Download Chapter 13 Mutation, DNA Repair, and Recombination

Mutation: Source of the Genetic Variability Required for
Evolution
 Mutation: Basic Features of the Process
 Mutation: Phenotypic Effects
 The Molecular Basis of Mutation
 Screening Chemicals for Mutagenicity: The Ames Test
 DNA Repair Mechanisms
 Inherited Human Diseases with Defects in DNA Repair

Mutations—inherited changes in the genetic material—
provide new genetic variation that allows organisms to
evolve.

Mutation
 A change in the genetic material
 The process by which the change occurs

Mutant—an organism that exhibits a novel
phenotype

Types of Mutations
 Changes in chromosome number and structure
 Point mutations—changes at specific sites in a gene
(substitution, insertion, or deletion)

Mutation is the source of all genetic variation.

Recombination mechanisms rearrange genetic
variability into new combinations.

Natural selection preserves the combinations best
adapted to the existing environment.

Mutations are heritable changes in the
genetic material that provide the raw
material for evolution.
Mutations occur in all organisms from viruses to
humans. They can occur spontaneously or be
induced by mutagenic agents. Mutation is usually
a random, nonadaptive process.

Germinal mutations occur in germ-line cells
and will be transmitted through the gametes
to the progeny.

Somatic mutations occur in somatic cells;
the mutant phenotype will occur only in the
descendants of that cell and will not be
transmitted to the progeny.

Spontaneous mutations occur without a known
cause due to inherent metabolic errors or unknown
agents in the environment.

Induced mutations result from exposure or
organisms to mutagens, physical and chemical
agents that cause changes in DNA, such as ionizing
irradiation, ultraviolet light, or certain chemicals.


Forward mutation—mutation of a wild-type
allele to a mutant allele.
Reverse mutation (reversion)—a second
mutation that restores the original
phenotype.
 Back mutation—a second mutation at the same
site.
 Suppressor mutation—a second mutation at a
different location in the genome.

Mutations occur in both germ-line and somatic cells, but only
germ-line mutations are transmitted to progeny.

Mutations can occur spontaneously or be induced by
mutagenic agents in the environment.

Mutation usually is a nonadaptive process in which an
environmental stress simply selects organisms with
preexisting, randomly occurring mutations.

Adaptive, or stationary-phase, mutagenesis occurs in
bacteria that have been exposed to an environmental stress
such as starvation.

Restoration of the wild-type phenotype in a mutant
organism can result from either back mutation or a
suppressor mutation.
The effects of mutations on phenotype range from no observable change to
lethality.

Isoalleles have no effect on phenotype or small effects
that can be recognized only by special techniques.

Null alleles result in no gene product or totally
nonfunctional gene products.

Recessive lethal mutations affect genes required for
growth of the organisms and are lethal in the homozygous
state.

Mutations may be dominant or recessive.

Because of the degeneracy and order in the
genetic code, man mutations have no effect
on the phenotype of the organism. These are
called neutral mutations.

Adult hemoglobin (Hemoglobin A) contains two
 chains and two  chains.

Hemoglobin in patients with sickle-cell anemia
(Hemoglobin S) differs from Hemoglobin A at
only one position.

The sixth amino acid in the  chain is glutamic
acid in Hemoglobin A and is valine in
Hemoglobin S. This substitution is caused by
mutation of a single base pair.
Tay-Sachs disease is
an autosomal
recessive disease.
 The mutation causing
Tay-Sachs disease is
in the gene encoding
hexosaminidase A.

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Phenylketonuria is caused by a
mutation in phenylalanine
hydroxylase.
Albinism is caused by a mutation
in tyrosinase
Alkaptonuria is caused by a
mutation homogentisic acid
oxidase.
Tyrosinosis is caused by a
mutation in tyrosine
transaminase.
Tyrosinemia is caused by a
mutation in phydroxyphenylpyruvic acid
oxidase.

The effects of mutations on the phenotypes of living
organisms range from minor to lethal changes.

Most mutations exert their effects on the
phenotype by altering the amino acid sequences of
polypeptides, the primary gene products.

