L3 Mutation and Mutation Rates

Question 1

Mutation

Answer 1

changes in DNA that have the potential to be propagated through DNA replication e.g. SNPs, indels, CNV

Question 2

Polymorphism

Answer 2

• frequencies too high to be explained by mutation alone

- every variant site

Question 3

Neutral theory of Evolution

Answer 3

Most common variation in gene sequences is neutral rather than adaptive

Question 4

Neutralists arguments

Answer 4

See OneNote

Most molecular variation that is fixed:
- is neutral and therefore evolution is governed by genetic drift

Accepts that deleterious mutations are purged from the mutation, negative selection
Accepts that there is SOME positive selection
BUT of all the variation that gets fixed, MOST of the variation is neutral, has no consequences

Question 5

Selectionist

Answer 5

Adaptive evolution explains much of the differences between species and much of the variation within species

MOST nucleotide variation is adaptive due to positive selection
MOST variation within population is affected by selection e.g. balancing selection - sickle cell anaemia

Question 6

Null Hypothesis

Answer 6

the neutral model provides the framework for molecular evolutionary studies often treated as the null hypothesis

Question 7

Neutral model

Answer 7

See OneNote

s = 0
probability of fixation = 1/(2N)
N = population size

fixation rate = mutation rate (at neutral sites)

Question 8

Mutations arise by

Answer 8

1. damage of molecular structure e.g. radiation, mutagenic compounds
2. failure of repair mechanisms to restore DNA to original state
3. misincorporation during DNA replication
4. TE insertion
5. unequal crossing over/segregation problems

Question 9

How do you calculate the mutation rate?

Answer 9

See OneNote

1. mutation accumulation experiment, direct calculation
2. estimating mutation rate from divergence data (as neutral model says fixation rate = mutation rate)

Question 10

How do you calculate the mutation rate - neutral model

Answer 10

See OneNote

• neutral model relates polymorphism to divergence
• as fixation rate = mutation rate, we can calculate mutation rate by looking at the divergence of neutral sites between species
• mutation rate can be estimated from divergence at a neutral locus

d = nd/n
d = divergence
nd = number of differences
n = length of locus 

rate = d/2T (as 2 lineages)

Question 11

nd/n

Answer 11

See OneNote

becomes an underestimate of number of changes when there’s parallel changes or revertants

d = number of mutations observed
k = number of mutations that actually occurred 

if all bases occur at an equal frequency then d approaches 0.75

Question 12

Jukes and Cantor Model

Answer 12

Assumes all changes are equally likely BUT there are more transitions than transversions

See FORMULA on OneNote

Question 13

Kimura’s 2-parameter model

Answer 13

See OneNote diagram

Allows transversions and transitions to happen at different rates
- more sophisticated models could have 12 parameters

Question 14

Drosophila parameters

Answer 14

See OneNote

• 6 parameters is appropriate

Question 15

Mammalian Genomes CpG

Answer 15

See OneNote
- deficient in 5’ CpG 3’ di-nucleotides and are enriched for TpG (and their complement CpA)
Because…
- CpG often methylated, 5-methyl cytosine can be deaminated to get thymidine therefore CG => TG occurs often

Methylation effects mutational biases

Flanking sites affect mutation frequency

Question 16

Mammalian mutation rates

Answer 16

See OneNote diagram

• composition does effect mutation rate
• mutation rates differ across regions of the genome

Question 17

Different species have different mutation rates

Answer 17

• point mutations occurred twice as frequently in rodents than humans
• deletions occur more frequently than insertions
• deletions were bigger than insertions

Question 18

How long will it take to lose half a pseudogene?

Answer 18

See OneNote

• Accumulating deletions, will get shorter over time, can calculate half life
• there are ancestral pseudogenes conserved between mice and humans