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Genes and Gene Mutations —
Lecture III
Dr. Steven J. Pittler
VH375B
Office 4-6744
Cell 612-9720
12-1
Suggested Reading: Lewis 2nd
Edition
Chapter on Gene Mutation
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Mutation
• Is a change in a genes nucleotide base sequence
– At the molecular level
• Substituting one DNA base for another
• Adding or deleting bases
• Chromosome level
• Chromosomes
– Can exchange parts
– Genetic material can jump from one chromosome to
another
12-2
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Mutation
• A mutation can stop or slow production of a
protein, can over-produce it, or impair its function
• Not all DNA changes are harmful: 1% of the
general population is homozygous for a recessive
allele that encodes the protein CCR5
– This is a cell surface protein
– HIV must bind to CCR5 and another protein to
enter a T-cell
– This mutation prevents CCR5 from traveling
from the cytoplasm to the cell surface and
therefore HIV cannot bind
12-3
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Mutation
• The term mutation refers to genotype - a change
at the DNA or chromosome level
• Mutant refers to an unusual phenotype
– How the alteration affects the genes product or activity
– Or , an unusual variant such as a red-haired child in a
class of brunettes and blondes
– Mutations that do not alter the phenotype are called
polymorphisms
• The next slide gives examples of genetic tests
that helps identify gene mutations
12-4
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12-5
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Mutation
A point mutation is a change in the nucleotide sequence
that composes a gene. This is a change or variation from
the most common or wild type sequence.
A mutant allele is an allele that differs from the common
allele in the population (also called the wild type allele).
A mutant phenotype refers to a phenotype that differs
from the common or wild type phenotype.
Mutations are not good or bad, just different from the
majority in the population.
12-6
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Mutation
• In the evolutionary sense mutation has
been essential to life
– It produces individuals with variant
phenotypes who are better able to
survive in a specific environment
12-7
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Somatic mutations
• Are mutations that occur in cells of the body
excluding the germ line and happens during DNA
replication before mitotic cell division
• Affect subsequent somatic cell descendants
• Are limited to impact on the individual and not
transmitted to offspring
• Are responsible for certain cancers (lecture IV)
Germline mutations
• Are mutations that occur in the germ line cells and the
change occurs during the DNA replication that precedes
meiosis
• Have the possibility of transmission to offspring
12-8
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Hemoglobin
Linus Pauling, 1949
• Four globular proteins
surrounding heme group
with iron atom: two beta
chains and two alpha
chains
• Function is to carry
oxygen in red blood cells
from lungs to body and
carbon dioxide from cells
to lungs
12-9
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Single base change in hemoglobin
gene causes sickle cell anemia
wildtype
allele
wildtype
phenotype
12-10
mutant
allele
mutant
phenotype
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Hemoglobin genotype causes
sickle cell anemia phenotype
Sickle cell anemia was the first illness understood at the
molecular level:
mutation encodes valine in place of glutamic acid (V->G).
Phenotype associated with homozygotes:
• Altered surface of hemoglobin allows molecules to link in
low oxygen conditions and creates sickle shape of red
blood cells.
• Sickling of red blood cells causes anemia, joint pain, and
organ damage when RBCs become lodged in small blood
vessels.
12-11
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Different sites in a gene can mutate
and cause distinct phenotypes
• Some beta hemoglobin mutations resulting in too few
protein molecules cause thalessemia.
• Excess of alpha hemoglobin compared to beta
hemoglobin leads to iron release which kills RBCs and
destroys heart, liver and endocrine glands.
heterozygous mutation -> milder thalassemia minor
homozygous mutation -> more severe thalassemia major
12-12
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Collagen
Comprises:
60% of protein in bone and cartilage
a significant proportion of skin, ligament, tendon, tooth
dentin and connective tissue.
