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What is DNA mutation and how does it occur?

• May occur spontaneously, or induced by mutagens (e.g. X‐rays, UV, toxins)
• Spontaneous mutations can occur during DNA replication, recombination, or repair
• Mutagens are physical or chemical agents that can cause mutations.


What is the effect of DNA mutation?

• Very much depends where the mutation occurs and the
change it causes when in a coding sequence (gene)
• Can be deleterious
- Cause disease
- Eliminate individuals from a population
• Can be beneficial
- Lead to evolutionary adaptation
- Used in breeding programs
- Powerful tool in research


Where can mutations occur?

On the chromosomal level:
* Whole gene deletion
* Multi-gene deletion
On the gene level:
* Intron mutation
* Whole intron deletion
* Within exon
* Whole exon deletion
* Splice site mutation
* Promoter mutation
* Mutation of termination codon
* Extragenic


Effect of mutation on splicing?

• Nucleotide signals at the splice sites guide the enzymatic machinery.
• If a mutation alters one of these signals, then
a) the intron is not removed and remains as part of the final RNA molecule, or
b) an exon is spliced out
• The translation of its sequence alters the sequence of the protein product.


Types of Mutations

* Somatic versus germline mutations
* Point versus chromosomal mutations
* Spontaneous versus induced mutations


Locations and general / specific classifications of mutations.

• Promoter, exon, splice site, intron
General Classification
• Substitution, insertion, deletion
Specific Classification
• Missense, nonsense, neutral, silent, frameshift


Somatic versus Germline Mutations

Germ‐line mutation –
• A mutation in germ cells (egg, sperm, or cells that produce eggs or sperm).
• It IS passed on to offspring.
• All cells affected.
Somatic mutation –
• Can occur in any of the cells of the body (except the germ cells: eg sperm and egg)
• Are NOT passed to offspring.
• Somatic cell mutations die with you.


Chromosomal versus Point Mutations

• Chromosomal mutations:
- include changes in number or structure and can lead to gross rearrangement of the chromosome.
• Point mutations:
- change in one or a few base pairs and usually less drastic ‐ only affect a single gene.
- Usually spontaneous
- Two main categories – substitution and insertion/deletion
- When in protein coding genes they are defined by their effect on the amino acid sequence in the protein.


What does degenerate mean?

• More than one codon occurs for each amino acid
• Third letter is the ‘wobble’ position.


Point mutation - base pair substitution; what are the seven types (a-g)?

a) Transition mutation: from one purine‐pyrmidine base pair to another eg A‐T to G‐C (purine changed to the other purine).
b) Transversion mutation: from a purine‐pyrimidine base pair to a pyrimidine‐purine base pair eg G‐C to C‐G or A‐T to C‐G.
c) Missense mutation: base pair change causes a change in an mRNA codon so that a different amino acid is inserted.
• Phenotypic change may occur.
d) Nonsense mutation: base pair change alters an mRNA
codon for an amino acid to a stop codon.
• Premature termination of the polypeptide (often results in nonfunctional protein).
e) Neutral mutation: a base pair change causes change in an mRNA codon with no detectable change in the function of the protein
• exchange for a chemically equivalent amino acid
• the amino acid is not functionally important in the protein.
f) Silent mutation: a base pair change results in an altered codon but the codon specifies the SAME amino acid.
• Occur most often at the third (‘wobble’) position of a codon eg AAA and AAG both code for lysine.
• NO change to the function of the protein.
g) Frameshift mutation: one or more bases added or deleted can lead to change in reading frame downstream of the mutation. Incorrect amino acids added after the mutation site (unless addition/deletion of a multiple of 3 bases).
• Usually results in non‐functional protein.
• Significantly alters amino acid sequence.
• Could generate shorter or longer polypeptide (change in stop codon position).


