Mutations

Question 1

What is the raw material of evolution?

Answer 1

mutations

Question 2

T or F: evolution or variation still occurs without mutations

Answer 2

false

Question 3

Are mutation rates high or low? Does this mean that mutations can act alone to support evolution?

Answer 3

mutation rates really low
would be too slow to act alone
requires other forces like natural selection

Question 4

What other forces, aside from mutations, can speed up evolution?

Answer 4

natural selection
gene flow

Question 5

What would happen if mutation rates were really high?

Answer 5

there would be a lot more prevalent harmful mutations
changes would be occurring more rapidly

Question 6

What are the two basic types of mutations (one contributes to organismal fitness and one is passed on through generations)?

Answer 6

germline (inherited)
somatic

Question 7

Where do mutations come from?

Answer 7

DNA replication errors, DNA damage, and improper DNA repair

Question 8

What are the 3 kinds of mutations?

Answer 8

1. Point mutations (synonymous, nonsynonymous)
2. insertions and deletions (indels)
3. inversions and large chromosomal mutations

Question 9

What are the 2 kinds of point mutations? Give an example

Answer 9

non-synonymous and synonymous

ex. SNPs

Question 10

Can insertions or deletions vary?

Answer 10

Yes, in size = how much is inserted/gained/deleted

Question 11

What is the result of nonsynonymous mutations?

Answer 11

nucleotide change that results in amino acid change - ie., they change the linear protein sequence

Question 12

What is the result of synonymous mutations?

Answer 12

nucleotide change that does not result in an amino acid change (bc of the redundancy of the amino acid code) and therefore do not affect the linear protein sequence

Question 13

Which mutation type, synonymous or non-synonymous, result most often in phenotype or fitness changes?

Answer 13

nonsynonymous

Question 14

T or F: synonymous mutations don’t change the phenotype or affect fitness

Answer 14

false! MOST do not, but SOME do

Question 15

synonymous polymorphisms are MORE or LESS abundant than nonsynonymous?

Answer 15

more

Question 16

Why are synonymous mutations more abundant than non-synonymous?

Answer 16

on average, SM are much more likely to be silent and not affect phenotype and therefore less likely to have natural selection act on them to prevent them

Question 17

Synonymous or non-synonymous are more likely to be subjected to natural selection?

Answer 17

likely NS because they are less likely to cause silent mutations and more likely to affect phenotype

if there’s an affect on phenotype which has a difference in fitness, there’s something for natural selection to act on

Question 18

Are spontaneous mutations random? how do we define random?

Answer 18

Depends on how we define ‘random’

could be in terms of frequency of types of mutations, mutation rates, their effects on fitness

Question 19

What aspects of spontaneous mutations are not random?

Answer 19

some types of mutations occur more frequently than others (ex. transitions more common than transversions) = not random

some genes have higher mutation rates = not random

Question 20

What aspects of spontaneous mutations are random?

Answer 20

how mutations affect fitness can be random because mutations cannot anticipate if they will become necessary/what they might be needed for = random

Question 21

Describe the replica plating experiment of Esther and Joshua Lederberg (including organism involved and the nature of mutations)

Answer 21

organism: E. coli

replicated colonies on different petri dishes

expose each dish to a virus = the same colonies were resistant to the virus in all 3 dishes

this experiment demonstrates that mutations to provide E.coli with resistance were random (the mutation already existed in the colonies that survived exposure prior to being exposed)

Question 22

What did the Lederberg replication experiment demonstrate about mutations?

Answer 22

this experiment demonstrates that mutations to provide E.coli with resistance were random (the mutation already existed in the colonies that survived exposure prior to being exposed - mutation didn’t know it would become useful)

Question 23

How do the results of the Lederberg experiment relate to evolution?

Answer 23

the appearance of new mutations is a major cause of variation
creating variation gives natural selection something to act on

Question 24

Why are new mutations difficult to measure directly?

Answer 24

because they occur so infrequently

Question 25

What does it mean to measure the new mutation rate indirectly? how can it be done?

