Human Genome variation Flashcards
(27 cards)
How many pairs of chromosomes do we have (gross structure)?
23
How big is the human genome?
- 3 billion bases (3000Mb)
- ~20,000 genes
- ~2% genome codes for protein = exome
What are Major macro-level differences?
• Major macro-level differences generally associated with disease (aneuploidy, translocations, etc) (not common)
Whar are micro or molecular-level pathogenic differences?
• Also micro or molecular-level pathogenic difference sometimes associated with disease (point mutation and SCA, 3bp deletion in CFTR)
Give some examples of Coding variants that effect traits
- height
- hair colour
- intelligence
What is a variant?
- ~99.7% DNA same between any 2 people (i.e. ~9 million bases different)
- Any position in the genome that varies between individuals is considered polymorphic = a variant
Define “common” in terms of genomics
- The frequency of the minor allele is relatively high in the population frequency and proportion of chromosomes that carry each allele in the population
- Or multiallelic
What are 2 of the same and different alleles called?
- 2 same alleles = homozygous
* 2 different alleles = heterozygous
What is a gene reference?
A gene reference is the most common allele in the population
What is Single Nucleotide Variant (SNV)/Polymorphism (SNP)?
A single base change
Describe the frequency of an SNV
Where are they mostly found?
How are they generated?
- 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
Describe the process of DNA replication and incorporate a SNP
- DNA is unwound by helicase
- DNA polymerase is used to generate new daughter strands based on parental template strands
- The bases are complementary AT and CG
- Repair mechanisms in place
- This diagram shows how DNA replicates and how it corrects itself if there is a mismatch. This produces variation. A single nucleotide variant. This is shown in read. We have introduced a variant into a population
What is biallelic?
2 alleles present
Where may a single nucleotide variant be found?
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:
- Without a deleterious effect or population annihilation, SNVs do not disappear
Give an example of a single nucleotide variant
On image
What is a polymorphism?
What percentage is a rare polymorphism, common and mutation?
What is a better description of one?
If minor allele freqy >1% (i.e. at least 1 in every 100 chromosomes has non-reference allele) = polymorphism
Rare polymorphism: MAF 1-5%
Common polymorphism: MAF >5%
Less than 1% is a mutation
Polymorphism is used to describe a single nucleotide variant that doesn’t have a bad effect, so use variant INSTEAD.
What causes single nucleotide variants?
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 are microsatellites?
Another name for them?
Repetitive bases
Also known as a short tandem repeat
Name the 6 types of microsateliltes
On image pg 5
How does the formation of microsatellites happen?
- Errors in DNA replication
- The polymerase stutters and causes repeat sequences. It will cause gaps in other words, bases will shift back to other bases leaving some unpaired bases.
- To fix this, it has to re-anneal back to the parental strand. It looks for complementary bases. It causes a gap in the parental strand and adds some bases
On image
Where are Microsatellites found?
Part of the 98% of genome not coding for protein
Intronic or UTR: may affect gene expression
Intergenic
Exonic
Extra amino acids in protein
Can you think of a pathogenic example?
Read summary of microsatellites
- 1000s in genome
- Repeat units
- Varying numbers of repeats
- Alters actual size of that region of the genome
- Multiallelic
- Can be anywhere in genome
What is “Copy number of variants”?
Copy number of variants >2000 identified – 100 per genome
• An entire chunk of bases may be repeated, as shown below.
How does copy number variation occur?
Non-allelic homologous recombination in meiosis
