

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).

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.

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.

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 Telangiectasia (AT), which is an autosomal recessive disorder. Heterozygotes with a defective AT gene have an increased risk for cancer.