WEEK 12: HUMAN EVOLUTIONARY GENETICS

Question 1

Does human evolution have a direct impact on disease.?

Answer 1

-yes

Question 2

Can we use models to stimulate the outcomes of evolutionary processes?

Answer 2

-YES

Question 3

What does fixation mean in a population?

Answer 3

• 100% frequency allele

Question 4

What does a loss in the population mean?

Answer 4

• 100% lost allele

Question 5

Is TIME to fixation dependent on the population size?

Answer 5

• YES

- Genetic drift works much faster in small populations than large populations

Question 6

Does genetic drift work much faster in small or large populations?-

Answer 6

• SMALL

Question 7

Do neutral alleles have to eventually become fixed or lost?

Answer 7

• YES

Question 8

What is the probability of fixation of a neutral INDEPENDENT on?

Answer 8

• Population size

Question 9

What is the probability of fixation of a neutral allele equal to?

Answer 9

• Its current frequency

Question 10

How do new neutral alleles arise?

Answer 10

-De Novo mutations.

Question 11

Are some genetic variants more likely to be neutral than others?

Answer 11

• YES

Question 12

What can we assume most 4-fold redundant sites are?

Answer 12

• Selective neutral

Question 13

What is required for new variation in the population?

Answer 13

• De novo (spontaneous) mutations

Question 14

Does the rate at which we get new mutations into the population vary across each species?

Answer 14

• YES

Question 15

Why is a selection not effective in small populations?

Answer 15

• Because the sampling error is very large due to randomness and this is stronger than selection.

Question 16

Is there any recombination between lineages for cancer?

Answer 16

• NO

- Because it is a somatic disease

Question 17

What are cancer divisions called and why?

Answer 17

• Called clonal expansion because they spread from mitotic divisions and shares characteristics with bacterial evolution

Question 18

In the Tibetan case study, how were the 5 SNPs most likely introdcued into the population?

Answer 18

• By gene flow

Question 19

Can evolution happen WITHOUT genetic variation?

Answer 19

• NO

Question 20

How we can use simple models to study complex systems:

Answer 20

• 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

Question 21

What are the five assumptions of the Wright-Fisher model?

Answer 21

 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

Question 22

How do we stimulate the production of the next generation?

Answer 22

-Sampling with REPLACEMENT so that the Frequency of the distribution is unchanged

Question 23

What is the situation if the population is very SMALL????(frequency of distribution)

Answer 23

• Individual sample could vary a lot vary a lot from its source population
• Random chance will play a bigger role because of LESS sampling

Question 24

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?

Answer 24

N=10

Question 25

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?

Answer 25

-N=10 because it has the LARGEST VARIATION

Question 26

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?

Answer 26

- NEITHER - Would fix more quickly in a small population however given enough TIME, any allele that is neutral will be fixed or lost

Question 27

What is time to fixation dependent on?

Answer 27

- Population size --> genetic drift works much faster in small than large populations

Question 28

What is the probability of fixation of a new neutral allele?

Answer 28

-1/N

Question 29

As the population size (N) increases, the probability of a newly arising neutral allele fixing_______ proportionally.

Answer 29

- Decreases proportionally

Question 30

Are missense mutations, frameshift mutations, and nonsense mutations of equal likelihood to occur?

Answer 30

- NO - Missense mutations are NOT as likely to occur - Nonsense and frameshift mutations are much more likely to occur

Question 31

What is an example of a synonymous substitution in terms of nomenclature?

Answer 31

- 2/4 possible substitutions at the third site are synonymous, therefore this is a 2 fold synonymous site

Question 32

What is the probability of fixation of a neutral allele independent on?

Answer 32

Population size -->equals the current frequency of that allele

Question 33

What do new mutations enter the population at?

Answer 33

- mutation rate U

Question 34

The number of mutations entering a diploid population :

Answer 34

- 2NU

Question 35

The chance that any of these will go to fixation is:

Answer 35

The chance that any of these will go to fixation is: ½ N

Question 36

So the EXPECTED number of mutations that we expect to FIX every generation is:

Answer 36

½ N x 2NU

Question 37

Because ½ x 2= 1 the expected number of mutations we expect to fix every generation= (also what is this the basis of)

Answer 37

mutation rate U | - The molecular clock

Question 38

What is the molecular clock basis?

Answer 38

-Can figure out how long two species have been different by counting the neutral differences b/w them (comparing DNA sequences)

Question 39

How does the molecular clock work? (3 steps)

Answer 39

1. Get DNA sequences of the species that you want to compare 2. Count the number of neutral differences between the two DNDA sequences 3. 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

Question 40

What is fitness?

Answer 40

- 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

Question 41

Examples of how a beneficial allele spreads through a population: (3)

Answer 41

- Peppered moth - Selective predation - Pesticide resistance in insects

Question 42

WHAT IS THE SELECTION COEFFICIENT (S)?

Answer 42

-The measure of the strength of selection acting on a genotype (aka the slope of a graph)

Question 43

What is the time to fixation proportional to ?

Answer 43

- The strength of selection

Question 44

mutation with twice the “s” (2S) will approx.. take____

Answer 44

½ the time to fix!

Question 45

How do we calculate fitness?

Answer 45

-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

Question 46

Which factors can modify the environment thus reducing the action of selection?

Answer 46

- 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

Question 47

STEPS IN THE EVOLUTION OF CANCER: (4 STEPS)

Answer 47

1. Growth of cells initially repressed. Driver mutation occurs in ONE cell that allows escape from the growth repressors 2. Secondary mutations occur --> few will drive further adaptation (increase in growth rate or capacity to spread) 3. Next, chemotherapy is applied to the cancer, drastically reducing population size 4. Finally, in this case one cell carries a mutation that confers RESISTANCE to the drug used for chemotherapy

Question 48

What are the mutations that drive cancer evolution called?

Answer 48

"Driver" mutations

Question 49

How do we identify “driver” mutations in complex sequence data?

Answer 49

- 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

Question 50

What is parallel evolution in terms of cancers?

Answer 50

- 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)

Question 51

What is the general definition of parallel evolution?

Answer 51

-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)

Question 52

What do the Tibetans have that makes them better adapted to higher altitudes?

Answer 52

- 5 SNPs in the EPAS1 gene causing REDUCED function of the EPAS1 protein (40% have it)