Causes of mutation: Spontaneous and Induced

• Spontaneous occur naturally
• Mostly due to errors during DNA replication,
• but also at rest, i.e. when DNA is not replicating
• Many corrected by cellular repair mechanisms
• Induced mutations occur when an organism is exposed to a physical or chemical agent that interacts with DNA to cause a mutation (mutagen)
• Accidental or deliberate
• Occur at a much higher frequency
• Used in genetic studies


Spontaneous Mutation During DNA Replication

Spontaneous mutation rate:
• Eukaryotes 10‐4 to 10‐6 per gene per generation
• Bacteria 10‐5 to 10‐7 per gene per generation
• This means that errors (mutations) do occur, particularly after repeated cycles of replication of large genomes
• Most errors are corrected by cellular repair systems.
DNA replication errors:
* Mismatch
- Normal keto bases pair together (A to T and C to G), but the bases can also exist in alternative states (tautomers), i.e. the enol forms, meaning the base pairing can be mismatched, (eg A to C or G to T).
* Looping out - when a repetitive sequence (eg. AAAAA) can form a loop, where one base 'loops out' of the strand (either template or new strand), giving the new coding of AAAA. So only TTTT will form across from it, for example.
Spontaneous chemical changes:
• Deamination = loss of amino group from a base
• At rest, DNA can spontaneously degrade, e.g. C‐>U. During next round of replication, if repair mechanisms don’t pick up the error, A will be inserted opposite U.


Induced mutations

Chemical and environmental:
• Can be naturally occurring or synthetic
• Base analogs (something that structurally represents our bases, but aren't. So if they get incorporated, that's a problem).
• Base modifying agents (will alter our base structure, again having a negative impact on the DNA molecule itself).
• Intercalating agents (something that gets within the double helical structure, eg. Athidium Bromide, which is actually used in the lab to stain DNA and visualise under UV light, because of its capacity to intercalate into DNA). Anything that can intercalate in your DNA can cause a mutation.
• Some chemicals are converted from nonmutagenic to mutagenic by our metabolism
• Some chemicals induce mutations that result in tumour growth = carcinogens.
Ionizing radiation:
• X‐rays, cosmic rays, radon
• Penetrates tissues, knocks electrons out of orbit ‐ creates ions that break covalent bonds (eg sugar‐phosphate backbone of DNA)
• High doses kill cells (cancer treatment).
UV light and thymine dimers:
• Increases the chemical energy of pyrimidines
• UV‐light causes covalent cross‐linking of T bases (link with each other in the same strand rather than the A in the opposite strand.
• Distorts DNA double helix
• Cross‐linked Ts can’t base‐pair with As


Chromosomal mutation

Chromosomal mutation results in a change in the structure or number of chromosomes, eg. Down's Syndrome


What are the four common types of changes in chromosome structure?

1. Deletions:
- Removal of a section of a chromosome
- Results in a reduction in the size of a chromosome
- It cannot revert to wildtype (wt)
- eg. Cri‐du‐chat
2. Duplications:
- Duplication of a section of a chromosome
- Results in an increase in the size of a chromosome
- Process critical for evolution of new genes.
- Can be inserted in tandem, reverse tandem, or terminal tandem positions.
3. Inversions:
- Chromosome breaks at two points, flips around 180o,
reinserted into the chromosome
- No change in size.
- Paracentric - does not include centromere
- Pericentric - does include centromere.
4. Translocations:
- Chromosome breaks at two points, then reinserted in a different location = change in position of chromosome segments
- Can be on same or different chromosomes, i.e. non-reciprocal intrachromosomal, non-reciprocal interchromosomal, reciprocal interchromosomal.
- No gain or loss of genetic material


Fragile sites, resulting in conditions such as Fragile X Syndrome.

• Most common known single‐gene cause of
• Recessive, X‐linked
• Incidence 1:4,000 (boys), 1:6,000 (girls)
• Intellectual disability
• Elongated face, large or protruding ears
• Behavioural characteristics (e.g. handflapping)
and social anxiety
• Caused by CGG triplicate repeat in the
FMR1 gene
• There are about 40 fragile sites on the human chromosome, but the one at the bottom in particular results in this condition.


What do I need to know for the exam?

Be able to classify mutations according to their:
• Cause:
- Spontaneous or induced
• Effect on DNA:
- Point mutation or chromosomal mutation
- Substitution or insertion/deletion
- Transition or transversion
• Effect on protein:
- Nonsense, missense, neutral, silent, frame‐shift