Has a precise structure:
triple helix of two alpha1 and one alpha2 proteins
the longer precursor called procollagen is trimmed to
form collagen
12-13
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Different collagen mutations => Distinct disorders
Disorder
Defect
phenotype
Alport syndrome
Type IV collagen mutation
Deafness and inflamed
kidneys
Aortic aneurysm
Missense mutation in a1 gene
Aorta bursts
Chondrodysplasia
Deletion insertion or
substitution of glycine with
larger amino acids
Stunted growth,
deformed joints
Epidermolysis
bullosa
Collagen attached to
epidermis breaks down
Skin blisters on touch
Ehlers-Danlos
syndrome
Missense , deletion or
disruption of splicing
Stretchy, easily scarred
skin and lax joints
Osteoarthritis
Cys->Arg in alpha1 gene
Painful joints
Osteogenesis
imperfecta
Inactivation of alpha1 allele
reduces collagen 50%
Easily broken bones,
blue eye whites,
deafness
Stickler syndrome
Nonsense mutation in
procollagen
Joint pain, eye
degeneraton
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Ehlers-Danlos Syndrome
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Alzheimer disease
Mutations in presenilin1 cause early onset
autosomal dominant Alzheimer disease
• Presenilin protein is a receptor anchored in the
Golgi membrane
• The protein functions to monitor beta amyloid
usage
• 30+ missense mutations in presenilin result in
beta amyloid accumulation.
12-16
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Genotype to disease phenotype
Cystic fibrosis disease
CFTR protein
Mutation: Many different mutations, common missing amino acid
Phenotype: Lung infections, pancreatic insufficiency
Duchenne muscular dystrophy
dystrophin protein
Mutation: Deletion of gene
Phenotype: Loss of muscle function
Familial hypercholesterolemia
LDL receptor protein
Mutation: Deficient LDL receptors lead to cholesterol buildup
Phenotype: High blood cholesterol, early heart disease
Hemophilia A
Factor VIII protein
Mutation: Absent or deficient factor
Phenotype: Slow or absent blood clotting
12-17
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Genotype to disease phenotype
Huntington disease
Mutation:
huntingtin protein
Extra nucleotides in gene result in extra amino acids
Phenotype: Uncontrollable movements, personality changes
Marfan syndrome
Fibrillin
Mutation: Too little elastic connective tissue protein
Phenotype: Long limbs, weakened aorta, spindly fingers, sunken
chest, lens dislocation
Neurofibromatosis
Neurofibromin
Mutation: Defect in protein
Phenotype: Benign tumors of nervous tissue beneath skin
12-18
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Genetic Disease of the Teeth
Amelogenesis Imperfecta is a genetic condition that causes teeth to be abnormally small or discolored. Teeth are also likely to be pitted
or grooved and more susceptible to being worn down and breaking. There are at least 14 forms of the condition, each with its own
characteristic display of tooth abnormalities and form of genetic inheritance. Amelogenesis imperfecta is caused by mutations to the
AMELX, ENAM and MMP20 genes and affects an estimated one in 14,000 people in the United States.
Dentinogenesis Imperfecta is a genetic disorder that interferes with normal tooth development. It affects approximately one in 6,000 to
8,000 people, according to the National Institute of Health. There are three types of dentinogenesis imperfecta. Type I occurs in
individuals who have another inherited disorder called osteogenesis imperfect (causes brittle bones), whereas type II and type III
occur in those without other genetic disorders. Some researchers believe types II and III are part of a single disorder along with
another condition called dentin dysplasia type II, which primarily affects baby teeth more than adult teeth. General symptoms of
dentinogenesis imperfecta include tooth discoloration (blue-gray or yellowish-brown), tooth translucency and weaker than normal
teeth which make them prone to erosion, breakage and loss.
48,XXYY Syndrome is a rare chromosomal condition that affects one in 18,000 to 50,000 males, 48,XXYY syndrome interferes with
sexual development, causing reduced height, facial and body hair, increased risk of breast enlargement, infertility, progressive
tremor and other serious medical problems that develop increasingly later in life. Dental problems are also common. According to
the NIH, the delayed appearance of primary and secondary teeth, crowded and/or misaligned teeth, numerous cavities and thin
tooth enamel often accompany the disorder.
