Genome Variation Flashcards
How big is the human genome?
3 billion bases
About 20,000 genes
About 2% of the genome codes for protein = exome
What are major macro-level differences associated with? Examples
Associated with disease (aneuploidy, translocations etc)
What are micro or molecular level pathogenic differences associated with? Examples
Sometimes associated with disease (point mutation and SCA, 3bp deletion in CFTR)
What do coding variants effect?
Effect traits such as height, hair colour, intelligence etc
What is a variant?
Any position in the genome that varies between individuals
Homozygous
Same alleles
Heterozygous
Different alleles
Reference allele
What you would expect the base to be at a particular position on the chromosome
Usefulness of the human genome mapping
Enabled us to base all our assumptions of what we expect given positions on the genome to be hence the reference alleles.
What is an SNP?
A change in a single base
How many SNPs are there when comparing the human genome?
Approx. once every 300 bases
In an individual, how many SNPs are there per base?
1 every 1000 bases
How many SNVs have been identified in the human genome?
About 17 million
How does a SNP occur?
Typically caused by faulty replication of DNA during mitosis. There is a mismatch repair mechanisms that should correct these mistakes, some don’t get corrected and end up as a SNP.
How does the mismatch repair system work?
Repair the parental strand and not the new strand resulting in the T being changed for a C. This will result in variation.
What is the polymerase slippage event?
- The polymerase in the template strand during replication slips.
- It causes the new strand to unpair (release) from the template strand.
- If occurs in the codon repeat region, then the new strand will reattach to the template strand and it will have many identical copies of the codon to choose from.
- With so many identical codon copies to reattach to, the new strand may reattach to the template at the wrong copy.
- The new strand forms a bubble of unpaired bases, which represents the expansion of the new strand.
- The template strand will realign with the new strand and bring the bases from the bubble back into line with the template strand.
- The brand new double helix of DNA contains more CAGs in the repeat region.
Where are SNPs located/
In the gene:
- No amino acid change (synonymous)
- Amino acid change (non-synonymous/missense)
- Stop codon (nonsense)
- Splice site
- UTR (gene expression)
Promoter
- Protein expression
Non-coding region
- Less likely to have a detrimental effect
Why do SNPs not disappear?
Without a deleterious effect or population annihilation, they remain.
Describe the distribution of the SCA variant allele in the european population
0.02% - 2 in every 10,000 chromosomes
Point mutation very rare in white European population
Describe the distribution of the SCA variant allele in the african population
4.5% - about 1 in every 20 chromosomes
But, relatively common in black African population
What is the heterozygous advantage of SCA?
Beneficial in places where malaria is rife
What is a minor allele frequency?
Frequency is greater than 1 then in at least 1 in every 100 chromosomes has non-reference allele
Describe the MAF levels in rare and common polymorphisms
Rare - MAF 1-5%
Common - MAF > 5%
What affects whether a variant remains rare?
- All variants start off rare (via the mismatch repair system).
- Evolutionary forces affect whether or not a variant remains rare.
- Rare variants may be damaging and/or recent,
- However, some minor allele frequencies may have just occurred therefore using the 1% measure may also be accurate to distinguish between a mutation and a polymorphism.
