Genome Variation Flashcards
What is considered a variant?
Any position in the genome that varies between individuals is considered a variant.
What is an SNV/SNP (single nucleotide variant/polymorphism)?
It is a change in a single base.
The genome is littered with them - if we compare human genomes we find these single base differences approximately once in every 300 bases. In total, 12 million SNVs have been found by studying human genomes.
They’re typically generated by faulty replication of DNA during mitosis. Although there are mismatch repair mechanisms which should correct these mistakes, some don’t get corrected and we end up with an SNV.
Describe how SNVs/SNPs come about.
During DNA replication, the two strands will separate and will be used as templates to synthesise complementary strands.
If that goes well, then we should end up with two identical copies.
However, when synthesising this strand, instead of incorporating an A, a G has been incorporated (THE MISTAKE). The mismatch repair system will identify this mistake and correct it so that the bases are a standard Watson-Crick base pair.
However, in this instance, it hasn’t corrected the G, it has instead replaced the T with a C. And thus, what we end up with is at this position there’s either a T or a C.
If these changes occur in the gametes and aren’t deleterious, then it will get passed on to the next generation, and as time goes on, it can spread throughout the population.
Where can SNVs end up in the genome, and what effect can they have?
SNVs can end up anywhere, such as:
THE GENE:
- no amino acid change (synonymous)
- amino acid change (non-synonymous/missense)
- stop codon (nonsense)
- splice split
- UTR (gene expression)
THE PROMOTER:
- protein expansion
THE NON-CODING REGION:
- n/a (unknown)
What is the difference between mutations and polymorphisms?
If the minor allele frequency is less than 1%, it’s a mutation.
If the minor allele frequency is more than 1%, it’s a polymorphism.
- rare polymorphisms: MAF 1-5%
- common polymorphism: MAF >5%
Thus, it is safer to use the term variant [all variant start off rare].
How do evolutionary forces affect SNVs?
MUTATION: a new allele arises, we now have a variant
GENE FLOW: migration leading to the introduction of that variant into another population
GENETIC DRIFT: random change in variant allele frequency between generations
SELECTION: non-random change in variant allele frequency between generations because the presence of one allele/genotype is pathogenic (negative selection) or beneficial (positive selection)
Describe the Polymerase Slippage Model.
During replication, polymerase slippage and subsequent reattachment may cause a bubble to form in the new strand. Slippage is thought to occur in sections of DNA with repeated patterns of bases (such CAG).
Then, DNA repair mechanisms realign the template strand with the new strand and the bubble is straightened out. The resulting double helix is thus expanded.
What are microsatellites?
These are a set of short, repeated DNA sequences in tandem (ie. after one another) at a particular locus on a chromosome. They vary in number in different individuals, and so can be used for genetic fingerprinting.
Microsatellites may be in the part of the 98% of the genome not coding for protein, or it may be exonic.
What are CNVs (copy number variants)?
CNV is a phenomenon is which sections of the genome are repated and the number of repeates in the genome varies between individuals.
How do CNVs come about?
They come about through non-allelic homologous recombination in meiosis.
Allelic recombination is good; it provides the shuffling of alleles.
However, non-allelic recombination results in the duplication/deletion, and thus a copy number change.
Where could CNVs be found?
They can be intergenic, but they are quite large (>1 kb), so they often affect one or more genes (parts of genes).
List the different types of common genetic variants.
- Single Nucleotide Polymorphisms (SNPs): ~17 million identified; ~3 million/genome
- Microsatellites: ~3% of the genome
- Copy Number Variants (CNVs): >2000 identified; ~100 per genome
What are some effects that variants can have?
- can be beneficial
- can be pathogenic
- most are neutral
Are variants of any use?
Yes, they can be used as markers to help find disease-causing genes and mutations.
Examples include:
- autozygosity mapping & linkage studies (Microsatellites, SNPs)
- association analysis (SNPs, CNVs)
