Module 5--Population Genetics & Genomics Flashcards
What causes temporal changes in the genetic makeup of a population?
Systematic and random evolutionary forces
What is the Theory of Allele Frequencies?
When the members of a population mate randomly, it is easy to predict the frequencies of the genotypes from the frequencies of their constituent alleles
How to calculate allele frequencies?
Frequency of an allele = number of the allele / total number of alleles
In the example, frequency of LM = (1787 x 2 + 3039) / (1787 + 3039 + 1303) x 2 = 0.53
frequency of LN = (1303 x 2 + 3039) / (1787 + 3039 + 1303) x 2 = 0.47
What is the probability that a homozygous dominant individual will be born?
p x p = p2
What is the probability that a carrier individual will be born?
p x q x 2 = 2pq
What is the probability that a homozygous recessive individual will be born?
q x q = q2
What assumption is made in the Hardy-Weinberg Principle (this table)?
Random mating between individuals in the population
What equation defines the frequency of the three genotypes, under random mating?
p2 + 2pq + q2 = 1
What is the Hardy-Weinberg Principle?
-Describes mathematical relationships between allele frequencies and genotype frequencies
p2 + 2pq + q2 = 1
-Allows the prediction of a population’s genotype frequencies form its allele frequencies
What is the Hardy-Weinberg equilibrium?
The Hardy-Weinberg genotype frequencies persist generation after generation, if mating is random and no differential survival or reproduction exists
How to check for agreement between observed data and predicted numbers?
By calculating chi-square statistic
X2 = Sum [(observed of one genotype-expected of one genotype)2/expected of one genotype]
-If X2 <0.001, population is in HW equilibrium
What effect does mutation have on Hardy-Weinberg equilibrium?
If the rate of mutation from A to a or from a to A changes, then the frequencies of A and a will change in Hardy-Weinberg equilibrium
(So HW equilibrium assumes that there is no mutation in population)
What are the results of non-random mating?
Non-random mating may lead to an excess of homozygous individuals
What is the result of inbreeding/consanguineous mating?
Homozygosity across the whole genome
What is the result of assortative mating/mating between alike individuals?
Homozygosity only in the genes associated with assortative mating, which increases linkage disequilibrium around
What effect does natural selection have on Hardy-Weinberg equilibrium?
Elimination of individuals carrying a deleterious phenotype will drive genotypic and allele frequencies away from H-W equilibrium
What is population subdivision?
When populations separate from one another, they become different
What effect does population subdivision have on Hardy-Weinberg principle?
Differences accumulated between populations violate the Hardy-Weinberg principle of uniform allele frequencies throughout the population
What processes play a major role in genetic differentiation?
- Genetic drift
- Migration
- Natural selection
What is migration?
Introduction of genotypes via migration can alter allele and genotypic frequencies
What is the effect of population merging?
Reduces heterozygosity (Wahlund effect)
What happens if populations remain in Hardy-Weinberg equilibrium?
Population are not evolving
How natural selection changes allele frequencies?
Allele frequencies change systematically in populations because of differential survival and reproduction among genotypes
What is fitness, w?
Ability to survive and reproduce
What does the fitness value represent?
Each member of the population has its own fitness value
- 0 if it dies/fails to reproduce
- 1 if it survives and produces 1 offspring
- 2 if it survives and produces 2 offsprings, etc.
How to calculate the average fitness of the population?
By averaging the fitness of individuals
What is the idea behind relative fitness?
Survival and/or reproductive rate of a genotype (or phenotype) is different in different environments
What is the relative fitness of the superior genotype(s) in each environment?
= 1
What is fitness deviation, s?
- It is the selection coefficient
- Measures the intensity of natural selection acting on the genotypes in the population
What is the relative fitness of the inferior genotype(s) in each environment?
= a deviation from 1
= 1 - s1
How to calculate the relative contributions of a genotype?
- p2 x fitness of genotype (AA)
- 2pq x fitness of genotype (Aa)
- q2 x fitness of genotype (aa)
How to obtain the proportional contributions of each genotype to the next generation?
