Population genetics

Question 1

What is population genetics?

Answer 1

Study of genetic diversity in biological populations, and of the processes that cause genetic diversity to change. Ultimately, population genetic processes underpin all phenomena in evolutionary biology.

Question 2

What happened in the 1930/40s?

Answer 2

Modern synthesis of Mendelian genetics and Darwinian natural selection.

Question 3

How can you measure genetic variation?

Answer 3

Genetic markers are genome regions that are useful for measuring and investigating genetic variation in populations.

Question 4

How have genetic markers progressed?

Answer 4

-human blood groups (1900) -allozymes (1966) -restriction fragment length polymorphisms (1971) -DNA sequencing (1977) -minisatellite and microsatellite DNA (1985) -single nucleotide polymorphism arrays (1999) -massively parallel pyrosequencing (2004)

Question 5

How do you measure genetic variation in a population?

Answer 5

How many organisms are heterozygous (carry 2 different alleles at a genetic locus) If the population is polymorphic (more than one allele commonly found at a genetic locus)

Question 6

Example of polymorphism?

Answer 6

Human Aldehyde Dehydrogenase (ALDH2) Found on chromosome 12, helps to breakdown alcohol Some Asian populations are polymorphic for ALDH2 - differs by 1 amino acid. ALDH2*2 homozygous individuals have almost no ALDH2 function and are must less likely to suffer from alcoholism, as alcohol makes them ill.

Question 7

Why is measure of heterozygosity useful?

Answer 7

It is equivalent to the probability that any two alleles randomly sampled from the population are different. It is greatest when there are many alleles, all at equal frequency. Values of h can be averaged across many loci to give average heterozygosity (H), which is equivalent to the proportion of loci expected to be heterozygous in an average individual.

Question 8

What is the most common type of genetic marker investigated?

Answer 8

DNA sequence variation.

As well as counting the number of distinct sequences we can calculate how many differences there are between the sequences.

Two common measures of sequence diversity are the proportion of segregating sites and the average pairwise differences

Question 9

Describe the Hardy Weinberg principle?

Answer 9

Blending of characteristics would gradually erode any phenotypic variation.
In the absence of any evolutionary force, Mendelian inheritance alone can maintain genetic diversity.
It is a null model - describes that state of world when nothing interesting is happening.

The frequencies of PP, PQ and QQ genotypes in the next generation are p2, 2pq and q2.
The principle extends to >2 alleles and to multiple loci that segregate independently.

Question 10

Assumptions of the Hardy Weinberg principle?

Answer 10

• Diploid organism with sexual reproduction
• Non-overlapping generations
• Infinite population size (no random genetic drift)
• Random mating (no inbreeding)
• Males and females have equal allele frequencies
• A closed population (no migration)
• No mutation
• No selection

Question 11

What does the Hardy Weinberg principle show?

Answer 11

In the absence of evolutionary forces…

• the predicted genotype frequencies are created after only one generation of random mating, regardless of the genotype frequencies in the parental generation.
• genotype frequencies are in equilibrium
• if the genotype frequencies in a real population differ from those predicted, then at least on evolutionary focus must be acting on the population.

Question 12

What is the source of DNA sequence variation?

Answer 12

Mutation.

Spontaneous rate of nucleotide mutation for cellular organisms is typically very low, between 10^-9 and 10^-11 changes per base pair per generation.

Virusses mutate much faster.

Other types of mutation (chromosomal change) may occur much more frequently.

Question 13

Equation for mutation?

Answer 13

If we have a locus with 2 alleles and no back mutation.

The frequency of P (from Q) after t generations…

U is the P to Q mutation rate.

With back mutation:
Pt = v / (u+v)
V is the Q to P mutation rate.

Question 14

Why is the mutation equation too simplified?

Answer 14

Many loci have more than 2 alleles.

Question 15

How does natural selection occur?

Answer 15

Organisms differ in their ability to survive and reproduce, in part due to genotype. Those alleles that enhance survival and successful reproduction in the current environment will contribute disproportionately to the next generation’s gene pool.
Repetition of this process leads to the positive selection of beneficial alleles, leading eventually to their fixation.

