Copyright © 2009 Pearson Education, Inc.
Chapter 15 Gene Mutation, DNA Repair, and Transposition
Copyright © 2009 Pearson Education, Inc.
15.1 Mutations Are Classified in Various Ways • A mutation is an alteration in DNA sequence
• Spontaneous and Induced Mutations
• The Luria-Delbruck Fluctuation Test: Are Mutations Spontaneous or Adaptive?
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
• Spontaneous mutations happen naturally and randomly and are usually linked to normal biological or chemical processes in the organism.
• Rates of spontaneous mutations vary among loci
in different organisms .
• Induced mutations result from the influence of an extraneous factor, either natural or artificial.
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
• Classification Based on Location of Mutation • Somatic mutations occur in any cell except germ cells and are not heritable. • Germ-line mutations occur in gametes and are inherited. • Autosomal mutations occur within genes located on the autosomes • X-linked mutations occur within genes located on the X chromosome.
• Mutations are also classified as dominant vs recessive. • Haploinsufficiency also is seen.
Copyright © 2009 Pearson Education, Inc.
• When a recessive autosomal mutation occurs in a somatic cell of a diploid organism, it is unlikely to result in a detectable phenotype.
• Inherited dominant autosomal mutations will be expressed phenotypically in the first generation.
• X-linked recessive mutations arising in the gametes of a homogametic female may be expressed in hemizygous male offspring.
Copyright © 2009 Pearson Education, Inc.
Classification Based on Phenotypic Effects
• Loss-of-function • Gain-of-function • Morphological • Nutritional • Behavioral • Lethal • Conditional
Copyright © 2009 Pearson Education, Inc.
• Lethal mutations interrupt an essential process and result in death.
• The expression of conditional mutations depends on the environment in which the organism finds itself.
• A good example is a temperature-sensitive mutation.
Copyright © 2009 Pearson Education, Inc.
Mutations can be classified based on type of molecular change.
Point mutations are base substitutions in which one base pair is altered.
Frameshift mutations result from insertions or deletions of a base pair.
Copyright © 2009 Pearson Education, Inc.
• If a pyrimidine replaces a pyrimidine or a purine replaces a purine, a transition has occurred. If a purine and a pyrimidine are interchanged, a transversion has occurred.
• A frameshift mutation occurs when any number of bases are added or deleted, except multiples of three, which would reestablish the initial frame of reading.
• Missense mutations change a codon resulting in an altered amino acid within a protein-coding portion of a gene.
• A nonsense mutation changes a codon into a stop codon and results in premature termination of translation.
• A silent mutation alters a codon but does not result in a change in the amino acid at that position of the protein.
Copyright © 2009 Pearson Education, Inc.
• Neutral mutations, the vast majority of all mutations, occur in the large portions of the genome that do not contain genes and therefore have no effect on gene products.
• Recent molecular techniques indicate that the rate of deleterious mutation in humans is at least 1.6 per individual per generation.
Copyright © 2009 Pearson Education, Inc.
15.2 Spontaneous Mutations Arise from Replication Errors and Base Modifications
Copyright © 2009 Pearson Education, Inc.
• DNA polymerase occasionally inserts incorrect nucleotides, generally due to mispairing.
• These types of errors predominantly lead to point mutations.
• Slippage during replication can lead to small insertions or deletions.
• Tautomeric shifts in nucleotides can result in mutations due to anomalous base pairing
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc. Deamination
DNA base damage by depurination and deamination is the most common cause of spontaneous mutation.
Copyright © 2009 Pearson Education, Inc.
• DNA may suffer oxidative damage by the by-products of normal cellular processes.
• Integrations of transposons into new genomic
locations can act as naturally occurring mutagens.
Copyright © 2009 Pearson Education, Inc.
Base analogs can substitute for purines or pyrimidines during nucleic acid replication.
Copyright © 2009 Pearson Education, Inc.
Alkylating agents donate an alkyl group to amino or keto groups in nucleotides to alter base-pairing affinity.
Copyright © 2009 Pearson Education, Inc.
crosslinks
Copyright © 2009 Pearson Education, Inc. A couple of intercalating agents
Acridine dyes cause frameshift mutations by intercalating between purines and pyrimidines.
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
UV radiation creates pyrimidine dimers that distort the DNA conformation in such a way that errors tend to be
introduced during DNA replication.
Copyright © 2009 Pearson Education, Inc.
Ionizing radiation in the form of X rays, gamma rays, and cosmic rays are mutagenic.
Copyright © 2009 Pearson Education, Inc.
15.4 Single-Gene Mutations Cause a Wide Range of Human Diseases
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
• Muscular dystrophy results from mutation in the gene encoding dystrophin.