Answer 25

measure the variation that occurs in nature (persists) and use this to estimate rate of new mutations

Question 26

What is a way to directly measure new mutation rates? give an example of an experiment

Answer 26

mutation accumulation experiments

ex. Ajie et al., looking at C. elegans (nematodes) and the phenotype: behavioural response to linoleic acid (repellent)

Question 27

What is a mutation accumulation experiment?

Answer 27

use to study the effect of new mutations by comparing phenotype of descendants with the starting line

by selecting a random individual and breeding that individual and then selecting a random individual from the second generation and continuing it etc. and measuring the same phenotype across them all
- removes all factors except possible new mutations (no losses)

Question 28

What were the results of Ajie’s experiment? How did they interpret it?

Answer 28

there was a change in behaviour from starting line and descendants

decreased directness and speed moving away from repellent in descendants compared to parents

there’s a mutation change with fitness consequences over time (nothing else changes except the individuals being bred)

Question 29

What is a common trend in mutation accumulation lines? How is this relevant to evolution?

Answer 29

spontaneous mutations are often deleterious = fitness usually declines

evolution: most new mutations have negative effects on fitness

Question 30

What do results from mutation accumulation lines allow us to do?

Answer 30

estimate spontaneous mutation rate and compare to what we see in nature (new mutations vs polymorphisms)

Question 31

What did researchers find when they directly sequenced the genomes of D. melanogaster after mutation accumulation experiment?

Answer 31

there were some really large pieces of DNA lost including whole genes

Question 32

How much genetic variation and what kind did the mutation accumulation experiment on D. melanogaster find?

Answer 32

very low mutation rates

mostly SNPs, small and large indels (point mutations = non-synonymous)

Question 33

What does the D. melanogaster experiment tell us about mutations and how does it compare to what we see in nature?

Answer 33

nonsynonymous mutations (insertions and deletions) way more abundant in mutation accumulation experiments compared to what we see in nature

Question 34

Why do we see a discrepancy between the mutations seen in the D. melanogaster experiment and in nature?

Answer 34

most of the mutations seen in the experiment must be deleterious –> natural selection acts against them in nature which is why we see less of these mutations in nature

Question 35

What happens on PopG if we simulate new mutations? How does this compare to what is seen in nature?

Answer 35

When a new mutation is added to the popG simulation, over time, the allele that is being mutated (ex. A to a) is lost (a is lost, A becomes fixed)

this can differ from what we see in nature because natural selection might act on a deleterious mutation that is causing the loss of an allele (maybe?)

Question 36

How can we use PopG to study mutations?

Answer 36

change the parameters of mutations from A to a and/or a to A

Question 37

What does it mean if you change the mutation rate parameter in PopG to be greater than 0?

Answer 37

adding a continuous, but small, rate of mutation from A to a (or a to A)

Question 38

What happens if you change the rate of mutation from A to a to 0.5 on PopG?

Answer 38

over a short period of time, the A allele will be lost and a becomes fixed (quick decline of A)

Question 39

What happens when the mutation rate for A to a becomes larger?

Answer 39

larger A to a = A is lost faster

Question 40

Do mutation rates vary? if so, why?

Answer 40

yes

depends on the gene location, some parts of the gene are more or less likely to be mutated

random DNA damage, radiation, exposures to carcinogens/mutagens

some types of mutations are more common than others

other factors:
environment
sex
age
species

Question 41

What are some non-genetic factors affect mutation rate?

Answer 41

environment (exposure to mutagens)
sex
age
species

Question 42

Give an example of mechanistic vs evolutionary reasons mutation rates can vary?

Answer 42

some RNA viruses have high mutation rates due to having polymerases without proofreading systems - but many viruses have evolved this proofreading system for their polymerases

Question 43

Explain how the mutation rate itself can evolve

Answer 43

the speed of which mutations occur in an organism can vary and allow natural selection to act on the differences

Drake’s rule (pattern) - variation in mutation rate inversely correlated to genome size (ie., organisms with small genomes have higher rates of mutation)

Question 44

How did researchers of the CEPH/Utah study measure spontaneous mutation rate? results?

