Causes of Mutations and Repair Mechanisms
BCH 304:
Metabolism of
Nucleic Acids
(2 Units)
6 November 2018
Mutation and repair
Lecture 8
Mutation and repair
Causes of mutation
Two classes of mutations are
1.
Spontaneous mutations (naturally occurring)
2.
Induced mutations caused by mutagens.
Mutation and repair
Causes of mutation
1.
Spontaneous mutations (naturally occurring)
1.
Errors in replication.
2.
Errors that occur during recombination events.
3.
Tautomerism
4.
Substitutions
5.
Frame-shift mutation
6.
Oxidative damage
7.
Spontaneous changes
Mutation and repair
Causes of mutation
1.
Spontaneous mutations (naturally occurring)
1.
Errors in replication
If a base that is non-complementory to the
template base added during replication, then a
mispairing or mismatch occurs.
This leads to a mutation during the next round of
replication if the error is not repaired.
Mutation and repair
Causes of mutation
1.
Spontaneous mutations (naturally occurring)
1.
Errors in replication
If a base that is non-complementory to the
template base added during replication, then a
mispairing or mismatch occurs.
This leads to a mutation during the next round of
replication if the error is not repaired.
2.
Errors that occur during recombination events
Recombinant DNA: molecules of DNA formed by inserting
portions of DNA from one organism into DNA of another.
Mutation and repair
Causes of mutation
1.
Spontaneous mutations (naturally occurring)
An example of a spontaneous
transition results from the
tautomerization
1.
Adenine tautomerizes to
generate a form, which can
base pair with cytosine.
2.
Amino group (-NH2)
tautomerizes to an imino
group (=NH)
3.
Other tautomers can form
from a keto group (-C=O)
changing to an enol group
(-C-OH).
3. Tautomerism
Mutation and repair
Causes of mutation
1.
Spontaneous mutations (naturally occurring)
One base is replaced by another. If this mutation occurs within the
coding sequence of a gene, it may lead to the use of a different amino acid
or generate a stop codon.
Substitutions fall into two categories:
1.
Transitions
- one purine is replaced by another (A -> G or G -> A), or one
pyrimidine is replaced by another (C -> T or T -> C)
2.
Transversions
- a purine is replaced by a pyrimidine (A -> C or T; G -> C
or T), or a pyrimidine is replaced by a purine (C -> A or G; T -> A or G)
4.
Substitutions
Mutation and repair
Causes of mutation
1.
Spontaneous mutations (naturally occurring)
Insertion or deletion on one strand, usually through a polymerase error
when copying repeated sequences.
1.
Deletions
- one or more bases is removed. Unless this mutation results
in the loss of a multiple of three bases, a
frame-shift
will occur in coding
sequences, drastically altering every codon downstream of the
mutation, and therefore the final amino acid composition of the
protein.
2.
Insertions
- one or more bases is added. The effects are the same as
deletions, resulting in frame-shift mutations.
5.
Frameshift mutation
Mutation and repair
Causes of mutation
1.
Spontaneous mutations (naturally occurring)
1.
Deamination
of cytosine (C) to form uracil (U).
2.
Spontaneous depurination
.
Purines are less stable under normal cellular conditions than pyrimidines.
The glycosidic bond that links purines to the sugar-phosphate backbone of
DNA often is broken.
If these purines are not replaced before a round of replication, any base may
be added to complement the missing base during replication.
6. Oxidative damage
Caused by oxygen radicals
7.
Spontaneous changes
Mutation and repair
Causes of mutation
2. Induced mutations
1.
Chemical mutations
2.
Irradiation
Mutation and repair
Causes of mutation
2. Induced mutations
1.
Chemical mutations
1.
Non-alkylating agents
1.
Formaldehyde
(HCHO)
reacts with amine groups and cross-links
DNA,
RNA and proteins.
2.
Hydroxylamine
(NH2OH)
specifically reacts with cytosine to form
derivatives that pair with adenines instead of guanines. This change
lead to a transversion (in which a purine is replaced by a pyrimidine
or a pyrimidine is replaced by a purine.
3.
Nitrous acid
(HNO2)
oxidatively deaminates cytosine, adenines, and
guanines to form uracil, hypoxanthines, and xanthines respectively.
These changes results in transitions in which a purine is replaced by
another purine or one pyrimidine is replaced by another pyrimidine.
2.
Alkylating agents
T
hese act as strong electrolytes, which become linked to many cellular
nucleophiles in particular the sevenths nitrogen of the guanine in the
DNA. This linkage causes breakage of DNA.
Mutation and repair
Causes of mutation
2. Induced mutations
2. Irradiation
1.
Ultraviolet (UV) light (200-400 nm)
I
nduces dimerization of adjacent pyrimidines,
particularly adjacent thymines. This direct mutation of
DNA distorts the DNA structure, inhibits transcription,
and disrupts replication until it is repaired.
2.
Ionizing radiation, such as Roentgen rays (x rays) and
gamma rays (
γ
-rays)
C
an cause extensive damage to DNA including opening
purine rings, which lead to depurination, and breaking
phosphodiester bonds.
Mutation and repair
Mutation rate
1.
DNA has so-called hotspots, where mutations occur up to 100
times more frequently than the normal mutation rate.
2.
A hotspot can be at an unusual base, e.g., 5-methylcytosine.
3.
Mutation rates also vary across species.
4.
