Transcript Recessive mutations

Gene Mutation
Classification of Mutations
Can Be Made at the:
•
•
•
•
DNA level
Protein level
Cellular level
Organismal level
Mutation at the DNA Level
Change from one allele to a different allele
Forward mutation
Wild type  mutant
Reverse mutation
Mutant  wild type
Quantifying Mutation
Mutation rate = number of mutations
per unit time
Mutation frequency = frequency of a
specific mutation in a population
of cells or individuals
Both are low in value and vary
by location.
Mutation at the DNA Level
• Spontaneous mutation
Results from natural processes
• Induced mutation
Results from exposure to
environmental chemicals or radiation
Mutation at the Cellular Level
• Somatic Mutation
– arises in body cells that will not give rise to
gametes (not passed to offspring)
– can lead to mutant cell population
– mutation of proto-oncogenes leads to cancer
development
• Germ-Line Mutation
– arises in cells giving rise to gametes
– can be passed on to offspring
Germ-line mutation to X-linked recessive
allele for hemophilia.
Characteristics of Mutations
at the DNA Level
•Base substitutions: change of one nucleotide
into another
Type of Mutation
Examples
Transition
ATGC TACG
GCAT CGTA
Purinepurine
Pyrimidinepyrimidine
Transversion
Purinepyrimidine
Pyrimidinepurine
ATCG
GCTA
TAGC
CGAT
ATTA
GCCG
TAAT
CGGC
Mutations at the DNA Level Lead to
Changes in Protein Composition
Transition
-A-A-G-T-T-C-
-A-G-G-T-C-C-
lysine
arginine
Transversion
-A-A-G-T-T-C-
-A-C-G-T-G-C-
lysine
threonine
Characteristics of Mutations
at the DNA Level
• Insertions and Deletions
– addition or removal of one or more
nucleotide pairs
– cause frameshift mutations
– changes in multiples of three cause
in-frame deletions or insertions
Characteristics of Mutations at the DNA Level
• Expanding Trinucleotide Repeats
– may arise as a result of formation of hairpin
structures during DNA replication
– could also be due to unequal crossing over when
repeated regions do not align properly
Effects of Mutations
at the Protein Level
Silent
Substitution of
a Nucleotide
Synonymous
(Neutral)
Missense
Nonsense
Deletion or
Insertion of
Nucleotide(s)
Frameshift
AGG CGG
Arg
Arg
AAA AGA
Lys
Arg
AAA GAA
Lys
Glu
CAG UAG
Gln
Stop
AA(A)GACUUACCAA
Lys-asp-leu-pro 
Lys-thr-tyr-gln
Classification of Mutations
Based on Protein Function
• Recessive mutations
– Loss of function
• Example: Mutant Tumor
Suppressor Genes
• Dominant mutations
– Gain of function
• Example: Oncogenes
Applying Your Knowledge
1.
2.
3.
4.
5.
Transversion
Germ-line mutation
Recessive mutation
Transition
Somatic mutation
Which type of mutation
A. can be passed on to offspring?
B. represents a loss of protein function?
C. involves a pyrimidine being substituted
for a purine?
Spontaneous Mechanisms of Mutation:
Replication Errors
• Nonstandard base pairings due to
flexibility in DNA structure  substitutions
Spontaneous Mechanisms of Mutation:
Replication Errors
• Strand slippage due to looping of one nucleotide
strand during replicationinsertions or deletions
Spontaneous Mechanisms of Mutation:
Replication Errors
• Unequal crossing overinsertions or
deletions
Spontaneous Mechanisms of Mutation:
Spontaneous Chemical Changes
• Depurination
– Hydrolysis of purine
base from the
sugar-phosphate
backbone
Spontaneous Mechanisms of Mutation:
Spontaneous Chemical Changes
• Depurination
– Random base inserted opposite the apurinic
site during replication can lead to mutation
-G-G-C-C-C-G-
-G- -C-C-C-G-
-G- -C-C-A-G-
-G-T-C-C-A-G-
Mutant codes
for valine
-G-G-C-C-C-G-
Wild type
codes for glycine
Spontaneous Mechanisms of Mutation:
Spontaneous Chemical Changes
• Deamination of cytosine
– Converts cytosine to uracil
Spontaneous Mechanisms of Mutation:
Spontaneous Chemical Changes
• Deamination of cytosine
– DNA replication causes G-C  A-T change
-C-G-C-G-C-G-
-C-G-C-G-U-G-
Is this a
1. transition or
2. transversion?
