chapter 15 gene mutation, dna repair, and...

Copyright © 2009 Pearson Education, Inc.

Chapter 15 Gene Mutation, DNA Repair, and Transposition


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?


• 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.


• 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.


• 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.


Classification Based on Phenotypic Effects

• Loss-of-function • Gain-of-function • Morphological • Nutritional • Behavioral • Lethal • Conditional


• 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.


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.


• 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.


• 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.


15.2 Spontaneous Mutations Arise from Replication Errors and Base Modifications


• 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. Deamination

DNA base damage by depurination and deamination is the most common cause of spontaneous mutation.


• 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.


Base analogs can substitute for purines or pyrimidines during nucleic acid replication.


Alkylating agents donate an alkyl group to amino or keto groups in nucleotides to alter base-pairing affinity.


crosslinks

Copyright © 2009 Pearson Education, Inc. A couple of intercalating agents

Acridine dyes cause frameshift mutations by intercalating between purines and pyrimidines.


UV radiation creates pyrimidine dimers that distort the DNA conformation in such a way that errors tend to be

introduced during DNA replication.


Ionizing radiation in the form of X rays, gamma rays, and cosmic rays are mutagenic.


15.4 Single-Gene Mutations Cause a Wide Range of Human Diseases


• 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.


• 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.


• 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


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.


Photoreactivation repair removes thymine dimers caused by UV light. The process depends on the activity of a protein called photoreactivation enzyme (PRE).


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


Nucleotide excision repair (NER) repairs bulky lesions and involves the uvr genes.


• 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).


• 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.


There are other pathways for DSB repair via homologous recombination. This type of repair is accurate, and is prominent in late S/G2 .


• 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.


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.


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.


15.8 Transposable Elements Move within the Genome and May Create Mutations


Insertion Sequences


Barbara McClintock Nobel Prize 1983

Transposons: The Ac–Ds System in Maize


Copia Elements in Drosophila

P Element Transposons in Drosophila


Transposons Create Mutations and Provide Raw Material for Evolution


Homologous recombination between transposable elements can result in deletions, duplications, and inversions


Creation of target site duplication in host chromosome DNA during transposition


Transposons Use Two Different Methods to Move Within Genomes: Nonreplicative and replicative methods of DNA transposition


Structural features of retroviruses and retrotransposons


Transposition by an LTR-containing retrotransposon, copia


Electron microscopic images of virus-like particles in yeast cells that contain the retrotransposonTy

chapter 15 gene mutation, dna repair, and...

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