Hypohidrotic Ectodermal Dysplasia is an inherited condition affecting approximately one in 17,000 people worldwide that causes
abnormalities of the skin, nails, hair, sweat glands and teeth. Those with the condition usually have absent teeth (hypodontia) or
malformed teeth. It is common for malformed teeth to appear small and pointed. According to the NIH, approximately 70 percent of
carriers of the gene that causes the condition (those with only one, but not both, recessive mutated genes) display symptoms,
including some missing or abnormal teeth, sparse hair and some sweat gland dysfunction.
Oculodentodigital Dysplasia is an extremely rare genetic disease (with fewer than 1,000 people diagnosed worldwide) that affects the
eyes, fingers and teeth. Common tooth abnormalities include small or missing teeth, numerous cavities, weak enamel and early
tooth loss. The condition can also lead to small eyes, vision loss, webbed skin and neurological problems. An autosomal dominant
disorder, it develops when only one mutated gene is inherited from a parent.
Recombinant 8 Syndrome is a rare disease of unknown incidence primarily affecting an Hispanic population descending from the San
Luis Valley of Colorado and Northern New Mexico. Inherited in an autosomal dominant pattern, recombinant 8 syndrome causes
distinctive facial abnormalities, moderate to severe intellectual disability and heart and urinary tract problems. Abnormal teeth, an
overgrowth of gums, small chin, thin upper lip and downturned mouth are all associated with the condition.
12-19
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Spontaneous mutation
• De novo or new mutations
• Not caused by exposure to
known mutagen
• Errors in DNA replication
• DNA bases have slight
chemical instability
(exists in alternating forms
called tautomers)
12-20
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Spontaneous mutation rate
• Rate differs for different genes
– Size dependence
– Sequence dependence
– Hot spots
• On average 1 in 100,000 chance of
acquiring a mutation in a gene each round
of replication.
• Each individual has multiple new
mutations. Most by chance are not in
coding regions of genes.
12-21
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Mutation rates of genes causing disease
Disorder
Mutations
per million
gametes
Phenotype
Duchenne muscular dystrophy
40-105
Muscle atrophy
Hemophilia A
30-60
Impaired clotting
Hemophilia B
.5-10
Impaired clotting
Achondroplasia
10
Very short stature
Aniridia
2.6
Absence of iris
Huntington disease
<1
Erratic movement, dementia
Marfan syndrome
4-6
Long limbs, weak blood vessels
Neurofibromatosis type1
40-100
Osteogenesis imperfecta
10
Polycystic kidney disease
60-120
Retinoblastoma
12-22
5-12
Benign tumors CNS/skin
Easily broken bones
Benign kidney growths
Retinal tumors
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Mutations in pathogens
Bacteria and viruses undergo mutation
• Mutation in bacteria can lead to antibiotic resistance.
• Overuse and incomplete course of treatment increases
chances of antibiotic resistance arising.
• Viruses mutate rapidly.
• Influenza vaccines are reassessed each season to
accommodate viral changes.
• Rapid mutation of HIV virus makes treatment difficult.
12-23
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Mutational hot spots exist
Short repetitive sequences
pairing of repeats may interfere
with replication or repair enzymes
Palindromes
often associated with insertions or
deletions
Duplications of larger regions
mispairing during meiosis
12-24
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Mutations
• More than 1/3 of the many mutations that cause
alkaptonuria occur at or near one or more CCC
repeats, even though these repeats account for
only 9% of the gene (hot spot)
• Mutations in the gene for clotting factor IX, which
causes hemophilia B occur 10 to 100 times at any
11 sites in the gene that have direct repeats of CG
(CGCGCG…..)
