Genome variation Flashcards
(36 cards)
What is karyotyping?
the process of sorting chromosomes into their matched pairs
an important technique for investigating chromosomal disorders
What are Macro-level differences in genome generally associated with?
Generally associated with disease:
- aneuploidy
- translocations
What are Micro or molecular differences in genome sometimes associated with?
Sometimes associated with disease:
- point mutation causing sickle cell anaemia
- 3bp deletion in CFTR
Which regions of a genome affect trait?
Exome region (about 2% of the genome)
the small proportion of variation accounts for all the genetic difference that then leads to phenotypic differences (the results in phenotype that we get is a combination of DNA and the environment, not solely DNA variation)
What is a polymorphism?
position on the genome that varies between individuals (a variant)
What is a reference sequence?
consensus sequence that tells us what we expect to see in the genome
this is used to determine whether there are any genetic variants (polymorphisms)
What are Single Nucleotide Variants (SNVs)/Polymorphism (SNP)?
Substitution of a single nucleotide at a specific position in the genome.
High in frequency and occurs 1 in 300 nucleotides in reference genome
Bi-allelic
In every individual, occurs once in every 1000 bases (1kb)
How are SNVs/SNPs generated?
During mismatch repair during DNA replication:
1) Mismatch during DNA replication
2) DNA mismatch repair system should excise out the base that doesn’t belong there
3) Instead, it incorrectly excises out the wrong base, resulting in genetic variation
Where are the majority of SNPs?
Not in the exome
Why are the majority of SNPs not in the exome?
because exome has strong selective pressure to not incoporate mutations which will lead to detriment in individuals
Describe the function of the selective pressure in the exome.
high selective pressure in the exome keeps the variation relatively low in comparison to the non-coding regions of the genome
HOWEVER, there still is variation in the exome causing for the variations amongst individuals (e.g. hair colour, height, intelligence, etc)
Where are SNVs found?
Gene >no amino acid change (synonymous) >amino acid change (non-synonymous/missense) >stop codon (nonsense) >splice site >UTR (gene expression)
Promoter
> affects protein expression
Non-Coding Region
>if in non-coding region, less likely to have a detrimental effect
What is the only way SNVs disappear?
If they have a deleterious effect or population annihilation.
Without a deleterious effect or population annihilation, SNVs do not disappear
What is sickle cell anaemia caused by?
Single nucleotide variant (point mutation: non-synonymous/missense) changing the base sequence and therefore the amino acid sequence.
GAG → GTG
Glutamic Acid → Valine
What is the Link between sickle cell anaemia and malaria?
Individuals who are heterozygous for SCA have some protective advantage against malaria. As a result, the frequencies of sickle cell carriers are high in malaria-endemic areas
SCA point mutation is therefore very rare in white European population (0.02%), but relatively common in black African population (4.5%)
When is an SNV described as a polymorphism or a mutation?
SNV is described as a:
- polymorphism if minor allele frequency is >1%
- mutation if minor allele frequency is <1%
HOWEVER, this doesn’t always hold true:
- rare polymorphism: MAF 1-5%
- common polymorphism: MAF>5%
What do SNVs arise from?
All SNVs arise from a mutation and so are rare to begin with
How do SNVs spread throughout the population?
through reproduction and migration unless there is negative selection pressure against these variants
What is positive pressure selection?
genotypes that result in a beneficial trait that increases fitness are chosen FOR
What is negative pressure selection?
genotypes that result in a disadvantageous trait that reduces fitness are chosen AGAINST
What are SNVs called when proven to be pathogenic?
Point mutations
Describe how evolution is tied with SNVs.
1) New allele arises from mutation, causing a variant
2) Gene flow through reproduction and migration leading to introduction of that variant into another population
3) Genetic drift as there is a random change in variant allele frequency between generation
4) Selection: non-random change in variant allele frequency between generations because presence of one allele/genotype is pathogenic (negative selection) or beneficial (positive selection)
What are Microsatellites (short tandem repeats)?
repetitive DNA units typically 2-5 nucleotides in length, which directly affect the physical length of the genome
unlike SNVs which are bi-allelic, micro-satellites are tri-allelic
Why do microsatellites arise?
due to a problem in DNA replication (Polymerase Slippage):
1) DNA Polymerase pauses to proofread, and elongating strand becomes disengaged from template
2) Elongating strand needs to re-anneal to template so polymerase can continue adding specific nucleotides, but because template strand consists of repetitive sequences, elongating strand re-anneals to incorrect base pairs because they are all identical
3) This causes a bubble of unpaired bases
4) DNA Repair Mechanism adds two extra bases into the parental strand and elongation therefore continues
