Human Evolutionary Genetics

Question 1

Forces of evolution

Answer 1

The forces of evolution: Selection, drift, migration, mutation shape genetic variation.

Question 2

We use simple models to study complex systems.

How do we actually use a model?

Answer 2

Null model is random and unbiased model
• Models make studying populations tractable. make a series of assumption
• Models portray an idealised population.
How do we actually use a model?
• Compare model to data from natural populations.
compare the null model with the observed data - if different then one of the assumption we made is not true.
• Simulate evolution through time.

Question 3

Wright-Fisher Model - what are the Assumptions used to build the null model for Wright-Fisher Model

Answer 3

• 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) each generation is different from the previous one
• Genes are transmitted to the next generation by sampling with
replacement.
• No selection or mutation

Question 4

what is a neutral allele ?

Answer 4

a single polymorphism that does not experience selection).

a form of a gene that when carried in an organism in no way alters the FITNESS of that individual to survive and reproduce. silent mutation

Question 5

formalization of the time now

Answer 5

t = now
t+1 next generation
T+2

Question 6

How do we model the next three generations of a neutral allele. - big population
In big population the allele frequency would be the ——- across generations

Answer 6

sampling with replacement
hence allele frequency of the first generation will be the same of the previous generation e.g. F(t) blue = 0.5 and f(t+1) blue = 0.5
if the population is really big the allele frequency would be the same across generations if no selection or evolutionary forces are acting

Question 7

What happens to allele gene frequency if the population is too small

Answer 7

If the population is small, an individual sample could vary a lot from its source population.

the predicted average frequency is still the
same… but This is only true if you repeat the experiment many times over and average …each sample could have a very different outcome

e.g. population t f(t) blue = 0.5
sample 1 : f(t+1) blue = 0.9
sample 2 : f(t+1) blue = 0.3

Question 8

what is genetic drift

Answer 8

if the population size is not very large genotype and allele frequency can change due to random sampling effect

Question 9

what happens to a neutral allele in population across generations?

Answer 9

• Neutral alleles must eventually become fixed or lost.
• Time to fixation is dependent on population size. In other words,
genetic drift works much faster in small populations than large
populations (remember bottle necks and founder effects)

Question 10

Probability of the fixation time of a neutral allele is independent on—-

Answer 10

• Probability of fixation of a neutral allele is independent on population size.
The probability of fixation of a neutral allele is its current frequency
e.g. current frequency 50%
probability of fixation 50%

Question 11

As Population size (N) increases the probability of a newly arising
neutral allele fixing ——

Answer 11

decreases proportionally.
The probability of fixation of a
new neutral allele = 1/N
e.g. one individual in population of 10 has new allele
the probability of fixation of that new allele (and allele frequency ) is 1/10 =0.1

Question 12

Effect of mutations

Answer 12

some mutations can change the protein sequence then smaller subset can change the phenotype and even smaller subset can change the fitness of the organism

mutation with neutral selection -1.5 –> +1.5
Positive mutation +1.5 ….

Question 13

how can we make a good guess of which substitutions will be neutral

Answer 13

by using the genetic codes

We can assume that most four-fold redundant sites are selectively neutral.

Question 14

Synonymous substitution

Answer 14

a nucleotide substitution that does not change the amino acid in the protein is called a synonymous substitution
GAG –> GAA Glutamate

Question 15

Non-synonymous substitution

Answer 15

A nucleotide substitution that changes the corresponding amino acid in the protein is called a nonsynonymous substitution
GAG–> GAU Aspartate

Question 16

what does it mean by 2 fold synonymous site

Answer 16

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

for valine
4/4 possible substitutions at the third site are
synonymous, there fore this is a 4 fold
synonymous site

Question 17

is the following true or false?

eventually all variants would be fixed or lost

Answer 17

false
,mutation resupplies populations with genetic variation.
• Mutation rates for a genome might seem high, but for any given locus in
the genome, mutation rates are low~ 10-7-10-9.
• Each individual in a population is a new opportunity for mutation to
occur!

Question 18

Mutation rates and rate of substitution

Answer 18

• New mutations enter the population at a mutation rate U
• U is the genomic mutation rate, or the expected number of mutation
to occur in each new offspring.
• Examples, for humans U is about 100, and for E. coli U is about 0.003

Question 19

The number of mutations entering a diploid population =

Answer 19

= 2NU

[2 (diploid)] multiplied by [population size] multiplied by [mutation rate]

Question 20

What is the probability of fixation of a neutral allele?

