mutations Flashcards
What happenes when DNA damage is not corrected
- there is an inherited change in genetic information (a mutation)
true or false - all mutations are created equal
false
mutation
a heritable change in the sequence of an organisms genetic material
- may alter the phenotype
- the process by which genetic change occurs
mutant
an organism that carries one or more mutations in its genetic material
mutation and evolution
- mutations are the source of all genetic variation
- natural selection preserves combinations best adapted to the existing environment
- recombination between homologous chromosomes in meiosis rearranges genetic variability into new gene combinations
somatic mutations
occur in somatic cells
- passed to new cells through mitosis
- will not be transmitted to the progeny
germinal mutations
occur in germ line cells
- passed to new cells through meiosis
- will be passed to about 1/2 progeny who will carry the mutation in all their cells
bacterial and phage mutants
- useful in genetic studies because they reproduce fast
point mutations
occur at localized sites in DNA
3 main types…
- base substitution
- frameshift mutation
- tautomeric shifts
dynamic mutation
when the nucleotide repeat copy can expand or contract dramaticaly
gross chromosomal rearrangement
a change in chromosome number or structure
base substitution
change in one base with a different base
- transition: replaces a pyrimidine with another pyrimidine (or purine with purine)
- transversion: replaces a pyrimidine with a purine (or visa versa)
frame shift
insertion or deletion of one or two base pairs alter the reading frame of the gene distal to the site of the mutation
- protein sequences change dramatically
tautomer
different arrangements of the same molecule - usually with H atoms
tautomeric shift
movement of H atoms from one position in a purine or pyrimidine base to another
- rare, can occur spontaneously during DNA replication where they alter DNA base pairing
rare A:C and G:T base pairing
- occurs due to tautomeric shifts
- when the bases are in their enrol or imino states
- A and C create 2 H-bonds
- G and T create 3 H-bonds
expanding nucleotide repeats
- during DNA replication a hairpin forms on the newly synthesized strand, part of the template is replicated twice
- the 2 strands of the new DNA molecule separate and the strand with the extra codon copies serves as a template for replication
- expansion of triplet repeats is the cause of numerous human diseases
forward mutation
genetic alteration that changes the wild-type phenotype to mutant
reverse mutation
changes the mutated site back to normal
missense mutation
a base substitution that results in an amino acid change in the protein
- change in a codon
nonsense mutation
a base substitution at the 3rd codon position that changes a sense codon to one of the three stop codons
- stops translation
- position of the mutation determines length of the protien
silent mutation
a base substitution at the 3rd codon position that changes the codon to one still specifying the same amino acid
- doesn’t affect the overall protein
neutral mutation
- missense mutation where the amino acid is changed to one of a similar chemical type
- little to no effect on protein function
a loss-of-function mutation
- cause complete or partial loss of normal protein function
gain-of-function mutation
causes the cell to produce a protein or gene product whose function is not normally present
conditional mutation
expressed only under certain conditions (ex. temp sensitive)
lethal mutation
causes premature cell death
suppressor mutation
a second site mutation that hides or suppresses the effect of a first mutation (reverse it)
intragenic suppressor
- suppressor mutation that occurs in the same gene
- when a missense mutation alters a single codon a second mutation at a different site in the same gene may restore the original amino acid
intergenic suppressor
- suppressor mutation present within a different gene
internal factors of mutations
- spontaneous
- something has gone wrong in the cell itself
- most DNA damage is caused by internal factors generated by normal metabolic processes
external factors of mutation
- induced
- such as chemicals and the environment
what can damage DNA inside the cell
- water (hydrolysis)
- oxygen (oxidation)
- alkylating agents (alkylation)
what can cause spontaneous DNA damage
- DNA replication errors
- DNA replication pausing
- Endogenous chemical reactions
DNA replication error: tautomeric shift
- causes spontaneous DNA damage
- movement of H atoms in a base results in non-standard base pairing
DNA replication error: wobble-induced base mispairing
- flexibility in base-pairing (wobble) can result in non standard GT and AC base pairs
DNA replication error: strand slippage during replication
- occurs in repeated DNA sequences and misalignments during recombination
DNA replication pausing
- replication stalling at a DNA nick
- generated by ROS or enzymes like topoisomerase
- double-stranded break (DSB) is a lethal or mutagenic lesion unless properly repaired by recombination mechanisms
