Mutation
An inherited change in genetic information.
It is the source of all new alleles and genes. If a cell is not viable, it does not mutate. If a sequence is repaired correctly, it is not a mutation because it is not passed on. A change is not a mutation unles
Genetic dissection
Involves the intentional disruption of wild type alleles to study of the effect the mutation has on the organism's phenotype.
Tinman gene
A gene that encodes a transcription factor that controls heart development in humans and flies. Genetic dissection was used to study this gene.
Somatic Mutations
Arise in somatic tissues, which do not produce gametes. The basis of cancers
Germ-line mutations
Arise in cells that ultimately produce gametes
Gene mutation
A relatively small DNA lesion that affects a single gene. The three basic types are base substitutions, insertions, and deletions.
Chromosome mutations
Large-scale gene mutations that affect chromosome structure of the number of chromosomes.
Base substitution
The alteration of a single nucleotide in the DNA. The two types are transitions and transversions.
Transition
A purine is replaced by a different purine, or a pyrimidine is replaced by a different pyrimidine. More common than transversions.
Transversion
A purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine. More possible transversions than transitions.
Insertion
The addition of a nucleotide to a base sequence, A mutation involving the addition of one or more nucleotide pairs to a gene.
Deletion
A mutational loss of one or more nucleotide pairs from a gene
Frame-shift mutation
Mutations that result in changes in the reading frame
In-frame insertion and in-frame deletion
Mutations that do not result in changes in the reading frame.
Expanding nucleotide repeats
The number of copies of a set of nucleotides increases
Fragile-X syndrome
Copies of CGG accumulate in the noncoding region of the X chromosome. This causes DNA to become methylated, which turns off the transcription of an essential gene.
Huntington disease
Results from an expanding nucleotide repeat encoding CAG in the coding part of the gene. This lads to the build up of a toxic protein that has extra glutamine residues.
Anticipation
Nucleotide-repeat expansions become more severe in each generation.
Due to the association between the number of copies of nucleotide repeats, the severity of the disease, and the probability of expansion.
By what mechanism do expanded nucleotide repeats occur?
Hairpins form during DNA replication, causing part of the template strand to be replicated twice.
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Forward mutation
A mutation that alters the wild-type phenotype
Reverse mutation
Changes a mutant sequence back into the wild-type sequence
Missense mutation
A base substitution that results in a different amino acid
Nonsense mutation
A base substitution that changes a sense codon into a nonsense codon (one that terminates translation).
Silent mutation
Changes a codon to a synonymous codon that specifies the same amino acid.
What phenotypic effects can silent mutations have?
When different isoaccpting tRNAs are used, the difference in abundance of the different tRNAs may affect the rate of protein synthesis or the folding of the protein.
Near exon-intron junctions, silent mutations can affect splicing.
Silent mutations can al
Neutral Mutation
A misense mutation that alters the amino acid sequence of the protein but does not significantly change its function.
Loss of function mutation
A mutation that causes the complete or partial absence of normal protein function. Usually recessive. Ex. cystic fibrosis
Gain of function mutation
Causes the cell to produce a protein whose function is not normally present. Usually dominant.
Ex. a gene that encodes a recepter may be mutated to stimulate growth all the time.
Conditional mutation
The effect of the mutations is expressed only under certain conditions.
Lethal mutation
Causes cell death
Suppressor mutation
A genetic change that hides or suppresses the effect of another mutation. It occurs at a site that is distinct from the site of the original mutation, but exhibits the phenotype of an unmutated wild type.
Intragenic suppressor mutations
Takes place in the same gene as that containing the mutation being suppressed.
In what 3 ways can an intragenic suppressor mutation work?
1. Changing a second nucleotide in the same codon - produces a codon that specifies the same amino acid.
2. Suppressing a frame-shift mutation. May lead to a couple different amino acids, but the reading frame is restored.
3. Compensatory changes in the p
Intergenic supressor mutations
Occurs in a gene other than the one bearing the original mutation.
In what 2 ways can an intergenic suppressor mutation work?
1. Changing the way mRNA is translated. A second mutation in a different gene that encodes a tRNA can be mutated to have a different codon.
