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Lecture 7
Mutation and its consequences
CAMPBELL BIOLOGY
  Natural variants and mutants
1.  Genetic analysis would not be possible without the existence
of natural variants:
individuals that differ in the phenotypic
expression of a given trait e.g. tall vs dwarf
2.  Evolution would also not be possible without variants
3.  Variants are sometimes referred to as mutants especially if
they have been deliberately produced in the laboratory
4. How do variants or mutants arise?
changes in the genetic information (DNA) that occur
due to a process called mutation
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Classification of Mutants – Some Examples
1. Auxotrophs – Nutritional Mutants (see lecture 6)
e.g. auxotrophic mutants of Neurospora crassa. Wild-type
can grow on minimal medium but mutants require
nutritional supplements.
2. Homeotic Mutants
These are mutants that show developmental defects i.e.
They may for example have body parts in the wrong location
e.g. the Drosophila antennapedia mutant has a pair of legs on
its head where the antennae should be. Mutations in a group of
genes central to development , the Hox genes, can cause in
many cases lethal developmental defects.
3. Lethal Mutants
The viability of the organism is affected. Typically such
mutations are recessive and the organism can only survive if
it is a heterozygote e.g. manx cat (tail-less).
Hox Genes
Mario Capecchi won the Nobel Prize in 2007
for his research on Hox genes & their role in
defining the mammalian development plan
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What causes mutations?
1. Internal Causes: errors in replicating genetic information
a. Errors in chromosome construction or
chromosome distribution e.g. into gametes
b. Errors in DNA replication
2. External Causes: mutagenic agents that damage DNA
a. Chemical mutagens
b. Physical mutagens: radiation
How frequently do mutations occur in nature?
i.e. what is the natural or spontaneous mutation rate?
  Measure the frequency with which particular mutants are
found in natural populations
Humans:
wild-type (normal) blood clotting
h+
abnormal clotting (hemophilia)
h-
Frequency = 2 X 10-5 per gamete
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MUTAGENS
  Mutagens are physical or chemical agents that cause mutations
(Chernobyl – example of induced mutations by mutagens)
  Mutagens act by increasing the spontaneous mutation rate.
  They can therefore be used to induce mutations
1.  Physical mutagens include many types of radiation
  X-rays: in the 1920’s the geneticist H. Muller discovered
that exposing the fruit fly Drosophila to X-rays greatly increased
the frequency of mutants.
the mutation rate is proportional to the radiation dose
  Ultra-violet (UV) light causes the production of
thymidine dimers. Such mutations can lead to skin cancer.
2. Chemical Mutagens
  Chemicals that damage DNA often cause mutations or
  Chemicals that insert between the bases can also cause mutations
  Many chemical mutagens also cause cancers. Such chemicals are
often called carcinogens
  Chemicals differ in how mutagenic they are e.g.
Type of Mutagen
Relative mutagenicity
Epoxy butane
1
Methyl methane sulfonate
105
Naphthyl amine
1,400
Aflatoxin B (mouldy peanuts)
1,200,000
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Mutation of DNA - Point Mutations
These are mutations that change only one (or a few) base pairs
in a DNA molecule
Types of point mutation
1. Base-pair substitutions: a single base is altered
g g g CCC a t a
g g g CTC a t a
2. Insertions: an extra base is incorporated
g g g CCC a t a
g g g CCGC a t a
3. Deletions: a single base is deleted
g g g CCC a t a
g g g CC a t a
Consequences of point mutations in DNA
A point mutation in a gene may cause catastrophic changes in
the properties of the protein product of that gene
e.g. partial or total loss of function of the encoded protein (some
recessive disorders) or may produce a protein which is toxic to the
cell (some dominant disorders)
  If the protein functions in blood clotting e.g. Factor VIII
Mutations in the Factor VIII gene can cause hemophilia –
resulting in uncontrolled bleeding
  If the protein functions to control cell division, then a
mutation may result in uncontrolled cell divisions i.e. cancer
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The sequence of bases in DNA determines the
properties of the protein encoded by the gene
Insertion or deletion of one base can shift the reading frame
Wild-type
Insertion of
one base
Deletion of
one base
nonsense
mutation
missense
mutation
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Point Mutations: Base-pair Substitutions
No effect on
protein
missence
mutation
nonsense
mutation
Recessive Epidermolysis Bullosa (EB) –
skin blistering disorder
http://3.bp.blogspot.com/IBDMaz94Akg/TfrI05AX9FI/AAAAAAAAAEs/
fqBSU4yqOFw/s1600/mutagen.jpeg
Point mutations can lead to
many inherited genetic disorders
http://library.med.utah.edu/kw/derm/mml/24820010.jpg
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Mutations in Rhodopsin can
cause an inherited eye disorder
termed Retinitis Pigmentosa (RP)
Rhodopsin protein
structure.
Mutations in the
gene encoding
rhodopsin can result
in an encoded protein
with a changed
structure &
this mutant protein
can eventually cause
photoreceptor cells to
die and lead to
blindness.
Mutations due to Chromosome Abnormalities
1.  Abnormal numbers of chromosomes
Aneuploidy = Loss or gain of individual chromosomes
e.g. extra chromosome 21 causes Down’s syndrome
Caused by nondisjunction = failure of chromosomes to separate
properly during meiosis
Some gametes carry an extra copy of one chromosome ( n + 1)
Some gametes lack a chromosome (n-1)
1.  Abnormal chromosome structures
(a) deletions
- a segment of a chromosome is deleted
(b) duplications
- a segment of a chromosome is duplicated
(c) translocations - a piece of one chromosome becomes
attached to a different chromosome
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Babies born with trisomy 13 frequently have
some combination of the following findings:
Central nervous system defects
Severe mental retardation (IQ 20-35)
Posterior scalp lesions
Oral-facial clefts
Small, abnormally shaped eyes (microphthalmia)
Heart defect
An extra pinky finger (polydactyly)
Additional organ anomalies
90% of babies born with trisomy 13 do not
survive past 1 year
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Next Generation Sequencing
(NGS) technology.
1,000 Genomes Project - A project
involving sequencing the
genomes of at least 1,000 people
to ascertain information on
biomedically relevant DNA
variation between humans was
announced in Jan 2008. Funded
by Groups / Institutes in many
countries
www.sanger.ac.uk
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Companies such as deCODE & 23andMe
provide services to genotype people for
certain disease mutations amongst other traits
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