Mutations/Repair

Relatively small alterations that affect a single gene or locus

Gene mutations

Large-scale alterations that affect chromosome structure or chromosome number

Chromosome mutations

Mutations that are inherited by daughter cells but not in offspring (progeny)

SOmatic mutations

Mutations that are transmitted to next generation of offspring, occur in gametes or gamete pre-cursors

Germ-line mutations

Three main types of gene mutations

Base substitutions
Indels
Expanding nucleotide repeats

Two forms of base substitutions

Transition
Transversion

Pyrimidine changed to a pyrimidine, or a purine changed to a purine

Transition

Pyrimidine changed to a purine or vice versa

Transversion

Three functional consequences of base substitutions

Missense mutations
Nonsense mutations
Silent mutations

Base substitution resulting in a changed amino acid sequence

Missense mutations

Base substitution resulting in an unchanged amino acid sequence

Silent mutations

Base substitution resulting in a shorter amino acid sequence due to a codon being changed to a stop codon

Nonsense mutation

Missense mutation where the chemical properties of the mutant AA are similar to the original amino acid. Substitution is to an AA in the same functional R group; often no effect on final product

Conservative mutation

Missense mutation where the chemical properties of mutant AA are functionally different from the original AA. Usually, a substitution to an AA in a different functional R group; Often has an effect on function of protein product

Nonconservative mutation

AKA synonymous mutations, occurs at degenerate codons (third position of codon)

Silent mutation

AKA nonsynonymous mutation

Missense mutation

Results in the truncation (cut short) of the C-terminal amino acid sequence

Nonsense mutation

Functional consequences of Indel mutations

Frameshift mutations

Indel mutation that alters translation reading frame, arises from Indels that are NOT multiples of 3.
C-terminal of polypeptide will be a mutant AA

Frameshift mutation

Indel mutation that doesn’t alter translation reading frame, arises from Indels that are of multiples of 3.
C-terminal of polypeptide will be same as original AA sequence

In-frame mutation

What is the three-nucleotide sequence that’s associated with expanded nucleotide repeats?

CNG

Are expanding nucleotide repeats localized to just coding or non-coding regions, or can they be in either?

Either

Many expanding nucleotide repeats show _______, meaning the disease becomes more severe with each generation

Anticipation

What is the functional consequence of expanding nucleotide repeat mutations?

Strand slippage during replication, which may result in trinucleotide repeat disorders if they grow large enough

Word for this process:

A hairpin of repeats forms on new DNA strand during DNA synthesis. Template is replicated twice, increasing the number of repeats on newly synthesized strand. Daught cell will use strand w/ additional repeats as template for next synthesis, making a longer repeat of nucleotide triplets in the DNA

Strand slippage

LOF mutations typically show ______ inheritance

Recessive

GOF mutations typically show ____ inheritance

Dominant

LOF mutation that completely blocks function of the gene product

Null mutation

LOF mutation that creates a product with weak, but detectable, activity

Hypomorphic mutation

GOF mutation that generates more gene product, or the same amount but a more efficient gene

Hypermorphic mutation

GOF mutation that generates a gene product with a new function or one that is expressed in the wrong place / time

Neomorphic mutation

Mutation that causes a mutant phenotype by changing wild-type allele to a mutant allele

Forward mutation

Mutation that changes a mutant phenotype back to the wild-type by changing the mutant allele back to the wild-type allele

Reverse mutation

Which are higher frequency:
Forward mutations or reverse mutations?

Forward mutation

Mutation that appears to be a reverse mutation, but is actually a second mutation in a new place

Suppressor mutation

Suppressor mutation that is in a different gene restores the gene function

Intergenic suppressor AKA second-site suppressor

Suppressor mutation where the second mutation is in the SAME gene and restores gene function

Intragenic suppressor

Three forms of intragenic suppressors

Suppressor is in same codon as first mutation, restoring the wild-type AA
Suppressor restores the altered reading-frame of from the first mutation
Suppressor mutation is a 2nd missense that restores final protein conformation similar to wild-type

Mutations that arise without exposure to any external agents

Spontaneous mutations

Mutations that are produced by interactions between DNA and a chemical or physical mutagen

Induced mutations

What are the sources of spontaneous mutations?

Mistakes in DNA replication
Depurination and deamination
Strand slippage during replication
Unequal crossing over

What are the sources of induced mutations?

UV
Ionizing radiation

Mistakes in DNA replication and depurination/deamination results in what type of mutation?

Base substitution

Strand slippage during replication and unequal crossing over create what type of mutation?

Indels

UV light causes what type of mutation?

Pyrimidine dimers

Ionizing radiation causes what type of mutation?

Double strand breaks

What is the repair mechanism for mistakes in DNA replication (base sub.)?

Mismatch repair

What is the repair mechanism for depurination and deamination (base sub.)?

Base excision repair

What is the repair mechanism for strand slippage during DNA replication (Indel)?

Mismatch repair

What is the repair mechanism for unequal crossing over (Indel)?

Usually not repaired

What is the repair mechanism for UV light (pyrimidine dimers)?

Nucleotide excision repair

What is the repair mechanism for ionizing radiation (DSBs)?

NHEJ and HR

Loss of a purine because of spontaneous breakage of the glycosidic bond of a nucleotide

Depurination

Depurination leads to formation of an ___ _____, which leads to an adenine across from it during replication. Leads to a transition mutation

AP site

Loss of an amino group from a base

Deamination

Deamination leads to mutations especially when the deamination is the deamination of ______

5-meC

Deamination results in __ to _ mutations

C to T

Deam/depur:

Not rrecognized by any epair mechanisms, hotspot for mutations in humans

Deamination

Repair mechanism that is only active during S phase of the cell cycle. repairs errors by enzymes removing a mismatched base and replacing with new nucleotides

Mismatch repair

Repair mechanism that fixes mismatched bases outside of S phase. Glycosylase enzymes recognize and remove certain modified bases (AP sites, deaminated sites, etc.) and replaces the section of the polynucleotide strand

Base excision repair (BER)

Repair mechanism for big things like thymine dimers. Removes and replaces many types of damaged DNA by separating the strands, removing the section containing the distortion, filling the gap, and re-seals the sequences together.

Nucleotide excision repair (NER)

Repair mechanism used for DSBs that uses sequences from homologous chromosome or a sister chromatid as a template

Homologous recombination (HR)

Repair mechanism that takes place in G1, repairs double strand breaks. No sister chromatid/homologous chromosome present

Nonhomologous end joining (NHEJ)

Which repair of DSBs is typically error-free?

Homologous recombination (HR)

Which repair of DSBs is typically error-prone?

NHEJ

Ku protein does what?

Associates with telomerase and maintains levels of telomerase RNA, allowing telomeres to stay long.