Lectures 5 and 6: Mechanisms of Mutation Flashcards
What is genetic variation?
The differences in the DNA sequence of individuals in a population
What are mutations?
Random events that occur due to environmental factors or failure of repair
Can mutations be repaired?
Yes
Define Mutation:
A change in the DNA sequence that arises de novo in an individual or tissue
Define Polymorphism:
A germline DNA sequence variation that can be stably inherited
What are the external factors that cause mutations?
- Mutagens like radiation and chemicals which cause depurination, demethylation and deamination
- Presence of Base Analogues
How do external factors cause mutations?
They can cause direct structural effects or act indirectly by causing cells to produce other chemicals that have an effect
What are the internal factors that cause mutations?
- Replication errors
- Replication must be faithful otherwise accumulated deleterious mutations would be incompatible with life
What are tautomers?
Isomers of a compound that exist in equilibrium
The stable form of T and G is the ______ form, the unstable form is the ______ form.
Keto
Enol
The stable form of A and C is the ______ form, the unstable form is the ______ form.
Amino
Imino
Unstable tautomers can form _____________.
Unstable pairs (i.e A-C or T-G)
What is a mutagen?
An agent that causes an increase in the rate of mutation by causing chemical changes to the bases
Deamination can be induced by _______ or occur _______________.
HNO2 or occur spontaneously
When cytosine is deaminated we get __________. When 5-methylcytosine is deaminated we get __________.
Uracil
Thymine
What do alkylating agents do?
Donate their alkyl groups to other molecules, this can cause transitions, transversions, frameshifts and chromosome aberrations
With respect to bases, what is a transition?
Change from one purine to another or from one pyrimidine to another
With respect to bases, what is a transversion?
Change from a purine to a pyrimidine
What is depurination?
The loss of a base caused by the hydrolysis of the N-glycosidic bond of a purine ring that binds to the sugar part of the nucleotide. The base is replaced at random
What is a base analogue?
A compound with similar structure to the normal bases but causes an increase in the freq. of mutations
What is 2-aminopurine?
An analogue of adenine that pairs with cytosine
What is 5-bromouracil?
An analogue of thymine that pairs with guanine
What are intercalating agents?
Thin plate-like hydrophobic molecules that insert themselves between adjacent bases, they are usually +’vely charged
What does ionising radiation do?
Breaks covalent bonds between bases and causes chromosome aberrations
How does UV light affect the DNA?
Causes purines and pyrimidines to form abnormal dimers .’. causes the DNA to bulge
What is the error rate of DNA polymerase?
~1 in 10^4 - 10^5 initially, but is reduced to ~1 in 10^9 by repair mechanisms
How do repair systems recognise a mistake?
Mismatched bases and loops cause bulges/bubbles in the DNA double helix that can then be recognised
What are the 2 types of abnormalities that need to be fixed by the repair systems?
Base Mismatching
Damage to nucleotide structure (i.e. breaks in the chromosome or pyrimidine dimers)
How are breaks in the DNA fixed?
DNA ligase
How are chemically modified bases and mismatched pairs repaired?
Excision by base-specific DNA-glycosylases and then resynthesis
How are pyrimidine dimers repaired?
Dimerization can be reversed by enzymes
A relatively ______ amount of errors can be repaired by direct repair. i.e. ________________, _______________ and ________________.
Small
Breaks in the chromosomes, Alkyl group removal and some dimerisation
What is the most common method of repair and how does it work?
Excision repair, damaged region is excised by endonucleases creating an apurinic or apyrimidinic site that is then resynthesized by DNA polymerase
How is base-excision repair different to nucleotide-excision repair?
In BER the base is removed first, then the surrounding nucleotides
In NER the whole nucleotide is removed in one go
How does a DNA glycosylase work?
It cuts between the base and sugar backbone
___________ of microsatellites is more common than ___________. Which occurs may be based on the _______________.
Expansion
Contraction
Parent of Origin
