5. GENETIC VARIATION

Question 1

What is a polymorphism & monomorphism?

Answer 1

• POLYMORPHISM = any single position in the genome that varies between individuals
• MONOMORPHISM = a position in the genome that doesn’t vary between individuals

Question 2

What are the three types of genetic variant?

Answer 2

1. Single Nucleotide polymorphism - bi-allelic (faulty mismatch repair)
2. Microsatellite - multi-allelic (polymerase slippage)
3. Copy Number Variant (non-allelic homologous recombination)

Question 3

*What is a SNP or SNV?

Answer 3

• A SNP or SNV is a type of polymorphism or genetic variant that involves a single base change/substitution
• SNPs are a type of mutation but not all mutations are SNPs
• SNPS occur in a high frequency (1 in 300 nucleotides)

Question 4

*How does a SNP occur?

Answer 4

• SNPs occur due o FAULTY MISMATCH REPAIR during DNA replication
• Sometimes, a mismatch will occur where DNA polymerase makes an error in the template strand
• The wrong base in the template strand needs to replaced but the mismatch repair cannot distinguish whether the error is in the parental or template strand
• Faulty mismatch repair occurs when the base on the parental strand is replaced instead of the copied strand
• Produces two daughter cells that are heterozygous at that position, gives rise to two new alleles (biallelic)

Question 5

Where are SNPs located?

Answer 5

• SNPs can be located in the intergenic region (harmless) or in the genes themselves which can be damaging
• But the majority of SNPs are located in the intergenic region

Question 6

What are four properties of SNPs?

Answer 6

1. Can be located anywhere in the genome
2. Can be neutral - do nothing, harmless
3. Can be pathogenic, SNPs are known as point mutations if they’re pathogenic
   - -> Can affect a trait linked to a disorder
4. Occur in a high frequency (1 in (300 nucleotides)

Question 7

What’s the difference between rare & common polymorphisms?

Answer 7

• RARE POLYMORPHISM = has a MAF of 1-5%

- COMMON POLYMORPHISM = has a MAF of greater than 5%. Common polymorphisms are less likely to be deleterious

Question 8

What’s the difference between a polymorphism & a mutation?

Answer 8

• A genetic variant with a minor allele frequency greater than 1% is considered a polymorphism
• there are 2 types of polymorphism : rare & common
• Whereas a mutation has a MAF less than 1%

Question 9

What is a microsatellite?

Answer 9

• A microsatellite is a type of genetic variant that is also known as short tandem repeats (STRs), where sequences of bases are repeated
• E.g ACACACAC
• The number of repeats can vary between individuals, so one individual may have 5 repeats whilst another has 7 repeats
• So microsatellites give rise to multiple alleles & are therefore multi-allelic

Question 10

What are the different lengths of microsatellite polymorphisms?

Answer 10

• Dinucleotides = 2 repeats
• Trinucleotides = 3 repeats
• Tetranucleotides = 4 repeats
• Pentanucleotides = 5 repeats

Question 11

**How do microsatellites occur?

Answer 11

• Microsatellites occur as a result of POLYMERASE SLIPPAGE during DNA replication
• The DNA polymerase disengages or dissociates from the template strand which leads to an overhang of bases
• These bases should be reannealed but as the sequence is repetitive, it can be reannealed at the wrong position
• The bubble of unpaired bases will be recognised as an error, creating a gap
• The repair mechanism will then add in a extra unit leading to a new number of repeats causing expansion

Question 12

Where can microsatellites be located?

Answer 12

• Microsatellites can be located anywhere in the genome:
  1. Intergenic region
  2. Intronic, UTR - regulate gene expression
  3. Exonic - leads to an extra AA in the protein

Question 13

What disorders can microsatellites cause?

Answer 13

• Disorders of microsatellites are known as EXPANSION DISORDERS or TRINUCLEOTIDE REPEAT DISORDERS
• E.g Huntington’s disease occurs when there are over 36-40 repeats of CAG
• However, most microsatellites aren’t pathogenic

Question 14

What is a copy number variant?

Answer 14

• A copy number variant (CNV) is a type of genetic variant where there are varying numbers of the copies of a gene due to duplications or deletions

Question 15

How can duplications or deletions lead to copy number variants?

Answer 15

• Duplications & deletions can alter the number of copies of a gene
• In order to count the number of copies of a gene, we need to look at both chromosomes

Question 16

What is non-allelic homologous recombination & how can it cause copy number variants?

Answer 16

• Normal allelic homologous recombination occur between allelic sequences (two regions at the same locus) which allows for variation
• However, non-allelic homologous recombination occurs between two sequences that are similar but are not allelic.
• This leads to a misaligned crossover and can result in duplications or deletions
• –> e.g two loci may be present on one chromosome, where one is deleted & the other is duplicated
• Gene duplications & deletions result in CNVs

Question 17

Where are copy number variants located?

Answer 17

• Copy number variants are located in the intergenic region so are mainly harmless but can sometimes be pathogenic

Question 18

What are disorders caused by copy number variants called & give an example?

Answer 18

• Disorders of copy number variants are known as MICRODELETION DISORDERS
• An example is diGeorge syndrome which involves the 22q deletion

Question 19

*Define locus

Answer 19

• A unique point in a genome

Question 20

Define allele

Answer 20

• An alternative form of a gene particular to a specific locus