12-25
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Small or large insertion or deletions
Palindromes can cause
small insertion or deletions
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Duplications can cause
large insertion or deletions
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Mutations
• The blood disorder alpha thalassemia illustrates the effect
of direct repeats of an entire gene
– Wild-type has four genes that specify alpha globin chains, two
next to each other on chromosome 16
– Homologs with repeated genes can misalign during meiosis
when the first sequence on one chromosome lies opposite the
second sequence on the homolog
– If crossing over occurs, a sperm or oocyte can form that has
one or three of the alpha globin genes instead of the normal
two
– A person with three alpha globin genes produces enough
hemoglobin and is considered healthy
– Individuals with only two copies of the gene are mildly anemic
– Single alpha globin individuals are severely anemic, and a
fetus lacking alpha globin does not survive
– Alpha thalassemia is common because carriers have an
advantage, they are protected against malaria
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12-28
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Induced mutations
Chemicals and radiation can cause
mutations.
Chemicals causing mutations are called
mutagens.
Chemicals causing cancer are called
carcinogens.
12-29
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Induced mutations
• Alkylating agents remove a DNA base, which is replaced
with any of the four bases-three of which creates a
mismatch with the complimentary strand
• Acridine dyes add or remove a single DNA base. Adding or
deleting a single base destroys a gene’s information,
altering the amino acid sequence of the encoded protein
• Mutagenic chemicals alter base pairs, so that an A-T
replaces G-C, or vice versa, thereby changing a genes DNA
sequence
• X-rays and other forms of radiation delete a few bases or
break chromosomes
12-30
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Ames test
is an in vitro test of the mutagenicity of a
substance using Salmonella bacteria with a
mutation in the gene for histidine.
• Bacteria are exposed to test substance.
• Growth of bacteria on media without histidine is
recorded.
• Bacteria only grow if mutations have occurred.
• Rate of mutation is determined.
• Substance can be mixed with mammalian liver tissue
prior to testing to mimic toxin processing in humans.
12-31
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Mutagen
Aflatoxin B
2-amino 5-nitrophenol
2,4-diaminotoluene
Furylfuramide
Nitrosamines
Proflavine
Sodium nitrate
Tris (2,3-dibromopropyl
phosphate)
UV radiation
Xray irradiation
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Source
Fungi growing on peanuts
and other foods
Hair dye
Hair dye
Food additive
Cigarette smoke, pesticides
Veterinary antiseptic
Smoked meats
Flame retardant in
children’s sleepwear
Sunlight, tanning booths
Medical Xrays
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Natural Exposure to Mutagens
• Natural environment sources of radiation include:
– Cosmic rays, sunlight, and radioactive minerals in the earth’s
crust
• Medical x-rays and radiation hazards
– Weapons facilities, research laboratories, health care facilities,
nuclear power plants, and certain manufacturing plants
• Radiation exposure is measured in millirems and the
annual exposure in the northern hemisphere: 360 millirems
• Most of the radiation that we are exposed to are ionizing
type which removes electrons from atoms
• Ionizing radiation breaks the sugar-phosphate backbone
DNA
12-33
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Natural Exposure to Mutagens
• There are three major types of ionizing radiation
– Alpha is the least energetic and most short-lived
– Absorbed by the skin
– Uranium and radium
–
–
–
–
Beta can penetrate deeper
Trtium (isotope of hydrogen), Carbon-14, and strontium-70
Both alpha and beta tend not to harm us
However if eaten or inhaled they will do damage
– Gamma can penetrate all the way through the body therefore it
damages our tissues
– Plutonium and cesium isotopes used in weapons
– This form of radiation is intentionally used to kill cancer cells
12-34
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Natural Exposure to Mutagens
• X-rays are non-ionizing radiation
– Have less energy and do not penetrate the body to the extent
that gamma rays do
• The effects of radiation damage to DNA depends on the
functions of the mutated genes
– Mutations in oncogenes or tumor suppressor genes can cause
cancer
• Chemical mutagens
– The risk that a chemical will cause a mutation is often less
than the natural variability in susceptibility within a population
12-35
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12-36
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Types of Mutations
12-37
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Point mutation
A point mutation is a change of a single nucleotide
to one of the other three possible nucleotides
Transition
• purine replaces purine
A  G or G  A
• pyrimidine replaces pyrimidine
C  T or T  C
Transversion
• purine replaces pyrimidine or
• pyrimidine replaces purine
A or G  T or C
T or C  A or G
12-38
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Missense mutation
• A point mutation that exchanges one codon for
another causing substitution of an amino acid
– Missense mutations may affect protein function severely,
mildly or not at all.