2. Genic interactions - In the case that 2 polypeptide chains interact to form a protein, a change in one that alte
Mutation rate
The frequency with which a wild-type allele at a locus changes into a mutant. Expressed as the number of mutations per biological unit.
Factors affecting mutation rates
1. Frequency with which a change takes place
2. Probability the change will be repaired
3. Probability that a mutation will be detected.
Mutation rate in bacterial genes
10-8 to 10-10 mutations per cell division
Mutation rate in eukaryotic genes
10-5 to 10-6 mutations per gamete
Adaptive mutation
Stressful environments can induce more mutations in bacteria.
Spontaneous mutations
Mutations that occur under normal conditions
Induced mutations
Mutations that result from changes caused by environmental chemicals or radiation
Tautomeric shifts
The positions of protons in the DNA bases change, allowing uncommon base pairings. The two tautomeric forms are in dynamic equilibrium, although one form is much more common than the other. There is now little evidence for tautomers in DNA.
What are the causes of spontaneous replication errors?
Tautomeric shifts
Wobble
Incorporated errors lead to replicated errors, which lead to permanent errors.
Strand slippage
Unequal crossing over
What are 2 types of spontaneous chemical changes?
Depurination and deamination
Depurination
The loss of a purine base from a nucleotide. An incorrect nucleotide (usually adenine) is incorporated into the newly synthesized DNA strand opposite the apurinic site.
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Deamination
The loss of an amino acid group (NH?) from a base
C?G?T?A
The deamination of cytosine produces uracil (which is usually removed by enzymes when found in DNA)
The deamination of 5mC (5'methylcytosine) becomes thymine.
Mutagen
Any environmental agent that significantly increases the rate of mutation above the spontaneous rate
What was the first discovery of a chemical mutagen?
Charlotte Auerbach exposed drosophila to mustard gas during WWI. They found that mustard gas reduces the viability of gametes and increases the number of mutations in offspring of exposed flies.
Base analogs
Chemical mutagens with structures similar to that of any of the four standard bases of DNA.
Can be reversed by treatment with analogs.
Base analog example
5-bromouracil (5BU) is an analog of thymine with a Br on the 5 carbon atom instead of a methyl group. 5BU occasionally mispairs with guanine.
T?A?5BU?A?5BU?G?C?G
Alkalating Agents
Chemical mutagens that add alkyl groups, such as methyl (CH?) and ethyl (CH?-CH?) groups to nucleotide bases. Can be reversed by additional treatment with alkalating agents.
Ex. EMS adds an ethyl group
to guanine C?G?T?A
and to thymine T?A?C?G
Ex. Mustard
Nitrous Acid
Deaminates cytosine, creating uracil. C?G?T?A
Changes adenine into hypoxanthine, which pairs with cytosine. T?A?C?G
Deaminates guanine, producing xanthine, which pairs with cytosine or thymine. C?G?T?A
Deamination can be reversed with continued use of nit
Hydroxylamine
Adds a hydroxyl group to cytosine, converting it to hydroxylaminocytosine, which increases the frequency of a rare tautomer that pairs with adenine. C?G?T?A Continued treatment with hydroxylamine will not reverse the mutations it produces.
Oxidative reactions
Reactive forms of oxygen damage DNA and induce mutations by bringing about chemical changes in DNA.
Ex. Guanine into 8-oxy-7,8-dihydrodeoxyguanine
G?C?T?A
Intercalating agents
Cause single nucleotide insertions and deletions. Can reverse the effects of their own mutations.
Ionizing radiation
Caused by x-rays
Dislodge electrons from atoms, leading to mutations
Pyrimidine dimers
Bases absorb UV light, resulting in the formation of chemical bonds between adjacent pyrimidine molecules on the same strand of DNA. UV light is usually an effective sterilizing agent against bacteria.
SOS system
Allows replication blocks to be overcome but, in the process, makes numerous mistakes and greatly increases the rate of mutation.
Ames test
The Ames test uses his? strains of bacteria to test chemicals for their ability to produce his??his? mutations. Because mutagenic activity and carcinogenic potential are closely correlated, the Ames test is widely used to screen chemicals for their cancer
Effects of Hiroshima
Somatic mutations, but no increased chance of germ-line mutations.