= Relative contribution of a genotype / Sum of all relative contributions of all genotypes
In the next generation, all of the alleles transmitted by aa homozygotes are a, and half the alleles transmitted by the Aa heterozygotes are a. How to calculate the frequency of a in the next generation, q’?
q’ = proportional contribution of aa + 1/2 x proportional contribution of Aa
- q’ will be less than q, if natural selection against allele a
- q’ will be larger than q, if natural selection in favor of allele a
How can fitness be influenced?
- By different alleles of a single gene
- By the allele of many genes that affect quantitative traits (more often)
How can natural selection affect the distribution of a quantitative trait?
Through directional selection, disruptive selection, or stabilizing selection
What are the 3 types of natural selection?
- Directional selection favors values of a trait at one end of its distribution
- Disruptive selection favors extreme values of a trait at the expense of intermediate values
- Stabilising selection favours intermediate values of a trait
What is random genetic drift?
Allele frequencies change unpredictably in popluations because of uncertainties during reproduction
What factors contribute to random genetic drift?
- The alleles of segregating genes are randomly incorporated into gametes
- Random variation in the number of offspring that a parent produces
What is the effect of random genetic drift on different population size?
- In large populations, the effect of genetic drift is minimal
- In small populations, genetic drift may be the primary evolutionary force
How is the effect of population size on genetic drift measured?
By monitoring the frequency of heterozygotes of a population over time
What is the equation of the frequency of heterozygotes in the next generation, H’?
H’ = (1 - 1/2N) x H
- N = popuation size
- H = current frequency of heterozygotes
In one generation, random genetic drift causes the heterozygosity to decline by a factor of ____
1/2N
In t generation, what equation indicates declining heterozygosity?
Ht = (1 - 1/2N)t x H
-If Ht reaches 0, all genetic variability is lost
What message does this graph show?
-In small population, heterozygosity decades faster
In alleles are selectively neutral and the population mates randomly,
- the probability that an allele will ultimately be fixed in the population is ____
- the probabiity that the allele will be lost is ____
- the probability of allele fixation or lost is ____
- its current frequency
- 1 minus its current frequency
- independent of population size
How is dynamic equilibrium created?
Evolutionary forces may acit in opposing ways to create a dynamic equilibrium in which there is no net change in allele frequencies
What is balancing selection?
It occurs when there is overdominance
How to calculate allele frequencies at equilibrium with balancing selection?
What produces a stable equilibrium?
Balancing selection
What is mutation-selection balance?
Continuous elimination of deleterious alleles by selection
- Input by mutation
- Output by selection
Draw the relative fitness table for mutation-selection balance.
In mutation-selection balance, how a dynamic equilibrium is created?
When selection eliminates deleterious alleles that are produced by recurrent mutation
In mutation-selection balance, how genetic equilibrium is reached?
When the introduction of the allele into the population by mutation rate, u, is balanced by the elimination of the allele by selection, with intensity, s, against the recessive homozygotes
- u = sq2
- q = sqr(u/s)
In mutation-selection balance, if the allele is lethal, then what is q?
q = u-1/2
u = sq2
q = sqr(u/s), when allele is lethal, s=1
q = sqr(u)
What is mutation-drift balance?
Mutation replenishes the variability that is lost due to drift
- Mutation increases heterozygosity
- Drift decreases heterozygosity
What equations represent what happens at equilibrium at mutation-drift balance?
In mutation-drift balance, what is the effect of population size?
-In small populations, drift dominates over mutation
–> loss of heterozygosity = fast
–> fixation = fast
–> drift = strong
–> mutational target = small
-In large populations, mutation dominates over drift
–> loss of heterozygosity = slow
–> fixation = slow
–> drift = weak
–> mutational target = large
What is linkage disequilibrium?
Non-random association of alleles at two or more loci in a general population
(2nd Law of Mendel does not apply)
How can linkage disequilibrium be measured from observed frequency and expected frequency?
D = observed frequency - expected frequency
D = x11 - p1 x q1
D = p1q1 x p2q2 - p1q2 x p2q1
What is the equation for D’ parameter?
