WEEK 12: HUMAN EVOLUTIONARY GENETICS Flashcards
Does human evolution have a direct impact on disease.?
-yes
Can we use models to stimulate the outcomes of evolutionary processes?
-YES
What does fixation mean in a population?
- 100% frequency allele
What does a loss in the population mean?
- 100% lost allele
Is TIME to fixation dependent on the population size?
- YES
- Genetic drift works much faster in small populations than large populations
Does genetic drift work much faster in small or large populations?-
- SMALL
Do neutral alleles have to eventually become fixed or lost?
- YES
What is the probability of fixation of a neutral INDEPENDENT on?
- Population size
What is the probability of fixation of a neutral allele equal to?
- Its current frequency
How do new neutral alleles arise?
-De Novo mutations.
Are some genetic variants more likely to be neutral than others?
- YES
What can we assume most 4-fold redundant sites are?
- Selective neutral
What is required for new variation in the population?
- De novo (spontaneous) mutations
Does the rate at which we get new mutations into the population vary across each species?
- YES
Why is a selection not effective in small populations?
- Because the sampling error is very large due to randomness and this is stronger than selection.
Is there any recombination between lineages for cancer?
- NO
- Because it is a somatic disease
What are cancer divisions called and why?
- Called clonal expansion because they spread from mitotic divisions and shares characteristics with bacterial evolution
In the Tibetan case study, how were the 5 SNPs most likely introdcued into the population?
- By gene flow
Can evolution happen WITHOUT genetic variation?
- NO
How we can use simple models to study complex systems:
- Models make studying populations easy to deal with
- The models portray the idealised population
- We COMPARE THIS to the “null” model to REALITY –> determine if the population we are observing is different from the null
What are the five assumptions of the Wright-Fisher model?
Haploid (each individual has only one copy of its genetic information)
Constant population size
No mating (just asexual clonal reproduction)
Discrete generations an entire population is replaced by its offspring in a single generation
Genes are transmitted to the next generation by sampling with replacement
NO SELECTION OR MUTATION
How do we stimulate the production of the next generation?
-Sampling with REPLACEMENT so that the Frequency of the distribution is unchanged
What is the situation if the population is very SMALL????(frequency of distribution)
- Individual sample could vary a lot vary a lot from its source population
- Random chance will play a bigger role because of LESS sampling
Have 10 Wright-Fisher simulations at different population sizes N=10, N=100 and N=1000.
For which population size was there the largest change in frequency b/w generations?
N=10
Have 10 Wright-Fisher simulations at different population sizes N=10, N=100 and N=1000.At which population size did fixation or loss happen more quickly?
-N=10 because it has the LARGEST VARIATION
Have 10 Wright-Fisher simulations at different population sizes N=10, N=100 and N=1000. Given a starting frequency of 0.5, is an allele more likely to fix in a small or large population?
- NEITHER
- Would fix more quickly in a small population however given enough TIME, any allele that is neutral will be fixed or lost
What is time to fixation dependent on?
- Population size –> genetic drift works much faster in small than large populations
What is the probability of fixation of a new neutral allele?
-1/N
As the population size (N) increases, the probability of a newly arising neutral allele fixing_______ proportionally.
- Decreases proportionally
Are missense mutations, frameshift mutations, and nonsense mutations of equal likelihood to occur?
- NO
- Missense mutations are NOT as likely to occur
- Nonsense and frameshift mutations are much more likely to occur
What is an example of a synonymous substitution in terms of nomenclature?
- 2/4 possible substitutions at the third site are synonymous, therefore this is a 2 fold synonymous site
What is the probability of fixation of a neutral allele independent on?
Population size –>equals the current frequency of that allele
What do new mutations enter the population at?
- mutation rate U
The number of mutations entering a diploid population :
- 2NU
The chance that any of these will go to fixation is:
The chance that any of these will go to fixation is: ½ N
So the EXPECTED number of mutations that we expect to FIX every generation is:
½ N x 2NU
Because ½ x 2= 1 the expected number of mutations we expect to fix every generation= (also what is this the basis of)
mutation rate U
- The molecular clock
What is the molecular clock basis?
-Can figure out how long two species have been different by counting the neutral differences b/w them (comparing DNA sequences)
How does the molecular clock work? (3 steps)
- Get DNA sequences of the species that you want to compare
- Count the number of neutral differences between the two DNDA sequences
- Find a way to calibrate the number of mutations with time
- 4-fold synonymous sites are our best guess about what a neutral mutation is
What is fitness?
- The capacity to contribute offspring to the next generation (DO NOT SAY SURVIVAL OF THE FITTEST)
e. g. Individual with HIGH fitness contributes more offspring than average to the next generation
Examples of how a beneficial allele spreads through a population: (3)
- Peppered moth
- Selective predation
- Pesticide resistance in insects
WHAT IS THE SELECTION COEFFICIENT (S)?
-The measure of the strength of selection acting on a genotype (aka the slope of a graph)
What is the time to fixation proportional to ?
- The strength of selection
mutation with twice the “s” (2S) will approx.. take____
½ the time to fix!
How do we calculate fitness?
-By measuring the CHANGE in frequency over a number of generations –>time to fixation is PROPORTIONAL to the strength of selection–> so mutation with twice the “s” will take half the time to fix
Which factors can modify the environment thus reducing the action of selection?
- Enzyme replacement (insulin for type I diabetes and clotting factors for Hemophilia)
- Antibiotics
- Sanitary living conditions
- Detection of heart and vascular defects
- Surgery
- Fixing of optical disorders
STEPS IN THE EVOLUTION OF CANCER: (4 STEPS)
- Growth of cells initially repressed. Driver mutation occurs in ONE cell that allows escape from the growth repressors
- Secondary mutations occur –> few will drive further adaptation (increase in growth rate or capacity to spread)
- Next, chemotherapy is applied to the cancer, drastically reducing population size
- Finally, in this case one cell carries a mutation that confers RESISTANCE to the drug used for chemotherapy
What are the mutations that drive cancer evolution called?
“Driver” mutations
How do we identify “driver” mutations in complex sequence data?
- Whole genome (or WES) of cancers
- Genomes of tumours found to contain 10 000 mutations (10s of 1000s) bc. the cancer cells have HIGH mutation rates
What is parallel evolution in terms of cancers?
- If you look at many tumours that have been treated with the SAME drug; you should see that the SAME mutations drive resistance
- Also genes that are present in genomes of a cancer more often than expected by chance (BRCA1 higher mutation rate)
What is the general definition of parallel evolution?
-The INDEPENDENT evolution of the SAME trait, or the fixation of mutations in the same gene (even if they were genetically different, they evolve from the SAME selective pressures)
What do the Tibetans have that makes them better adapted to higher altitudes?
- 5 SNPs in the EPAS1 gene causing REDUCED function of the EPAS1 protein (40% have it)