• Hemoglobin mutation
– glutamic acid -> valine causes sickle cell anemia
• The DNA sequence CTC encodes for mRNA GAG which specifies
glutamic acid
• There is a point mutation in sickle cell disease that changes
(transversion) the DNA sequence to CAC, that encodes for mRNA
GUG that specifies valine, and this causes an alteration in
function
12-39
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Nonsense mutation
• In 15% of people who have Becker muscular
dystrophy (milder adult form of the condition) the
muscle protein dystrophin is normal, but, its
levels are reduced
– The mutation causing the protein shortage is in the
promoter for the dystrophin gene and thus slows the
transcription process
• The other 85% who have Becker muscular
dystrophy have shortened proteins, not a
deficiency of normal-length proteins
• Point mutations can disrupt the trimming of long
precursor molecules
– A type of Ehlers-Danlos syndrome
12-40
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Splice Site Mutations
• Point mutations can affect a gene’s product when
it alters a site where introns would normally be
removed from mRNA
• It can affect the phenotype if an intron gets
translated into amino acids, or an exon is skipped
instead of being translated
• When we retain an intron the bases are added to
the protein coding portion of mRNA
– Cystic fibrosis: missense mutation alters an intron site
so that it is not removed
12-41
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Splice Site Mutations
• A missense mutation can cause harm if it
disrupts intron/exon splicing
– A missense mutation in the BRCA 1 gene that causes
breast cancer is due to the missing of several amino
acids resulting from an intron splicing site that skipped
an entire exon when mRNA is translated into a protein
– Familial dysautonomia (FD) results from a splice site
mutation that causes exon skipping. An exon in the
gene encoding an enzyme called I-kappa beta kinaseassociated protein is not translated because a point
mutation in one of its splice site signals the
spliceosome not to translate the segment.
12-42
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Insertion or deletion mutations
• The genetic code is read in triplet nucleotides
during translation.
• Addition or subtraction of nucleotides not in
multiples of three leads to a change in the
reading frame used for translation. Amino acids
after that point are different, a phenomenon
called a frameshift.
• Addition or subtraction of nucleotides in
multiples of three leads to addition or subtraction
of entire amino acids but not a change in the
reading frame.
12-43
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Insertion or deletion mutations
Deletion is the removal of sequences.
• Two-thirds of Duchenne muscular
dystrophy cases are large deletions.
Insertion is the addition of sequences.
• Gaucher disease is caused by a single base
insertion creating a frameshift.
A tandem duplication is a particular form
of insertion in which identical sequences
are found side by side.
• Charcot-Marie-Tooth disease is caused by
a tandem duplication of 1.5 million bases
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12-45
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Pseudogenes
• A pseudogene is a DNA sequence
reminiscent of a gene but which is not
translated (may or may not be transcribed).
• Pseudogenes may have evolved from
original functional gene by duplication and
acquired mutation.
• Crossing over between a pseudogene and a
bona fide gene can disrupt gene expression.
12-46
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Expanding repeats
• Insertion of triplet repeats leads to extra amino acids.
• Some genes are particularly prone to expansion of
repeats.
• Number of repeats correlates with earlier onset and
more severe phenotype.
• Expansion of the triplet repeat and coincident increase
in severity of phenotype occur with subsequent
generations, a phenomena termed anticipation.