endogenous chemical reactions: depurination
- spontaneous loss of a purine base through hydrolysis of a glycosidic bond (A is lost more often than G)
- loss of a pyrimidine base is less common
- leave an AP site
- during replication, single-stranded DNA containing an AP site is susceptible to replacement with A or C generating transition or transversion mutations
endogenous chemical reactions: deamination
- ## spontaneous loss of -NH2 group on DNA bases, causes transition mutations
endogenous chemical reactions: oxidation
- ROS damage DNA
- can produce oxidized bases which frequently mispairs with C or A to produce transversion mutations (G:C to A:T)
endogenous chemical reactions: alkylation
endogenous alkylating agents can add methyl groups to DNA bases
Induced DNA damage
- results from exposure to known mutagens
- such as chemical agents and radiation
categories of chemical-induced mutations
- chemicals that are mutagenic to both replicating and non-replicating DNA
- chemicals that are mutagenic only to replicating DNA
chemical mutagens affect replicating and non-replicating DNA
- alkylating agents
- nitrous acid
- hydroxylamine
- base analogs
- acridines
alkylating agents
- mutagens that react with DNA bases and add methyl or ethyl group
- directly or indirectly induce transitions, trans versions or frameshifts
nitrous acid
- delaminating agent
- removes amino NH2 from DNA bases A, C and G, cause transition mutations
hydroxylamine
- hydroxylates the NH2 group of cytosine causing the modified base to pair with adenine after replication
base analogs
- two common base analogs are 5-bromouracil and 2-aminopurine
- incorporated into DNA during replication
- don’t change bases themselves but they look like alternate bases
acridines
- intercalation of an acridine dye causes a frameshift mutation during DNA replication
- long aromatic compounds that slip between bases and cause DNA backbone to become buckled
- it is no longer straight causing polymerase to slip and mess up
mutations induced by radiation
- uv light induces mutations through excitation
- x-rays induce mutation through ionization
mutagenesis by ultraviolet irradiation
- forms thymine dimers which block DNA replication
- can cause DNA breaks
- can lead to skin cancer
- damages vitamin D
mutagenesis by X-rays
- ionizing radiation can cause DNA breaks
- result in changes in chromosome structure
- causes nicks in DSB in chromosomes
- faulty repair can cause gross chromosomal rearrangements such as deletions, duplications, inversions and translocations
DNA repair mechanisms
- direct reversal of DNA damage
- excision repair
- mismatch repair
- recombination
- translation DNA polymerases
direct reversal of DNA damage
- light-dependent repair: direct repair of thymine dimers by the enzyme photolyase (only in prokaryotes)
- enzymatic removal of alkyl groups from DNA bases
- ligation of single-stranded nicks in DNA
excision repair
- DNA repair endonuclease recognize, bind to and excises the damaged bases
- a DNA polymerase fills in the gap using undamaged complementary strand of DNA as a template
- DNA ligase seals the break (nick) left by DNA polymerase
2 kinds…
1) base excision repair
2) nucleotide excision repair
base excision repair
- recognizes and repairs DNA bases damaged by deamination, alkylation or oxidation
nucleotide excision repair
-removes thymine dimers and other bulky forms of DNA damage
- enzyme complex recognizes distortion, strands are separated and damaged part is removed, short tract DNA synthesis takes place
mismatch repair (MMR)
- recognizes a mismatched base in the newly synthesized DNA through hemimethylated GATC sequence
- an exonuclease removes a portion of the new DNA that includes the incorrect base
- DNA poly !!! fills in the longer gap and ligase seals the nick
- mismatch is always associated with unmethylated
Recombination DNA repair mechanism
- have important roles in repairing spontaneous or induced DNA double-stranded breaks (DSB)
2 types… - homologous (HR)
- non-homologous (NHEJ)
homologous recombination repair
- occurs during or after DNA replication
- if one sister chromatid suffers DSB it can be repaired using an identical sister chromatid
- used to ensure proper chromosome separation during meiosis
- can result in accurate repair or potential loss of homozygosity
non-homologous recombination repair
- available throughout eukaryotic cell cycle
- provides a mechanism for T:T to be by-passed so that replication can continue
- non-homologous end joining repairs double-stranded breaks and can result in loss of homozygosity due to lost sequences
translesion synthesis DNA polymerases
- recruited to replicate through the DNA damage, bypassing the lesion, normal DNA replication is to follow
- TLS DNA polymerases replicate inaccurately, get error-prone DNA synthesis at site of the original blocking lesion
SOS response of TLS DNA polymerases
- DNA is heavily damaged
- involves the activation of a host DNA recombination, DNA repair and DNA replication proteins
- increases chance of cell survival but with an increased frequency of replication errors
