Genome Variation

Question 1

What is the size of the human genome?

Answer 1

3 billion bases (3000Mb) which is about 20,000 genes

Question 2

What causes sickle cell anaemia?

Answer 2

point mutation

Question 3

What causes CFTR?

Answer 3

3bp deletion

Question 4

How much DNA is the same between any 2 people?

Answer 4

99.7%

Question 5

What is different in the 0.3% of DNA that is different between any 2 people?

Answer 5

• phenotypic differences between people

- all the differences that are not visible eg blood pressure, cholesterol levels, susceptibility to different diseases

Question 6

What does polymorphic mean?

Answer 6

any position in the genome that can vary between 2 individuals

Question 7

What is a major allele on a position?

Answer 7

it is more common (more common variant)

Question 8

How do we know which gene is normal at that given point i.e. reference DNA?

Answer 8

human genome mapping project

• 4 anonymous individuals had donated their DNA, and whichever allele was most common was determined to be the reference allele
• this reference allele is what is expected, and is considered normal
• when a position in the genome deviates from that reference, it is called a polymorphic site

Question 9

What is a polymorphic site?

Answer 9

when a position in the genome deviates from that reference, it is called a polymorphic site

Question 10

What is a Single Nucleotide Polymorphism?

Answer 10

change in a single base

Question 11

How common are SNPs?

Answer 11

very common
find SNPs every 300 bases
through studies= 17 million SNPs have been identified in human genome

Question 12

How do you get SNPs?

Answer 12

• mutations

- faulty mismatch repair

Question 13

Explain a faulty mismatch repair:

Answer 13

see mohib’s notes page 3

Question 14

What happens if a SNP happens during meiosis?

Answer 14

lead to polymorphism which goes onto next generation

Question 15

What type of a difference do SNPs lead to?

Answer 15

biallelic- means there are only two different alleles involved

Question 16

Give an example of something that is multiallelic?

Answer 16

microsatellite

Question 17

Where in the DNA can SNPs occur?

Answer 17

in the gene
promotor region of the DNA
in the large amounts of non coding regions

Question 18

What happens if SNPs are found in the gene?

Answer 18

• maybe no impact on the phenotype if there are no amino acid changes (synonymous)
• could have impact and result in an amino acid change
• could get stop codon- lead to nonsense mutation
• affect splice sites
• affect an untranslated region which could change gene expression

Question 19

What happens if SNPs were in the promotor region of the DNA?

Answer 19

changes in protein expression

Question 20

What is the difference between SNPs and point mutations?

Answer 20

SNPs- no detrimental effect

point mutations- detrimental effect

Question 21

How can you tell the difference between SNP and a point mutation?

Answer 21

• SNPs can be differentiated from point mutations (which are essentially a change in a single base) by looking at the minor allele frequency
• minor allele= allele which occurs least number of times on polymorphic site
• if the minor allele frequency is more than 1% it is a polymorphism

Question 22

How does the allele population differ in different places?

Answer 22

eg the sickle cell anaemia allele is more common in African populations (4.5% in Africans whilst 0.02% in Caucasians)

thus using the earlier definition of a polymorphism, the sickle cell anaemia allele is polymorphic in African populations and a mutation in Caucasian populations

Question 23

Every variant starts off rare. What does this mean?

Answer 23

this means that every base change occurs for the first time only in a very small number of individuals

Question 24

How does evolution determine whether a gene will stay or not?

Answer 24

1. mutation occurs ie a new allele arises and there is a single nucleotide variation
2. gene flows around population through migration
3. reproduction- further spread of SNP (genetic drift)
4. this is random depending on mating partner etc.
5. natural selection= single nucleotide variation will get selected and its allele will increase if it is beneficial, and will decrease if it is pathogenic

Question 25

What is a microsatellite or a short tandem repeat?

Answer 25

• particular unit is repeated ‘n’ number of times
• the number of times it can be repeated can vary between different individuals
• everyone has same microsatellites but number of repeats vary

Question 26

What model explains the number of repeats in a microsatellite?

Answer 26

polymerase slippage model

Question 27

What happens in the polymerase slippage model?

Answer 27

1. polymerase is moving along
2. it slips (at the microsatellite)
3. The complementary strand gets released from the parent strand
4. complimentary strand now needs to re-anneal to the parent strand
5. since the slippage has occurred at the microsatellite, the slipped strand can anneal to any of the microsatellite units in the repeated sequence (bc they are all complimentary to the slipped strand)
6. When slipped strand anneals to a microsatellite unit that’s earlier than the one it is normally supposed to anneal, there is a bubble of unpaired bases that forms
7. at the end of replication, the DNA repair mechanisms detect this
8. they put in another unit of microsatellites to pair with the unpaired bases
9. so you have added extra units of microsatellites
10. you get variation

Question 28

Where can microsatellite repeats take place?

Answer 28

98% in intron of DNA (not coding for protein)

rest exonic- could lead to extra gene (huntingtons)

Question 29

What is copy number variation?

Answer 29

big chunks of DNAs (1Kb to 5Mb) repeated different number of times in different people

Question 30

How can CNV (copy number variation occur)?

Answer 30

1. deletion

2. duplication

Question 31

Why does CNV occur?

Answer 31

because of non-allelic homologous recombination in meiosis

Question 32

Where do CNVs normally occur?

Answer 32

intergenic (between 2 genes)