What are the different types of genetic variation that are associated with disease?
- Major macro-level differences - e.g. Aneuploidy, translocations
- Micro or molecular-level pathogenic differences - e.g. Single point mutation in sickle cell anaemia
Does genomic variation usually lead to major differences in phenotype, e.g. disease?
- No the vast majority of genomic variation doesn’t lead to major differences/changes.
- Major-macro level and micro-level pathogenic differences that are associated with disease are very rare.
If a position within the genome varies between any two individuals, i.e. there is more than one possible allele at that position, what is that position known as?
That position is known as polymorphic - in other words a genetic variant exists at this position
If a position with the genome shows no variation between individuals, i.e. there is only one possible allele that can be at that position, what is that position known as?
That position is known as monomorphic
Define the term “major allele”
The major allele is the allele that is most commonly observed at any one position within the genome
Define the term “minor allele”
The minor allele is the allele that is less commonly observed at any one position within the genome
What is a consensus sequence?
A generated sequence that tells you what base/allele you should expect to see at any position within the entire genome - In other words it tells you the most frequent base/allele seen at each position.
What is a single nucleotide variant (SNV)?
A change/substitution of a single nucleotide at a specific position within the genome
Why are the majority of SNVs located outside of the exome?
Because outside of the exome there is less selection pressure. The exome encodes for protein which means there’s a higher selection pressure within the exome not to incorporate harmful mutations into it.
What is the name of the mechanism that leads to the generation of SNVs within the genome?
Incorrect mismatch repair during DNA replication
How does incorrect mismatch base reapir lead to the generation of SNVs?
- During DNA replication the 2 parental strands are separated and then replicated individually to form 2 double stranded DNA strands.
- Sometimes during this process the DNA polymerase will incorporate the wrong base into the daughter strand
- Usually when this occurs the mismatch repair system will cut out the base and incorporate the correct one but sometimes it misreads the transcript and cuts out the wrong base.
- This results in a single nucleotide variant being created in that particular position as one parental strand will have the original base while the other parental strand will have a different base at that position.
What are the 3 main postions where an SNV can occur within the genome?
- Coding region
- Promoter region
- Non-coding region
What are some of the effects of an SNV occuring within a gene?
- No amino acid change (synonymous variation)
- Amino acid change (non-synonymous/missense variation)
- Result in the production of a premature stop codon (nonsense variation)
What is synonymous variation?
When a change in a single base doesn’t change the amino acid sequence
What is non-synonymous/missense variation?
When a change in a single base does change the amino acid sequence therefore changing the protein produced
What is nonsense variation?
When a premature stop codon is seen within a DNA sequence resulting in the production of an incomplete protein
How is minor allele frequency used to try and classify a single nucleotide variant as either a polymorphism or a mutation?
- If the minor allele frequency is > 1% then that SNV would be classified as a polymorphism
- If the minor allele frequency is < 1% then that SNV would be classified as a mutation
Why is it misleading to use minor allele frequency to try and classify a single nucleotide variant as a mutation or polymorphism?
Because all variants will start off rare and so will start off with a allele frequency of < 1%. These variants may not even be pathogenic (cause disease) which means that it isn’t a mutation despite having the allele frequency of one. It just hasn’t had a chance to spread throughout the population.
How does the allele frquency of the sickle cell anaemia varaint allele in different parts of the world prove that classifying SNVs as polymorphisms or mutations based on minor allele frequency is misleading?
- In European countries the frequency of somebody having the SCA variant allele within their genome is around 0.02%
- However, in African countries the frequency of somebody having this SCA variant allele, and therefore, having the mutation that causes them to have this variant, is around 4.5%
- If you only looked at the SCA variant allele frequency in African countries you would expect the SCA variant to be a polymorphism rather than a mutation but it is indeed a mutation as having the variant causes disease.
How does mutation affect SNVs?
SNVs can arise via mutations - mutation results in creation of new allele (variant) in a specific place within genome
How does gene flow affect SNVs?
Reproduction and migration leads to that SNV being introduced into a new population - This phenomenon is called gene flow
How does genetic drift affect SNVs?
Genetic drift results in a random change in variant allele frequency between generations
How does selection affect SNVs?
Selection results in a non-random change in variant allele frequency between generations as a variant is either beneficial, and so will be slected for, or pathogenic, and so will be slected against.
What is a microsatellite?
A short section of repetitive DNA in which a unit of DNA is repeated in tandem
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DNA complementarity, hybridisation and its effects30
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PCR and its roles in diagnostics25
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Molecular Evolution36
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Genome structure34
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Genome variation32
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Inheritance patterns42
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Enzyme and restriction mapping42
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Recombinant DNA and cloning vectors30
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DNA Sequencing by Dideoxy-chain termination18
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Linkage Analysis30
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Microarrays36
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Next generation sequencing24
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The Metagenome25
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The functional genome30
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The Mitochondrial Genome35
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The Epigenome31
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Mapping Mendelian Disease28
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Genetics of common disease32
