Human Genome Variation Flashcards
What are the types of common genetic variants?
Single nucleotide polymorphism (SNPs): ~17 million identified ~3 million/genome Microsatellites: ~3% of the genome Copy number variants (CNPs): >2000 identified ~100 per genome
How do we know how common a variant is?
If biallelic (one allele or another) , the frequency of the minor allele is relatively high, we can calculate that through knowing:
- Population frequency
- i.e. proportion of chromosomes that carry each allele in the population
Or multiallelic
How do we calculate minor allele frequency?
Position 17 = T/A = polymorphism The reference allele = T Most common allele = T Minor allele = A Minor allele frequency = 25% or 0.25
What are the characteristics of SNPs?
Single Nucleotide Variant (SNV)/Polymorphism (SNP)
High frequency: 1 every 300 nucleotides in reference genome
One individual: 1 every 1000 bases
Millions SNVs identified in human genomes
Majority not in exome
Generated by mismatch repair during DNA replication
How are SNPs created?
The DNA is unwound by DNA helicase and DNA polymerase is used to generate new daughter strands based on the parental strand as a template
The bases that are added should always be complementary but sometimes you get a mismatch
Mismatch repair should remove the new unwelcome base but sometimes the parental template strand’s base is replaced instead
If this happens in the gametogenesis it can be passed on/ inherited
How does SNVs location result in different effects?
SNVs may be in a… Gene: - No amino acid change (synonymous) - Amino acid change (non-synonymous/missense) - Stop codon (nonsense) - Splice site - UTR (affecting gene expression) Promoter - Affecting protein expression Non-coding region (mostly) Without a deleterious effect or population annihilation, SNVs do not disappear
What are the four evolutionary forces?
Mutation
- New allele arises, we now have a Variant
Gene flow
- Migration leading to 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 presence of one allele/genotype is pathogenic (negative selection) or beneficial (positive selection)
What is a microsatellite?
Is every base identical between individuals? Is every genome exactly 3000Mb?
Example of a microsatellite
Also known as a short tandem repeat
The AC = repeat, it is repeat in tandem (i.e. one after another)
The number of repeat units changes what its called:
Dinucleotide is two, trinucleotide is three, tetra is four etc.
The sequence in unit (the bases) does not vary but the number of times unit appears does vary
How do microsatellites first appear?
Polymerase slippage model – error in DNA replication
The DNA polymerase slips or stutters
This has a tendency to occur in repeat sequences so where you get these repeats sometimes as the polymerase moves along the polymerase can disengage from the strands of DNA so the daughter strand can be hanging free from the template strand
So for replication to carry it has to reanneal
Because that sequence is repetitive can be connected at the wrong spot as seen below
The repair mechanism creates a gap so the dangling bases can fit and pops in the complementary bases onto the template strand
How does the location affect microsatellites?
Microsatellites may be in a….
Part of the 98% of genome not coding for protein
- Intronic regions or UTR: may affect gene expression
- Intergenic regions (no genes at all)
Exonic:
- Extra amino acids in protein
- Can you think of a pathogenic example?
Expansion disorders, e.g. Huntington’s = trinucleotide repeat expansion disorder, basically a “bad” microsatellite
What are copy number variants?
Copy number variation can alter the size in the same way that microsatellites can
In CNP an entire chunk can be duplicated or deleted
Most of the time it doesn’t cause disease
How do CNPs occur?
Non-allelic homologous recombination in meiosis
A-D = loci on chromosome
Grey and blue = homologous chromosomes aligning in meiosis I
Red bands = regions of high sequence similarity, often viral/bacterial genomes that have been incorporated through evolution
Allelic recombination is good! – shuffling of alleles
But non-allelic recombination results in duplication/deletion and copy number change
Sometimes homologous pairs of chromosomes can misalign
They’ve shifted out of alignment due to sequence similarity in different parts of the chromosome (indicated by the red band)
One explanation for this similarity is that virus and bacterial genomes have been incorporated into our genomes throughout our evolution and can be in both chromosomes
What are some common variants and disease/trait associations?
Height Allergies Dyslexia Memory Sexual desire Nicotine dependence Faithfulness Sciatica Haemochromatosis Faithfulness Anti-social behaviour
How can we use variant effects for our benefit?
Yes, can be used as markers to help find disease-causing genes and mutations
- Auto zygosity mapping & linkage studies (Microsatellites, SNPs) - Association analysis (SNPs, CNVs)