Answer 20

= 1/2N

Question 21

the expected number of mutations

we expect to fix every generation

Answer 21

= the mutation rate U

Question 22

How does a molecular clock work?

Answer 22

1. Get DNA sequences of the species that you want to compare.
2. Count the number of neutral differences between the two DNA sequences. (4 folds synonymous site)
3. Find a way to calibrate the number of mutations with time.

Question 23

why molecular clock may not be right?

Answer 23

• Mutation rates could have changed If U = ½, then it should take twice
as long to accumulate mutations

Generation times- the per generation mutation rate might be the same, but since
humans and chimps have longer generations times, the clock would slow down

Population size: prolonged periods of small population size can cause to increased variation of the molecular clock.

Question 24

What is fitness?

Answer 24

• Fitness is the capacity to contribute offspring to the next generation.
• An individual with a high fitness contributes more offspring than
average to the next generation.

Question 25

How does a beneficial allele spread through a population?

Answer 25

A new mutation starts a frequency of 1/N.
• If it is beneficial, it will increase in frequency with every generation
When the frequency goes to 1, it is said to have fixed, or substituted in the population.

Question 26

Selection coefficient

Answer 26

Is the measure of the strength of selection acting on a genotype

Question 27

Time Fixation of beneficial mutations is dependent on

Answer 27

s = x

Time to fixation is proportional to the strength of selection
• So, a mutation with twice the “s” will approximately take half the time to fix.

Question 28

how can w calculate fitness?

Answer 28

We can calculate fitness by measuring the change in frequency over a number of generations

Question 29

deleterious mutation are acted by

Answer 29

purifying selection
deleterious mutation happening close to beneficial mutation are linked. as the beneficial mutation spread the deleterious mutating increases with it
or a positive mutation can turn into deleterious in different environment

Question 30

How can human reduce the action of selection

Answer 30

Humans modify their environment, 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

those deleterious mutations can be neutral then

Question 31

The capacity for selection to discern between the fitness effects of alleles also depends

Answer 31

on population size.
If s is smaller than 1/N, then natural selection cannot distinguish
between that allele and a neutral allele

If N = 100
1/N = 0.01
Therefore all alleles with a selective effect less
Than 0.01 are seen as “neutral” by natural selection

Question 32

Why is a selection not effective in small populations?

Answer 32

In small populations, selection is less effective, and the relative importance of genetic drift is higher because deleterious alleles can become more frequent and ‘fixed’ in a population due to chance.

Question 33

long term experimental evolution in E. coli

Answer 33

• Daily cycle of grow and dilute.
• Started by Professor Richard Lenski in 1987, now ~67,000 generations of evolution have accumulated.
• We did an experiment where we sequenced all of the populations
at different time points evolution, to study the mutations.
Highlighting mutations in pykF – mutations we know to be beneficial.
some genes acquired the mutation again and again

Question 34

The evolution of cancer

Answer 34

• The mutations that drive cancer evolution are called “driver”
mutations instead of beneficial mutations.
• Cancer is a somatic disease, there is no recombination between lineages.
• Since cancer spreads from a single cell by mitotic (not meiotic) cell divisions, it is called a “clonal expansion” and shares characteristics with bacterial evolution.

Question 35

The evolution of cancer

Answer 35

1. Initially growth of cells is repressed. A driver mutation occurs in one cell that allows escape from the growth repressors.
2. Secondary mutations occur, a few will drive further adaptation (increase 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 carry’s a mutation that confers resistance to the drug used for chemotherapy.

Question 36

How to identify the “driver” mutations in complex sequence data?

Answer 36

• We need to know this to develop strategies that account for tumour evolution in
our treatments.
• Parallel evolution. If you look at many tumours that have been treated with the
same drug, you should see the same mutations drive resistance.

Question 37

Parallel evolution

Answer 37

• Parallel evolution is the independent evolution of the same trait, or the fixation of mutations in the same gene in different population.
- acted by similar selective pressure
• This happens in evolution experiments, such as mutations in the pykF gene that evolved in
every population.

Question 38

What beneficial mutations have you heard of

in recent human evolution?

Answer 38

Lactase	persistence	(LCT	gene)
• Tooth	number

Question 39

Case study: EPAS1

Answer 39

• Tibetan’s are better adapted to high altitudes. They have a range of adaptations.
One of these is a set of five snp’s in the gene EPAS1.
The fitness effect of an allele depends on environment:
High Altitude: EPAS1 allele has a high fitness
Low Altitude: EPAS1 allele might have a low fitness effect
ow Altitude: EPAS1 allele might have no fitness effect - This would explain why the EPAS1 allele is low in the Han Chinese populatio