The mutant polypeptides, in turn, cause
blocks in metabolic pathways.

Conditional lethal mutations provide
powerful tools with which to dissect
biological processes.
Mutations alter the nucleotide sequences of genes in
several ways, for example the substitution of one base
pair for another or the deletion or addition or one or a few
base pairs.
A transition replaces a pyrimidine with another
pyrimidine or a purine for another purine.
 A transversion replaces a pyrimidine with a purine
or a purine with a pyrimidine.

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Accuracy of the DNA replication machinery
Efficiency of the mechanisms for the repair of
damaged DNA
Degree of exposure to mutagenic agents in
the environment
Induced mutations occur upon exposure to physical
or chemical mutagens.
 Hermann J. Muller and Edgar Alternburg measured
the frequency of X-linked recessive lethal mutations
in Drosophila.
 Muller demonstrated that exposing Drosophila
sperm to X-rays increased the mutation frequency.

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Hydrolysis of cytosine to
a hydrate may cause
mispairing during
replication
Cross-linking of adjacent
thymine forms thymidine
dimers, which block DNA
replication and activate
error-prone DNA repair
mechanisms.


Simple tandem repeats are repeated sequence of one to
six nucleotide pairs.
Trinucleotide repeats can increase in copy number and
cause inherited diseases.

Examples: Fragile X Syndrome, Huntington disease,
spinocerebellar ataxia

These diseases are characterized by anticipation, the
increased severity of disease or earlier age of onset in
successive generations as the trinucleotide copy number
increases.

Mutations are induced by chemicals, ionizing irradiation,
ultraviolet light, and endogenous transposable genetic
elements.

Point mutations are of three types:
(1)
(2)
(3)
Transitions—purine for purine and pyrimidine for pyrimidine
substitutions,
Transversions—purine for pyrimidine and pyrimidine for purine
substitutions, and
Frameshift mutations—additions or deletions of one or two
nucleotide pairs, which alter the reading frame of the gene distal to
the site of the mutation.

Several inherited human diseases are caused by
expanded trinucleotide repeats.
The Ames test provides a simple and inexpensive method for detecting the
mutagenicity of chemicals.

Bruce Ames and coworkers developed an
inexpensive and sensitive method for testing
the mutagenicity of chemicals with histidine
auxotrophic mutants of Salmonella.
Living organisms contain many enzymes that scan
their DNA for damage and initiate repair processes
when damage is detected.

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Light-dependent repair (photoreactivation)
Excision repair
Mismatch repair
Postreplication repair
Error-prone repair system (SOS response)

A DNA repair endonuclease or endonucleasecontaining complex recognizes, binds to, and
excised the damaged base or bases.

A DNA Polymerase fills in the gap, using the
undamaged complementary strand of DNA as a
template.

DNA ligase seals the break left by DNA polymerase.

Base excision repair pathways remove
abnormal or chemically modified bases.

Nucleotide excision repair pathways remove
larger defects, such as thymine dimers.

Multiple DNA repair systems have evolved to
safeguard the integrity of genetic
information in living organisms.

Each repair pathway corrects a specific type
of damage in DNA.
Several inherited human disorders result from defects in DNA repair
pathways.
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Individuals with XP are
sensitive to sunlight.
The cells of individuals
with XP are deficient in
the repair of UV-induced
damage to DNA.
Individuals with XP may
develop skin cancer or
neurological
abnormalities.

The importance of DNA repair pathways is
documented convincingly by inherited
human disorders that result from defects in
DNA repair.

Certain types of cancer are also associated
with defects in DNA repair pathways.
Recombination between homologous DNA molecules
involves the activity of numerous enzymes that cleave,
unwind, stimulate single-strand invasions of double
helices, repair, and join strands of DNA.

In eukaryotes, crossing over is associated with the
formation of the synaptonemal complex during
prophase of meiosis I.

Crossing over involves the breakage of parental
chromosomes and rejoining of the parts in new
combinations.

The Holliday model and the double-strand break
model are two explanations of the molecular basis of
recombination.