Mutations Flashcards
What is the raw material of evolution?
mutations
T or F: evolution or variation still occurs without mutations
false
Are mutation rates high or low? Does this mean that mutations can act alone to support evolution?
mutation rates really low
would be too slow to act alone
requires other forces like natural selection
What other forces, aside from mutations, can speed up evolution?
natural selection
gene flow
What would happen if mutation rates were really high?
there would be a lot more prevalent harmful mutations
changes would be occurring more rapidly
What are the two basic types of mutations (one contributes to organismal fitness and one is passed on through generations)?
germline (inherited)
somatic
Where do mutations come from?
DNA replication errors, DNA damage, and improper DNA repair
What are the 3 kinds of mutations?
- Point mutations (synonymous, nonsynonymous)
- insertions and deletions (indels)
- inversions and large chromosomal mutations
What are the 2 kinds of point mutations? Give an example
non-synonymous and synonymous
ex. SNPs
Can insertions or deletions vary?
Yes, in size = how much is inserted/gained/deleted
What is the result of nonsynonymous mutations?
nucleotide change that results in amino acid change - ie., they change the linear protein sequence
What is the result of synonymous mutations?
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
Which mutation type, synonymous or non-synonymous, result most often in phenotype or fitness changes?
nonsynonymous
T or F: synonymous mutations don’t change the phenotype or affect fitness
false! MOST do not, but SOME do
synonymous polymorphisms are MORE or LESS abundant than nonsynonymous?
more
Why are synonymous mutations more abundant than non-synonymous?
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
Synonymous or non-synonymous are more likely to be subjected to natural selection?
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
Are spontaneous mutations random? how do we define random?
Depends on how we define ‘random’
could be in terms of frequency of types of mutations, mutation rates, their effects on fitness
What aspects of spontaneous mutations are not random?
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
What aspects of spontaneous mutations are random?
how mutations affect fitness can be random because mutations cannot anticipate if they will become necessary/what they might be needed for = random
Describe the replica plating experiment of Esther and Joshua Lederberg (including organism involved and the nature of mutations)
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)
What did the Lederberg replication experiment demonstrate about mutations?
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)
How do the results of the Lederberg experiment relate to evolution?
the appearance of new mutations is a major cause of variation
creating variation gives natural selection something to act on
Why are new mutations difficult to measure directly?
because they occur so infrequently
What does it mean to measure the new mutation rate indirectly? how can it be done?
measure the variation that occurs in nature (persists) and use this to estimate rate of new mutations
What is a way to directly measure new mutation rates? give an example of an experiment
mutation accumulation experiments
ex. Ajie et al., looking at C. elegans (nematodes) and the phenotype: behavioural response to linoleic acid (repellent)
What is a mutation accumulation experiment?
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)
What were the results of Ajie’s experiment? How did they interpret it?
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)
What is a common trend in mutation accumulation lines? How is this relevant to evolution?
spontaneous mutations are often deleterious = fitness usually declines
evolution: most new mutations have negative effects on fitness
What do results from mutation accumulation lines allow us to do?
estimate spontaneous mutation rate and compare to what we see in nature (new mutations vs polymorphisms)
What did researchers find when they directly sequenced the genomes of D. melanogaster after mutation accumulation experiment?
there were some really large pieces of DNA lost including whole genes
How much genetic variation and what kind did the mutation accumulation experiment on D. melanogaster find?
very low mutation rates
mostly SNPs, small and large indels (point mutations = non-synonymous)
What does the D. melanogaster experiment tell us about mutations and how does it compare to what we see in nature?
nonsynonymous mutations (insertions and deletions) way more abundant in mutation accumulation experiments compared to what we see in nature
Why do we see a discrepancy between the mutations seen in the D. melanogaster experiment and in nature?
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
What happens on PopG if we simulate new mutations? How does this compare to what is seen in nature?
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?)
How can we use PopG to study mutations?
change the parameters of mutations from A to a and/or a to A
What does it mean if you change the mutation rate parameter in PopG to be greater than 0?
adding a continuous, but small, rate of mutation from A to a (or a to A)
What happens if you change the rate of mutation from A to a to 0.5 on PopG?
over a short period of time, the A allele will be lost and a becomes fixed (quick decline of A)
What happens when the mutation rate for A to a becomes larger?
larger A to a = A is lost faster
Do mutation rates vary? if so, why?
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
What are some non-genetic factors affect mutation rate?
environment (exposure to mutagens)
sex
age
species
Give an example of mechanistic vs evolutionary reasons mutation rates can vary?
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
Explain how the mutation rate itself can evolve
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)
How did researchers of the CEPH/Utah study measure spontaneous mutation rate? results?
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
What were some of the major findings of the CEPH/Utah study?
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)
What is Drake’s rule?
mutation rate is inversely related to genome size
= mutation rate is higher in smaller genomes
ex. microbes have high mutation rate
What are some possible explanations for why Drake’s rule is consistent in microbes?
smaller genome, less time to replicate = more replication = more mutation
may not have proofreading mechanisms for replication
smaller genomes may have higher transcription rates
How does the ribavirin case relate to Drake’s rule?
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
Why do viruses tend to have high mutation rates?
to generate variation and evolve faster to overcome hosts
What is ribavirin? what is its mode of action?
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
How does ribavirin cause lethality in viruses?
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
What is the effect of increasing mutations in the poliovirus?
can viruses evolve resistance to ribavirin? if so, what’s the mechanism?
yes, it is caused by a single non-synonymous mutation in poliovirus RNA-dependent RNA polymerase
how many mutations are necessary to evolve resistance to ribavirin?
just one mutation, the nonsynonymous mutation
are the resistance mutations synonymous or non-synonymous?
non-synonymous
under what conditions does a ribavirin-resistant poliovirus have higher fitness than wildtype poliovirus?
when studied individually
the ribavirin-resistant poliovirus has higher fitness because of its replication fidelity and lower mutation rate than the WT
under what conditions does a ribavirin -resistant poliovirus have lower fitness than wildtype poliovirus?
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
if viruses can evolve resistance to ribavirin, why don’t we see these viruses in nature?
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
how does studying ribavirin help us understand the high mutation rates of RNA viruses?
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
How does the ribavirin resistance relate to alleles, natural selection, or selection coefficients?
an INDIRECT consequence of high mutation rates could be that it leads to some advantageous genetic variation
How can RNA viruses with high mutation rates be connected to the spandrels of San Marco?
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