Answer 44

sequenced genome of the individuals in the pedigree dataset and tracked new mutations

found:
- higher mutation rates in males (related to how often sperm replicates)
- new mutations increased with parental age
- really low mutation rates (natural selection still occurring)
- most new mutations were point mutations

Question 45

What were some of the major findings of the CEPH/Utah study?

Answer 45

overall low mutation rate, mostly point

that there were higher mutation rates in males (sperm replication rate is very high)

new mutations increased with parental age (longer time to mutate)

Question 46

What is Drake’s rule?

Answer 46

mutation rate is inversely related to genome size

= mutation rate is higher in smaller genomes

ex. microbes have high mutation rate

Question 47

What are some possible explanations for why Drake’s rule is consistent in microbes?

Answer 47

smaller genome, less time to replicate = more replication = more mutation

may not have proofreading mechanisms for replication

smaller genomes may have higher transcription rates

Question 48

How does the ribavirin case relate to Drake’s rule?

Answer 48

ribavirin is a drug that acts against RNA viruses (ex. respiratory viruses, hep C, polio) and it’s a purine analog

without ribavirin, RNA viruses grow well
higher concentrations of ribavirin, the viruses are less successful

being a purine analog, ribavirin is incorporated into the virus’s genome during RNA synthesis and changes the amino acid sequence causing a lot of mutations

viruses have smaller genomes and tend to have higher mutation rates so they can have high variation and evolve faster to overcome their hosts

Question 49

Why do viruses tend to have high mutation rates?

Answer 49

to generate variation and evolve faster to overcome hosts

Question 50

What is ribavirin? what is its mode of action?

Answer 50

a resistance drug to RNA viruses (ex. polio, respiratory viruses)

acts as a purine analog and can be incorporated into the viruses genome as an adenine or guanosine during RNA synthesis

Question 51

How does ribavirin cause lethality in viruses?

Answer 51

when it’s incorporated into the genome it induces a lot of insertions and inducing mutations (ie., highly mutagenic) which mostly lead to the viruses death

Question 52

What is the effect of increasing mutations in the poliovirus?

Question 53

can viruses evolve resistance to ribavirin? if so, what’s the mechanism?

Answer 53

yes, it is caused by a single non-synonymous mutation in poliovirus RNA-dependent RNA polymerase

Question 54

how many mutations are necessary to evolve resistance to ribavirin?

Answer 54

just one mutation, the nonsynonymous mutation

Question 55

are the resistance mutations synonymous or non-synonymous?

Answer 55

non-synonymous

Question 56

under what conditions does a ribavirin-resistant poliovirus have higher fitness than wildtype poliovirus?

Answer 56

when studied individually

the ribavirin-resistant poliovirus has higher fitness because of its replication fidelity and lower mutation rate than the WT

Question 57

under what conditions does a ribavirin -resistant poliovirus have lower fitness than wildtype poliovirus?

Answer 57

when the viruses are exposed to each other, wildtype outcompeted the resistant type and was less pathogenic

resistant variant grew slower and had lower fitness

Question 58

if viruses can evolve resistance to ribavirin, why don’t we see these viruses in nature?

Answer 58

when they both exist together, the resistant variant grew slower than the WT and was outcompeted by the WT which is why we don’t see this mutation in the wild

Question 59

how does studying ribavirin help us understand the high mutation rates of RNA viruses?

Answer 59

high mutation rate of RNA viruses may be due to selection for rapid replication

when exposed together, the WT outcompeted the resistant variant because it replicated faster

even slightly increasing the mutation rate caused lethality

Question 60

How does the ribavirin resistance relate to alleles, natural selection, or selection coefficients?

Answer 60

an INDIRECT consequence of high mutation rates could be that it leads to some advantageous genetic variation

Question 61

How can RNA viruses with high mutation rates be connected to the spandrels of San Marco?

Answer 61

viruses evolve quickly, but there’s disadvantages to evolving too quickly (lethality)

so, having to keep up with hosts is likely not a correct hypothesis because we don’t see these mutations naturally