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| 11.1 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, where as somatic mutations cannot. The Beta Globin Gene 1. Sickle cell disease is a recessive disorder 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. Collagen is a highly symmetrical protein that is 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. A Mutation that Causes Early-Onset Alzheimer Disease 1. In one form of Alzheimer disease, a mutation in a receptor protein may lead to beta-amyloid buildup. 11.2 Causes of MutationSpontaneous 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 Mutations 1. Researchers use mutagens (chemicals or radiation) to cause mutations in genes, which they study to reveal normal gene function. 2. Site-directed mutagenesis is PCR based technique using primers with intentional mismatches to engineer and amplify specific mutations. 3. Accidental exposure to mutagens may come from nuclear accidents, 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. 11.3 Types of MutationsPoint 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. Deletions and Insertions Can Cause Frameshifts 1. Inserting or deleting bases in DNA alters the gene's reading frame, causing a frameshift mutation. 2. A tandem duplication repeat 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. Expanding Repeats Lead to Protein Misfolding 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. The extra amino acids in an expanded gene may impart a new function to the expanded protein. 4. Some triple repeat mutations affect the export or translation of a mRNA. 11.4 The Importance of a Mutation's Position in the Gene 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. Inherited Susceptibility to Prion Disorders 1. Certain mutations in the prion gene predispose individuals to at least two inherited prion disorders. 2. The disorders fatal familial insomnia and Creutzfeldt-Jakob syndrome both involve mutations in two key parts of the prion protein (amino acids 129 and 178). 11.5 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 and amino acid with a structurally similar one. 3. The phenotypes of conditional mutations are expressed only in certain environments. 11.6 DNA RepairThree 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 to 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 (0.4-1.5% of the population) have an increased risk for breast and other cancers. 5. People with DNA repair disorders often have broken chromosomes and increased cancer risks for certain types of cancer. |