• The more severe Duchenne muscular dystrophy (DMD) is typically the result from a frameshift mutation in the dystrophin gene.
• This leads to a nonfunctional truncated protein.
• The less severe Becker muscular dystrophy (BMD) is primarily due to alteration of the protein sequence.
Copyright © 2009 Pearson Education, Inc.
• Trinucleotide repeat sequences are responsible for: • Fragile X syndrome • Huntington disease (HD) • Myotonic dystrophy (MD) • Spinobulbar muscular atrophy
• The greater the number of repeats, the earlier
disease onset occurs.
• In affected individuals, the number of repeats may increase in each subsequent generation, a phenomenon known as genetic anticipation.
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
• Bacterial DNA polymerase III is able to recognize and correct errors in replication, a process called proofreading.
• Mismatch repair corrects errors that remain after proofreading.
• The correct DNA strand is recognized based on DNA methylation of the parental strand.
• Postreplication repair occurs when DNA replication skips over a lesion and requires homologous recombination mediated by the RecA protein.
15.5 Organisms Use DNA Repair Systems to Counteract Mutations
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
SOS Response
SOS response in bacteria
The SOS repair system allows DNA synthesis to become error-prone.
Although SOS repair is itself mutagenic, it may allow the cell to survive DNA damage that might otherwise kill it.
Copyright © 2009 Pearson Education, Inc.
Photoreactivation repair removes thymine dimers caused by UV light. The process depends on the activity of a protein called photoreactivation enzyme (PRE).
Copyright © 2009 Pearson Education, Inc.
Excision repair involves three steps: removal of the mutation by a nuclease gap filling by DNA polymerase sealing of the nick by DNA ligase
Base excision repair (BER) involves: recognition of the erroneous base cutting of the DNA
Copyright © 2009 Pearson Education, Inc.
Nucleotide excision repair (NER) repairs bulky lesions and involves the uvr genes.
Copyright © 2009 Pearson Education, Inc.
• Individuals with xeroderma pigmentosum (XP) have lost the ability to undergo nucleotide excision repair.
• Pol eta is the key enzyme that replicates through UV irradiation-induced DNA damage. Genetic defects in pol eta result in Xeroderma Pigmentosum Variant (XP-V).
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
• DNA double-strand break (DSB) repair is activated when both DNA strands are cleaved. It is responsible for reannealing the two strands.
• Homologous recombinational repair fixes a double-strand DNA break by digesting back the 5' ends of the broken helix to leave overhanging 3' ends that interact with a region of an undamaged sister chromatid to allow DNA polymerase to copy the undamaged DNA sequence into the damaged strand.
Copyright © 2009 Pearson Education, Inc.
There are other pathways for DSB repair via homologous recombination. This type of repair is accurate, and is prominent in late S/G2 .
Copyright © 2009 Pearson Education, Inc.
• DSBs can also be repaired via nonhomologous end-joining, which is error-prone and is prominent during G1.
• End joining repairs double-stranded breaks but does not require a homologous region of DNA during repair.
Copyright © 2009 Pearson Education, Inc.
15.6 The Ames Test Is Used to Assess the Mutagenicity of Compounds
• The Ames test uses any of a dozen strains of Salmonella typhimurium selected for their increased sensitivity to mutagens and their ability to reveal the presence of specific types of mutations.
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
15.7 Geneticists Use Mutations to Identify Genes and Study Gene Function
• In order to identify the genes and processes that regulate biological functions, geneticists often induce mutations in model organisms.
Copyright © 2009 Pearson Education, Inc.
15.8 Transposable Elements Move within the Genome and May Create Mutations
Copyright © 2009 Pearson Education, Inc.
Insertion Sequences
Copyright © 2009 Pearson Education, Inc.
Barbara McClintock Nobel Prize 1983
Transposons: The Ac–Ds System in Maize
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
Copyright © 2009 Pearson Education, Inc.
Copia Elements in Drosophila
P Element Transposons in Drosophila
Copyright © 2009 Pearson Education, Inc.
Transposons Create Mutations and Provide Raw Material for Evolution
Copyright © 2009 Pearson Education, Inc.
Homologous recombination between transposable elements can result in deletions, duplications, and inversions
Copyright © 2009 Pearson Education, Inc.
Creation of target site duplication in host chromosome DNA during transposition
Copyright © 2009 Pearson Education, Inc.
Transposons Use Two Different Methods to Move Within Genomes: Nonreplicative and replicative methods of DNA transposition
Copyright © 2009 Pearson Education, Inc.
Structural features of retroviruses and retrotransposons
Copyright © 2009 Pearson Education, Inc.
Transposition by an LTR-containing retrotransposon, copia
Copyright © 2009 Pearson Education, Inc.
Electron microscopic images of virus-like particles in yeast cells that contain the retrotransposonTy