10 - Population Genetics

Question 1

What is a transition? How common are these? Why?

Answer 1

Substitution of a pyrimidine (C or T) by a pyrimidine, or a purine (A or G) by a purine.

Twice as common as a transversion due two high rate of C > T transitions since methylated cytosines can become spontaneously deaminated to T.

Question 2

What is a transversion?

Answer 2

Pyrimidine for a purine or a purine for a pyrimidine.

Question 3

What type of changes due transitions usually lead to? What about transversions?

Answer 3

Transitions: lead to synonymous changes, amino acid stays the same.

Transversions: lead to non-synonymous, amino acid changes.

Question 4

What is required for a mutation to be passed on to the offspring?

Answer 4

It has to be a germline mutation.

Question 5

What factors influence whether or not a germline mutation will increase in the population?

Answer 5

Selection, genetic drift, and inbreeding.

Question 6

What is genetic drift?

Answer 6

The random process in which some mutations are transmitted and ride in frequency in the general population while others disappear frequently.

Question 7

What does it mean when a mutation is under selection?

Answer 7

That the mutation effects the relative fitness of an individual (ie the ability to have children) then it’s under selection.

Can be negative selection or positive.

Question 8

What is negative selection?

Answer 8

Aka purifying selection.

Reduces the allele frequency of the mutation in the population (ie allele wont be transmitted since individuals that would transmit the allele have reduced reproductive success).

Question 9

What is positive selection?

Answer 9

Mutations that increase reproductive fitness will increase in allele frequency over time.

Question 10

How common is it for diseases to be under selection? Give an example to support this point.

Answer 10

Vast majority of mutations not under selection because they do not affect reproductive fitness.

Even Alzheimer’s disease is not selected against because individuals carrying the disease are healthy during reproductive years

Question 11

Why does selection rarely completely eliminate a deleterious allele?

Answer 11

The lower the frequency of deleterious allele in a pop, the more frequently it occurs in heterozygotes compared to homozygotes.

This makes selection against it difficult as freq diminishes b/c the less frequent it becomes, the greater percentage of what is left is protected in the heterozygous state.

Question 12

What occurs when there’s migration and mating between two sub-populations where the frequency of the allele is different?

Answer 12

There will be an altered allele frequency in the resulting offspring population, and potentially an increase in the variation of the gene.

Question 13

The change in frequency and variation following migration and mating between two sub-populations is influenced by what?

Answer 13

The size of the population over successive generations.

Question 14

What does inbreeding (mating of close relatives) within a population lead to?

Answer 14

Complete homozygosity, which reduces the overall variation in the population.

Increases chance of recessive disorders in the offspring.

Question 15

How can allele frequency within a population be calculated? Use Aa as an example for the first and subsequent generations.

Answer 15

Frequency of A in original pop = p = f(AA) + 1/2 f(Aa)

Frequency of a in original pop = q = f(aa) + 1/2 f(Aa)

For the subsequent generations allele frequency is:

p^2 = f(AA) 
2PQ = f(Aa)
q^2 = f(aa)

(these should add up to 1 and the allele frequencies should NOT change over time).

Question 16

What assumptions are made in order estimate allele frequency in a population (ie for the equilibrium to remain in effect)?

Answer 16

No mutations occuring, thus no new alleles enter the pop.

No gene flow occurs, no migration.

Random mating must occur.

Population must be large so there’s no genetic drift.

No selection.

Question 17

What does the Hardy Weinberd Equilibrium model state?

Answer 17

That if no evolution is occurring, then an equilibrium of allele frequencies will remain in effect in each succeeding generation of sexually reproductive individuals.

Question 18

If the hardy-weinberg equilibrium model is unachievable, why the hell do we use it?

Answer 18

It serves as a baseline of what to expect and can be used for comparison.

If genotypes differ from what we would expect under equilibrium, we can assume that one or more of the assumptions are being violated and investigate what might be occurring.

Question 19

What is an example of a disease-causing mutation whose frequency departs from HW equilibrium?

Answer 19

Sickle cell anemia.

Instead of remaining at low frequency, allele frequency of the mutation began to increase.

Question 20

What caused the allele frequency of the mutation causing sickle-cell to increase and thus break HW equilibrium?

Answer 20

It was positively selected for because in subsaharan Africa it conveyed a reproductive advantage against malaria.

Question 21

According to HW, for any p + q, genotype frequencies after one generatoin of random mating will equilibrate according to ______?

Answer 21

P^2 + 2pq + q^2

Question 22

What is linkage disequilibrium?

Answer 22

Non-random association of SNP alleles at closely linked loci.

Question 23

Describe linkage equilibrium for an individual who is heterozygous for two neighboring biallelic SNPs?

Answer 23

There are 4 possible combinations of alleles that can be present on each of the two chromosome copies.

Equilibrium would mean that all 4 combinations are possible and present in the population at significant frequencies.

Question 24

Describe linkage disequilibrium (LD) for an individual who is heterozygous for two neighboring biallelic SNPs?

Answer 24

Not all combinations are found in the population, and rather, certain allelic combinations are more likely.

This means that they are non-randomly associated and some SNPs are more common than others.

Question 25

How is the extent of linkage disequilibrium between any two SNPs determined?

Answer 25

By the extent of recombination over generations.

Linkage disequilibrium declines with increasing distance between SNPs; However, human genome is block like and has regions (LD blocks) of strong LD with each other near regions of low LD.

Question 26

What is the average length of LD blocks in individuals of Northern European descent? What about for those with African descent?

Answer 26

~60 kb for northern europeans

~6 kb for africans

Question 27

What are haplotypes? How many possible haplotypes for a given number of SNPs?

Answer 27

Patterns of SNP alleles on a single chromosome (haploid) in a block.

For any number of SNPs (n) the number of possible haplotypes is 2^n (deviation from this number indicates linkage disequilibrium).

Question 28

What are regions of high LD are characterized by what?

Answer 28

Preferential arrangement (association) of SNP alleles on a chromosome, leading to significantly smaller number of haplotypes in these regions.

SNPs called tagSNPs.

Question 29

If you knew for a particular individual what haplotype his genome has for any particular region of high linkage disequilibrium (LD), what else would we be able to infer? What is the benefit of this?

Answer 29

The genotypes for ALL SNPs across this region.

In regions of high LD, one only needs to genotype a small subset of SNPs that allow determination of the haplotypes present and all other SNP genotypes can be predicted.

Question 30

What is a Chi square test? How it is calculated? How do you know the degrees of freedom?

Answer 30

Used to test for significant departure from HW.

X^2 = sum of (O - E)^2 / E

Where:
O = observed allele frequency
C = expected allele frequency

DOF = n-1 where n is the number of different genotypes.