Question 16

What is the “current environment” for a single gene?

Answer 16

The outside world and also other genotypes that it shares a genome with.

Question 17

Define relative fitness?

Answer 17

The average number of offspring produced by individuals with a particular genotype relative to the number produced by individuals with another genotype.

One genotype gets given a fitness of 1 for simplicity.

Fitness of a new allele is expressed as a selection coefficient. This equals the fractional increase/decrease in fitness conferred by the allele compared to another.

S = 0.13 means a 13% greater fitness than the previous one.

Question 18

How fast can natural selection change allele frequencies?

Answer 18

Suppose q is the current freq of allele which has fitness (1+s) compared to allele p.

Change in q = spq
s - increase in fitness

Consequently…

1. Q increases when s is positive and decreases when s is negative
2. Greater absolute s values lead to faster allele frequency change
3. Allele frequency change is slower when p or q are rare and fastest when both 50%
4. Plots of allele frequency against time are sigmoidal (t on x axis and q on y axis)

Question 19

What is h?

Answer 19

Degree of dominance, varies from 0-1

Question 20

How does selection occur in diploids?

Answer 20

• If the selected allele is dominant, change is initially rapid but very slow as it nears fixation.
• A new, rare allele initially creates many heterozygotes. Selection can only favour these if the allele is dominant.
• Near fixation, dominance allows the less-fit allele to ‘hide’ in heterozygotes, making it difficult to remove.

Question 21

What are the three types of selection?`

Answer 21

Overdominant selection - phenotype of the heterozygote lies outside the phenotypical range of both homozygous parents.

Frequency-dependent selection - allele fitness is high when the allele is rare, low when common

Fluctuating selection - allele fitness depends on an aspect of the environment that is rapidly and constantly changing

Question 22

What happens if a deleterious mutation is slightly dominant?

Answer 22

There will be a massive drop in the observed frequency of the allele.

Question 23

How does recombination contribute to genetic diversity?

Answer 23

Creates new combinations of genetic diversity, including combinations very unlikely to be generated by mutation and selection alone.

Explaining the existence of recombination is an unsolved probem in evolutionary genetics. It is possible that it evolved to help organisms ameliorate the effects of deleterious mutations.

Question 24

What is Linkage Disequilibrium?

Answer 24

Used to study recombination. It reflects the degree of non random association between the alleles at two loci.

When alleles at the two loci are randomly associated, as if haplotypes were created by drawing alleles from a hat, then (fpa x fqb) = (fpb x fqa).

Hence linkage disequilibrium can be measured as the deviation, D, from this expectation: D = (fpa x fqb) - (fpb x fqa)

Better measures (e.g. D’) are created by taking allele frequencies into account.

Question 25

How can Linkage Disequilibrium be increased?

Answer 25

Recent positive selection
Population bottlenecks
Population subdivision
Balancing selection

Question 26

What can decrease Linkage Disequilibrium?

Answer 26

Recombination.

In the absence of other evolutionary forces, it will reduce D between two loci at a rate determined by rate of recombination. Genes on different chromosomes will usually have D ~ 0 as a result of their independent segregation at meiosis.

Question 27

How can knowledge of LD help with diagnosing diseases?

Answer 27

A SNP (genetic marker) near the human IL28B gene partly predicts whether drug therapy against the hep C virus will fail. This explains why African Americans respond less well to treatment than other groups, as can see that they have higher frequencies of this SNP.

Question 28

How is LD in the human genome structured?

Answer 28

Contains discrete haplotype blocks within which recombination is rare, separated by hot spots of recombination.
Each block is descended from a single ancestral chromosome.

European populations went through a recent strong population bottleneck, which likely raised LD. Recombination has yet to lower LD to the levels seen in Africa

Question 29

How do recombination and selection interact?

Answer 29

In the absence of recombination, beneficial mutations compete with each other for fixation and are hindered by being linked to deleterious mutations.

Recombination can combine competing mutations into a single haplotype, and free them of free loading deleterious mutations. This greatly increases the efficiency of fixation of new alleles by natural selection.

Question 30

How is random mating defined?