12-47
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Type of
mutation
Example
Normal
Missense
Nonsense
Frameshift
Deletion
Insertion
Duplication
THE ONE BIG FLY HAD ONE RED EYE
THQ ONE BIG FLY HAD ONE RED EYE
THE ONE BIG
THE ONE QBI GFL YHA DON ERE DEY
THE ONE BIG HAD ONE RED EYE
THE ONE BIG WET FLY HAD ONE RED EYE
THE ONE BIG FLY FLY HAD ONE RED EYE
Expanding mutation
generation 1 THE ONE BIG FLY HAD ONE RED EYE
generation 2 THE ONE BIG FLY FLY FLY HAD ONE RED
EYE
generation 3 THE ONE BIG FLY FLY FLY FLY FLY HAD
ONE RED EYE
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Different mutations may cause the
same disorder
Mutations in the LDL receptor disrupt function leading to
increased blood cholesterol and early heart disease.
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Myotonic dystrophy: an expanding triplet
repeat disease
5 -37 copies of CTG repeat
50-1000 repeats
normal phenotype
myotonic dystrophy
Genes with 40+ copies are unstable and can gain
(or less commonly lose) repeat copies in
successive generations.
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Prion disorders
Prion disorders are caused by mutation in the prion
gene which leads to an abnormally shaped prion
protein.
The mutant form of the protein can convert normal
prion proteins to mutant protein shapes.
Mutant protein occurs in two ways:
1. A mutation in the gene can be inherited.
2. The mutant protein can be transmitted like an infection
from tissue with the mutant protein.
In cows a mutant prion protein causes mad cow
disease (bovine spongiform encephalitis).
Humans can obtain the protein by eating beef
with mutant prions and develop CreutzfeldtJakob disease.
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Not all mutations impact protein function
Silent mutations are mutations that do not alter the
amino acid encoded.
AAA and AAG both encode the amino acid lysine.
A mutation from AAA to AAG in a gene alters the DNA
sequence but protein sequence remains unchanged.
These codons are called synonymous codons.
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Not all mutations impact protein function
Missense mutations are those that alter the
encoded amino acid to another amino acid.
The alteration creates a nonsynonymous codon.
Some nonsynonymous mutations are conservative;
chemically similar amino acid may not alter function
The impact of a missense mutation is not predictable
from protein sequence alone.
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Not all mutations impact protein function
Conditional mutations are those that only
produce a phenotype under particular conditions
or environments.
G6PD enzyme is used to respond to oxidants,
chemicals that strip electrons from other molecules.
High levels of oxidants occur when eating fava beans
or taking antimalarial drugs.
Conditions
Low oxidants
High oxidants
12-55
Individuals with mutations in G6PD
no phenotype
red blood cells burst, anemia
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DNA Repair
• Errors in DNA replication or damage to DNA
create mutations.
• Most errors and damage are repaired by the cell.
• The manner in which DNA repair occurs depends
upon the type of damage or error.
• Different organisms vary in their ability to repair
DNA.
• In humans, mutations in DNA replication occur in
1 in 100 million bases.
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Excision repair
Damaged DNA is removed
by excision of the bases and
replacement by a DNA
polymerase.
Nucleotide excision repair
•Replaces up to 30 bases
•Used in repair of UVB and
some carcinogens
Base excision repair
•Replaces 1-5 bases
•Repairs oxidative damage
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Mismatch repair
Mismatch repair occurs
when enzymes detect
nucleotides that do not
base pair in newly
replicated DNA.
The incorrect base is
excised and replaced.
The detection of
mismatches is termed
proofreading.
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Xeroderma
Pigmentosa
Deficient excision repair
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Failure of DNA repair
• When DNA repair fails, fewer mutations are corrected
leading to an increase in the number of mutations in the
genome.
• The protein p53 monitors repair of damaged DNA.
If damage is too severe, the p53 protein promotes
programmed cell death or apoptosis.
• Mutations in genes encoding DNA repair proteins can
be inherited and lead to overall increase in mutations
when DNA errors or damage are no longer fixed
efficiently.
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