1 Geneticists Mutants Mutations are essential for: Genetic analysis and gene mapping Identifying and isolating disease genes Understanding gene function Discovering biochemical pathways Evolution: Most new mutations - deleterious Some provide selective advantage
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1 Geneticists Mutants Mutations are essential for: Genetic analysis and gene mapping Identifying and isolating disease genes Understanding gene function.
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Geneticists Mutants
Mutations are essential for:
Genetic analysis and gene mapping
Identifying and isolating disease genes
Understanding gene function
Discovering biochemical pathways
Evolution:
Most new mutations - deleterious
Some provide selective advantage
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Types of Mutations
Wild type Mutant Wild type Forward Reverse
(Backward)
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Types of Mutations
Point Mutations - Base-pair substitutions
transition
transversion
purpur; pyrpyr
purpyr; pyrpur
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Types of Mutations
Point Mutations - can change how codons are read
missense
nonsense
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Types of Mutations
Translation of a nonsense mutation
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Types of Mutations
Point Mutations - may not be obvious due to code redundancy
neutral
silent
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Types of Mutations
Point Mutations - can have polar effects
Frameshift:
insertion or deletion
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Types of Mutations
Deletion - Null Mutant - ‘knock out’
Large segment or entire gene lost
No functional product possible
Reverse mutation impossibleunless gene replaced
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Suppressor Mutations
Second mutation cancels out effects of firstrestores wild-type phenotype to mutants
Intragenic suppressionBoth mutations in same gene
UGU (cys) - UGA (stop) - UGC (cys)
Intergenic suppressionTwo different genes involved
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Intergenic Suppressor Mutations
Second mutation often in tRNA gene
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Intergenic Suppressor Mutations
Nonsense suppressor
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Intergenic Suppressor Mutations
Missense suppressor
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Classifying Mutations
Conditional - mutant phenotype expressed in certain conditions
Temperature sensitivity - tyrosinase (melanin production)
Useful for studying genes required for essential functions
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Classifying Mutations
Somatic - mutation occurs in body cells
affects only the individual
Germ line - mutation in gamete producing tissues
passed on to next generation
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Classifying Mutations
Spontaneous - random mistake
rate 1 in 104 to 109 mutations/cell/generation
Induced - caused by exposure to mutagen
mutagenesis
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Causes of Spontaneous Mutations
Tautomeric Shifts
enol form of G with T
imino form of A with C
imino form of C with A
enol form of T with G
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Causes of Spontaneous Mutations
Consequences of Tautomeric Shifts - transitions
Causes of Spontaneous Mutations
DNA looping-out during replication (replication slippage)
Deletion
Insertion
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Causes of Spontaneous Mutations
Replication slippage in trinucleotide repeat regions
Repeat expansion
Anticipation
Huntington disease
Fragile X syndrome
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Causes of Spontaneous Mutations
Deamination
C:G > U:A > T:A
A > Hypoxanthine:C
methylcytosine > TC:G > T:A
Transitions
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Induced Mutations
Base analogs - 5-bromouracil
incorporated into DNA during synthesis
higher incidence of tautomeric shifts
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Induced Mutations
Base analogs - 5-bromouracil
Transitions
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Induced Mutations
Intercalating agents - misalignment mutagens
proflavin, acridine orange, ethidium bromide
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Induced Mutations
Intercalating agents - addition of nucleotide (base)
insertionframeshift
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Induced Mutations
Intercalating agents - deletion of nucleotide (base)
deletionframeshift
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Base Modifying Agents
Nitrous acid - oxidative deamination Transitions
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Base Modifying Agents
Hydroxylamine (NH2OH)
Transitions
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Base Modifying Agents
Alkylating agents
CH3
Nitrogen mustard Cl-CH2-CH2-N-CH2-CH2-Cl
Ethylmethanesulfonate CH3-Ch2-O-SO2-CH3
Nitrosoguanidine HN=C-NH-NO2
O=N-N-CH3
Transfer methyl or ethyl group to bases
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Base Modifying Agents
Alkylating agents
Methylmethane sulfonate
Transitions, Mispairing, Crosslinking and Breakage