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Welcome to Genetics:
Unit 8 Seminar!
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Agenda
• Brief Review of Unit Material
• Self Assessment Questions
• Question
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Molecular Mechanisms of
Mutation and DNA Repair
Mutations
• A mutation is any heritable change in the genetic
material
• Mutations are classified in a variety of ways
• Most mutations are spontaneous: they are random,
unpredictable events
• Each gene has a characteristic rate of spontaneous
mutation, measured as the probability of a change in
DNA sequence in the time span of a single generation
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Table 12.1
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Mutations
• Rates of mutation can be increased by treatment
with a chemical mutagen or radiation, in which case
the mutations are said to be induced
• Mutations in cells that form gametes are germ-line
mutations; all others are somatic mutations
• Germ-line mutations are inherited; somatic
mutations are not
• A somatic mutation yields an organism that is
genotypically a mixture (mosaic) of normal and
mutant tissue
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Mutations
• Among the mutations that are most useful for
genetic analysis are those whose effects can be
turned on or off by the researcher
• These are conditional mutations: they produce
phenotypic changes under specific (permissive
conditions) conditions but not others (restrictive
conditions)
• Temperature-sensitive mutations: conditional
mutation whose expression depends on
temperature
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Mutations
• Mutations can also be classified according to their
effects on gene function:
 A loss-of-function mutation (a knockout or null) results in complete
gene inactivation or in a completely nonfunctional gene product
 A hypomorphic mutation reduces the level of expression of a gene
or activity of a product
 A hypermorphic mutation produces a greater-than-normal level of
gene expression because it changes the regulation of the gene so
that the gene product is overproduced
 A gain-of-function mutation qualitatively alters the action of a gene.
For example, a gain-of-function mutation may cause a gene to
become active in a type of cell or tissue in which the gene is not
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normally active.
Mutations
• Mutations result from changes in DNA
•
A base substitution replaces one nucleotide pair
with another
• Transition mutations replace one pyrimidine base
with the other or one purine base with the other.
There are four possible transition mutations
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Discussion Question 1
• Please give an example
of a transition mutation?
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Discussion Question 1
• Please give an example of a
transition mutation?
• G -> A; purine -> purine
• C -> T; pyrimidine -> pyrimidine
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Mutations
• Transversion mutations replace a pyrimidine with
a purine or the other way around. There are eight
possible transversion mutations
• Spontaneous base substitutions are biased in
favor of transitions:
• Among spontaneous base substitutions, the ratio
of transitions to transversions is approximately
2:1
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Discussion Question 2
• Please give an example of
a transversion mutation?
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Discussion Question 2
• Please give an example of
a transversion mutation?
• G -> T; purine -> pyrimidine
• C -> A; pyrimidine -> purine
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Mutations
• Mutations in protein-coding regions can change an
amino acid, truncate the protein, or shift the
reading frame:
• Missense or nonsynonymous substitutions result
in one amino acid being replaced with another
• Synonymous or silent substitutions in DNA do not
change the amino acid sequence
• Silent mutations are possible because the genetic
code is redundant
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Mutations
• A nonsense mutation creates a new stop codon
• Frameshift mutations shift the reading frame of
the codons in the mRNA
• Any addition or deletion that is not a multiple of
three nucleotides will produce a frameshift
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Sickle-cell anemia
The molecular basis of sickle-cell anemia is a mutant gene
for b-globin
The sickle-cell mutation changes the sixth codon in the
coding sequence from the normal GAG, which codes for
glutamic acid, into the codon GUG, which codes for valine
Sickle-cell anemia is a severe genetic disease that often
results in premature death
The disease is very common in regions where malaria is
widespread because it confers resistance to malaria
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What is sickle cell
anemia? (cont’d)
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Transposable Elements
• In a 1940s study of the genetics of kernel mottling in
maize, Barbara McClintock discovered a genetic
element that could move (transpose) within the
genome and also caused modification in the
expression of genes at or near its insertion site
• Since then, many
transposable elements
(TEs) have been discovered
in prokaryotes and
eukaryotes
n-equals-one.com
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Transposable Elements