Evolutionary Biologists have theorized that higher mutation
rates are beneficial in some situations, because they allow
organisms to evolve and therefore adapt faster to their
environments.
Mutations can be classified into spontaneous and induced mutations based on their origin. Spontaneous mutations occur naturally, while induced mutations are caused by mutagens. Understanding the causes of mutations and repair mechanisms is vital in studying genetic variation and disease development.
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Presentation Transcript
Lecture 8 6 November 2018
Causes of mutation Mutation and repair Two classes of mutations are 1. Spontaneous mutations (naturally occurring) 2. Induced mutations caused by mutagens.
Causes of mutation Mutation and repair 1. Spontaneous mutations (naturally occurring) 1. Errors in replication. 2. Errors that occur during recombination events. 3. Tautomerism 4. Substitutions 5. Frame-shift mutation 6. Oxidative damage 7. Spontaneous changes
Causes of mutation Mutation and repair 1. Spontaneous mutations (naturally occurring) 1. Errors in replication If a base that is non-complementory to the template base added during replication, then a mispairing or mismatch occurs. This leads to a mutation during the next round of replication if the error is not repaired.
Causes of mutation Mutation and repair 1. Spontaneous mutations (naturally occurring) 1. Errors in replication If a base that is non-complementory to the template base added during replication, then a mispairing or mismatch occurs. This leads to a mutation during the next round of replication if the error is not repaired. 2. Errors that occur during recombination events Recombinant DNA: molecules of DNA formed by inserting portions of DNA from one organism into DNA of another.
Causes of mutation Mutation and repair 1. Spontaneous mutations (naturally occurring) 3. Tautomerism An example of a spontaneous transition results from the tautomerization 1.Adenine tautomerizes to generate a form, which can base pair with cytosine. 2.Amino group (-NH2) tautomerizes to an imino group (=NH) 3.Other tautomers can form from a keto group (-C=O) changing to an enol group (-C-OH).
Causes of mutation Mutation and repair 1. Spontaneous mutations (naturally occurring) 4. Substitutions One base is replaced by another. If this mutation occurs within the coding sequence of a gene, it may lead to the use of a different amino acid or generate a stop codon. Substitutions fall into two categories: 1.Transitions - one purine is replaced by another (A -> G or G -> A), or one pyrimidine is replaced by another (C -> T or T -> C) 2.Transversions - a purine is replaced by a pyrimidine (A -> C or T; G -> C or T), or a pyrimidine is replaced by a purine (C -> A or G; T -> A or G)
Causes of mutation Mutation and repair 1. Spontaneous mutations (naturally occurring) 5. Frameshift mutation Insertion or deletion on one strand, usually through a polymerase error when copying repeated sequences. 1.Deletions - one or more bases is removed. Unless this mutation results in the loss of a multiple of three bases, a frame-shift will occur in coding sequences, drastically altering every codon downstream of the mutation, and therefore the final amino acid composition of the protein. 2.Insertions - one or more bases is added. The effects are the same as deletions, resulting in frame-shift mutations.
Causes of mutation Mutation and repair 1. Spontaneous mutations (naturally occurring) 6. Oxidative damage Caused by oxygen radicals 7. Spontaneous changes 1. Deamination of cytosine (C) to form uracil (U). 2. Spontaneous depurination. Purines are less stable under normal cellular conditions than pyrimidines. The glycosidic bond that links purines to the sugar-phosphate backbone of DNA often is broken. If these purines are not replaced before a round of replication, any base may be added to complement the missing base during replication.
Causes of mutation Mutation and repair 2. Induced mutations 1. Chemical mutations 2. Irradiation
Causes of mutation 2. Induced mutations 1. Chemical mutations Mutation and repair 1.Non-alkylating agents 1.Formaldehyde (HCHO) reacts with amine groups and cross-linksDNA, RNA and proteins. 2.Hydroxylamine (NH2OH) specifically reacts with cytosine to form derivatives that pair with adenines instead of guanines. This change lead to a transversion (in which a purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine. 3.Nitrous acid (HNO2) oxidatively deaminates cytosine, adenines, and guanines to form uracil, hypoxanthines, and xanthines respectively. These changes results in transitions in which a purine is replaced by another purine or one pyrimidine is replaced by another pyrimidine. 2. Alkylating agents These act as strong electrolytes, which become linked to many cellular nucleophiles in particular the sevenths nitrogen of the guanine in the DNA. This linkage causes breakage of DNA.
Causes of mutation Mutation and repair 2. Induced mutations 2. Irradiation 1. Ultraviolet (UV) light (200-400 nm) Induces dimerization of adjacent pyrimidines, particularly adjacent thymines. This direct mutation of DNA distorts the DNA structure, inhibits transcription, and disrupts replication until it is repaired. 2. Ionizing radiation, such as Roentgen rays (x rays) and gamma rays ( -rays) Can cause extensive damage to DNA including opening purine rings, which lead to depurination, and breaking phosphodiester bonds.
Mutation and repair Mutation rate 1.DNA has so-called hotspots, where mutations occur up to 100 times more frequently than the normal mutation rate. 2.A hotspot can be at an unusual base, e.g., 5-methylcytosine. 3.Mutation rates also vary across species. 4.Evolutionary Biologists have theorized that higher mutation rates are beneficial in some situations, because they allow organisms to evolve and therefore adapt faster to their environments.