-C-G-C-G-C-G-
-C-A-C-G-U-G-
Wild type
codes for arginine
-C-A-C-G-T-G-C-A-C-G-U-G-
Mutant codes
for histidine
Inducing Mutations
Mutagens are environmental
agents that increase the rate of
mutation.
•Chemicals
•Radiation
Mechanisms of Mutation Due to Chemicals
Causing
Type of Mutagen
Example
Change
Substitutions
Base analogs
5-bromouracil
(analog of T)
T:AC:G
(incorporated into DNA
due to structural
similarities)
Mechanisms of Mutation Due to Chemicals
Causing
Type of Mutagen
Example
Change
Substitutions
Alkylating agents
EMS
(ethylmethylsulfonate)
C:GT:A
(cause mispairing
through chemical
modification of bases)
Mechanisms of Mutation Due to Chemicals
Causing
Type of Mutagen
Example
Change
Substitutions
Deaminating agents
Nitrous Acid
C:GT:A
A:TG:C
(chemicals that convert
cytosine to uracil)
Mechanisms of Mutation Due to Chemicals
Causing
Type of Mutagen
Substitutions
Hydroxylating agents Hydroxylamine C:GT:A
(adds a hydroxyl group to
cytosine, causing C to A
pairing)
Example
Change
Mechanisms of Mutation Due to Chemicals
Causing
Type of Reaction
Substitutions
Oxidative reaction Hydrogen
(oxidative changes to peroxide or
bases that cause
Oxygen radicals
mispairing)
Example
Change
G:CT:A
Mechanisms of Mutation Due to Chemicals
Causing
Type of Mutagen
Deletions or
Insertions
Intercalating agents
Examples
Acridine Orange
(insert between adjacent Ethidium Bromide
DNA bases)
Mechanisms of Mutation
Due to Radiation
• Formation of Pyrimidine dimers
– Ultraviolet radiation produces dimers from
adjacent thymines (thymine-thymine dimers)
– Dimers interfere with DNA function
Applying Your Knowledge
1. Substitution
2. Deletion or Insertion
3. Pyrimidine Dimer Formation
Which type of mutation is caused by
A. intercalating agents like acridine
orange?
B. ultraviolet light?
C. alkylating agents like EMS?
Repair Mechanisms
Type of Repair
Directed at
Mismatch Repair
(methyl-directed in bacteria)
Mispaired bases
Portion of
new DNA
strand with
mismatch
is removed
Mismatch is
recognized
along with
nearby
methyl-A
DNA
polymerase
restores
missing
nucleotides
Repair Mechanisms
Type of Repair
Directed at
Photoreactivation
Thymine-Thymine Dimers
(Type of direct repair)
In Bacterial
Cells
Repair Mechanisms
Type of Repair
Directed at
Direct Repair:
restores original
structure
O6-Methylguanine which pairs
with adenine
Repair Mechanisms
Type of Repair
Base-Excision Repair:
Base removed then
entire nucleotide replaced
Directed at
Modified bases such as
uracil product of cytosine
deamination
Adds new nucleotide
to exposed 3’-OH group
Removes damaged base
Seals gap in backbone
Cleaves backbone
removes sugar
Repair Mechanisms
Type of Repair
Directed at
Nucleotide Excision Thymine-Thymine Dimers (eukaryotes)
Repair
Other large distortions in helix
Uses of Mutants
• Genetic dissection:
understanding how normal biological
processes work
Antennapedia
Bithorax
Fruit Fly mutants used to study developmental processes
Uses of Mutants
• Mutation breeding:
selection of traits induced by a mutagen
Applying Your Knowledge
1. Mismatch Repair
2. Photoreactivation
3. Direct Repair
4. Base Excision Repair
5. Nucleotide Excision Repair
Which mechanism
A. is used to reverse Thymine-Thymine dimers in
bacteria?
B. identifies an old DNA strand based on
methylation of bases?
C. is used to remove chemically modified bases?