Answer 30

Random with respect to a particular genotype.

Question 31

Define inbreeding?

Answer 31

A type of non random mating that occurs when individuals mate with relatives more often than expected by chance.

Affects all genes of an organism, but could be an adaptive trait. For example, self fertilisation in plants enables isolated individuals to reproduce.

Question 32

Define positive assortative mating?

Answer 32

Occurs when individuals mate with similar traits to themselves. Affects only a subset of genes in an organism.

Question 33

How does homozygosity increase?

Answer 33

Increases with inbreeding and positive assortative mating. Offspring are more likely to inherit the same allele from both parents.

Such alleles are Identical By Descent (IBD). The locus is said to be autozygous.

Question 34

What does the inbreeding coefficient measure?

Answer 34

The level of recent inbreeding.

= probability that the alleles of a randomly chosen locus are IBD

For full sibling mating, F = 0.25

Question 35

Negative effects of inbreeding?

Answer 35

Leads to reduced survival and fecundity (inbreeding depression).

Leads to phenotypic expression of deleterious recessive alleles.

Question 36

What is genetic drift?

Answer 36

In small populations, chance events can significantly alter allele frequencies.

This sampling effect arises because the number of gametes or offspring exceeds the number of reproducing adults. It leads to random fluctuations in allele frequencies, termed genetic drift. The Hardy-Weinberg principle assumes infinite population size and therefore the sampling effect is absent

Genetic drift is most important for neutral alleles/mutations.

Fluctuations due to genetic drift combine through time, eventually leading to the fixation or elimination of alleles. Genetic drift thus reduces genetic variation and increases homozygosity.

Question 37

Relationship between genetic drift and pop size?

Answer 37

Effects of genetic drift are inversely proportional to population size.

Question 38

How is genetic variation determined in the absence of natural selection?

Answer 38

Balance between mutation (generates diversity) and genetic drift (removed diversity)

In diploids, this will lead to an equilibrium level of average heterozygosity (H) which is

H = (4Nu)/(4Nu+1)

The heterozygosity of neutral alleles depends only on population size and mutation rate, and will be close to 1 when 4Nu is large.

Question 39

Is genetic drift also important for advantageous alleles?

Answer 39

When such alleles alleles are rare then even tiny random fluctuations can push them to extinction.

However, beneficial alleles are more likely to be fixed than neutral ones.

The probability of fixation of a new mutation under codominant selection is:

= (1 - e^-2s) / (1 - e^-4Ns)

When Ns>>1 or Ns<<-1, the new mutation’s fate is mostly determined by selection. But when -1<ns>
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Question 40

What is effective population size?

Answer 40

In population genetics effective population size (Ne) is often used in place of census population size (N). Typically Ne<<n.></n.>A real population described by Ne loses variation by genetic drift at the same rate as a theoretically perfect population of size N.

Question 41

What is a population bottleneck?

Answer 41

Occurs when a population rapidly contracts in size. Homozygosity may increase due to exceptionally strong genetic drift.

The genetic effects of a bottleneck are long lasting and may continue after the popultion has recovered in size.

Bottlenecks occur when a small number of individuals colonise a new region or habitat. The genetic differences between the parent and daughter populations are called founder effects.
Although a very small daughter population may exhibit random mating within itself, it will have high IBD and appear inbred with respect to the parent population. This highlights the relative nature of measures of inbreeding.

Any level of inbreeding is removed after a single generation of outcrossing with an unrelated population.

Question 42

How does population structure affect popultion genetics?

Answer 42

The Wahlund effect. Refers to reduction of heterozygosity (that is when an organism has two different alleles at a locus) in a population caused by subpopulation structure.

Question 43

How is gene flow measured?

Answer 43

The gene flow among any pair of demes is given by m, the migration rate. This equals the probability that any randomly-chosen allele comes from a just-arrived migrant.

Consider a locus with 2 alleles under the island model of migration. Let p₀ be the initial frequency of allele P in deme X and let p_mean be the mean of the allele frequencies in each deme. After t generations the allele frequency in deme X will be:

P_t = P_mean + (P₀ + P_mean)(1 - m)^t