Genome Variation

Question 1

Describe how humans differ at the level of their DNA

Answer 1

• genetic variants, caused by recombination or various DNA replication mishaps which are repaired

Question 2

Describe in detail what a single nucleotide variant/polymorphism (SNV/SNP) is, how they are inherited and how common they are

Answer 2

• SNO caused by an error in mismatch repair.
• When base error is found in daughter strand, the parent strand base is altered to complement
• If present in one parent, child stands 25% chance of inheriting, w/ person having SNV for 1 in 1000 bases
• can be located anywhere w/in genome, and freq may randomly fluctuate if found to not be pathogenic

Question 3

Describe how SNVs arise by mismatch repair

Answer 3

• separation of DNA strands, forming replication fork
• mismatch error of singular base during replication stages
• repair mechanisms complement the error instead of removing it.

Question 4

Describe the difference between a polymorphism and a mutation

Answer 4

Mutations are associated with pathogenic variants when interacting with environment
Polymorphism = multiple variants, can be used for both genotypes / phenotypes

Question 5

Describe the evolutionary pressures on a variant

Answer 5

eg: sickle cell anaemia
distribution of malaria disease heavily correlates with inheritance of HbS mutation.
heterozygote advantage increases freq as inheriting recessive allele offers resistance against malaria

Question 6

Describe in detail what a short tandem repeat (STR or microsatellite) is and how it is inherited

Answer 6

tandem = next to
short repeat sequences next to each other
variant = number of repeats
gives rise to multiallelic inheritance
eg: Huntingtons = trinucleotide CAG expansion

Question 7

Describe how STRs arise due to polymerase slippage, where they are seen and what effect they might have

Answer 7

Polymerase slippage
- processing repeats during replication confuses the enzyme
- briefly slips and realigns incorrectly causing ‘bubble’ of bases (repeats) to slip out
- repair mechanism straightens the emerging bubble, causing expansion of repeats on one strand

Question 8

Describe a ‘copy number variant’ and how it can arise by non-allelic homologous recombination (NAHR)

Answer 8

• CNV caused by chromosome misalignment, followed by recombination. the repairs may cause duplication / deletion of repeat sequence
• exclusively intergenic
• duplication/deletion can alter presence or absence of genes
• copy number can be 1kb - 5Mb long
• chromosomes uses identical sequences to try and find their partner chromatid but if there are multiple loci of sequence similarity, it will misalign.
  most CNV are neutral but micro deletion disorders are associated.