• The genomes of most organisms contain multiple copies
of each of several distinct families of TEs
• Once situated in the genome, TEs can persist for long
periods and undergo multiple mutational changes
• Approximately 50 % of the human genome consists of
TEs; most of them are evolutionary
remnants no longer
able to
transpose
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staff.jccc.net
Transposable Elements
• TEs can cause mutations by insertion or by
recombination
• In Drosophila, about half of all spontaneous mutations
that have visible phenotypic effects result from
insertions of TEs
• Genetic aberrations can also be caused by
recombination between different (nonallelic) copies of
a TE
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Spontaneous Mutations
• Mutations are statistically random events—there
is no way of predicting when, or in which cell, a
mutation will take place
• The mutational process is also random in the
sense that whether a particular mutation
happens is unrelated to any adaptive advantage
it may confer on the organism in its environment
• A potentially favorable mutation does not arise
because the organism has a need for it
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Mutation Hot Spots
• Mutations are nonrandom with respect to position
in a gene or genome
• Certain DNA sequences are called mutational
hotspots because they are more likely to undergo
mutation than others
• For instance, sites of cytosine methylation are
usually highly mutable
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Mutagenes
• Almost any kind of mutation that can be induced by a mutagen can
also occur spontaneously, but mutagens bias the types of
mutations that occur according to the type of damage to the DNA
that they produce
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DNA Repair Mechanisms
• Many types of DNA damage can be repaired
• Mismatch repair fixes incorrectly matched base
pairs
• The AP endonuclease system repairs nucleotide
sites at which the base has been lost
• Special enzymes repair damage caused to DNA by
ultraviolet light
• Excision repair works on a wide variety of
damaged DNA
• Postreplication repair skips over damaged bases
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Ames test
• In view of the increased number of chemicals used
and present as environmental contaminants, tests
for the mutagenicity of these substances has
become important
• Furthermore, most agents that cause cancer
(carcinogens) are also mutagens, and so
mutagenicity provides an initial screening for
potential hazardous agents
• A genetic test for mutations in bacteria that is
widely used for the detection of chemical mutagens
is the Ames test
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Ames test
• In the Ames test for mutation, histidine-requiring
(His-) mutants of the bacterium Salmonella
typhimurium, containing either a base substitution
or a frameshift mutation, are tested for
backmutation reversion to His+
• In addition, the bacterial strains have been made
more sensitive to mutagenesis by the incorporation
of several mutant alleles that inactivate the excisionrepair system and that make the cells more
permeable to foreign molecules
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Molecular Genetics of Cell
Cycle and Cancer
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The Cell Cycle
• There are two major parts in the cell cycle:
Interphase: G1 = gap1 S = DNA synthesis G2 = gap2
Mitosis: M
• There are two essential functions of the cell cycle:
 To ensure that each chromosomal DNA molecule is replicated
only once per cycle
 To ensure that the identical replicas of each chromosome are
distributed equally to the two daughter cells
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The Cell Cycle
• The cell cycle is under genetic control
• A fundamental feature of the cell cycle is that it is a
true cycle: it is not reversible
• Many genes are transcribed during the cell cycle
just before their products are needed
• Mutations affecting the cell cycle have helped to
identified the key regulatory pathways
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Key Mutational Targets
• Many cancers are the result of alterations in cell
cycle control, particularly in control of the G1-to-S
transition
• These alterations also affect apoptosis through
their interactions with p53
• The major mutational targets for the multistep
cancer progression are of two types:
Proto-oncogenes
Tumor-suppressor genes
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Key Mutational Targets
• The normal function of proto-oncogenes is to
promote cell division or to prevent apoptosis
• The normal function of tumor-suppressor genes is
to prevent cell division or to promote apoptosis
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Oncogenes
• Oncogenes are derived from normal cellular genes
called proto-oncogenes
• Oncogenes are gain-of-function mutations
associated with cancer progression
• Oncogenes are gain-of-function mutations because
they improperly enhance the expression of genes
that promote cell proliferation or inhibit apoptosis
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Tumor-Suppressor Genes
• Tumor-suppressor genes normally negatively
control cell proliferation or activate the apoptotic
pathway
• Loss-of-function mutations in tumor-suppressor
genes contribute to cancer progression.
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Questions?
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