D’ = D/Dmax
What is the range of D?
0-1
What is the range of D’?
-1 to 1
How to measure linkage disequilibrium using r2?
r2 = D2 / (p1 x p2 x q1 x q2)
What is the relationship between linkage disequilibrium and distance?
Linkage disequilibrium decays over distance
-closer markers have greater linkage disequilibrium than distant markers
What is the relationship between linkage disequilibrium and time?
Linkage disequilibrium decays over time
-young new mutations exist in long haplotypes
What is genetic hitchhiking?
When an allele changes frequency not because it itself is under natural selection, but because it is near another gene that is undergoing a selective sweep and that is on the same DNA chain
What is background selection?
Loss of genetic diversity at a non-deleterious locus due to negative selection against linked deleterious alleles
How to measure linkage disequilibrium from parental and recombinant gametes?
LD = p1q1 p2q2 - p1q2 p2q1
LD = x11x12 - x12x21
Where is the equilibrium point at linkage equilibrium?
When the fraction of parental gametes equals the fraction of recombinant gametes
p1q1 x p2q2 = p1q2 x p2q1
p1q1 x p2q2 - p1q2 x p2q1 = 0
What is the value of linkage disequilibrium if recombinant gametes are not produced?
LD > 0
What is the value of linkage disequilibrium if parental gametes are not produced?
LD < 0
Why linkage disequilibrium decays with distance?
Because close (linked) loci in chromosome produce few recombinants, whereas farther apart loci produce many recombinants
Why linkage disequilibrium decays with time?
Every generation, a round of recombination between two genes will reduce their genetic association
How will happen to linkage disequilibrium if a new mutation arises?
Alleles will be in linkage disequilibrium with that new mutation
They will form a haplotype
What is the selection coefficient of deleterious or slightly deleterious mutations?
s > 1
What is the selection coefficient of neutral mutations?
s = 0
What is the selection coefficient of advantageous mutations?
s < 1
Why molecules with fewer functional constraints evolve faster?
Because the number of effectively neutral substitutions is higher
What does the Neutral Theory assume?
It assumes that favourable mutations are rare
Would most silent (synonymous) mutations be neutral, favourable, or deleterious?
Neutral
Would most replacement mutations be neutral, favourable, or deleterious?
Deleterious
What will happen to most new neutral mutations in a population initially (first 20 generations): fixation, loss, or polymorphism?
Loss
What will happen to most new deleterious mutations in a population initially (first 20 generations): fixation, loss, or polymorphism?
Loss
How does the size of the population change the number of new mutations that occur at a locus each generation?
The larger the population size is, the more new mutations occur
How does the size of the population change the probability that a new neutral mutation will fix in a population?
Probability of fixation increases in small populations
On average, will it take longer to fix a new neutral mutation in a small or large population?
The larger the population is, the longer it takes
How does the size of the population change the level of polymorphism expected (= number of different alleles at a locus, assuming that all of them are neutral)?
The larger the population is, the higher the level of polymorphism is
Overall, out of all the polymorphisms at a locus in a population, would you expect more of them to be replacement or silent mutations?
Same
How to calculate the number of mutations per generation?
μ0 = 2Nμ
2N = number of mutant copies
μ = mutation rate
How to calculate the probability of fixation?
p0 = 1/2N
What is the result of multiplying the number of mutations per generation and probability of fixation?
substitution rate = mutation rate
What does the Neutral Theory hypothesise?
Most substitutions are neutral across species
What is the relationship between the rate of evolution, the rate of substitution, and the mutation rate when evolution proceeds by genetic drift?
All same
Under drift, how does population size affect the generation and maintenance of genetic diversity?
Larger population generate and carry more variability than in small populations
What is the main difference between the Neutral Theory and the Nearly Neutral Theory?
Population size only has effect in the Nearly Neutral Theory
In Nearly Neutral Theory, what factor is considered?
Probability of fixation for slightly deleterious mutations
In Nearly Neutral Theory, _____ overpowers _____ in large populations
Selection overpowers drift in large population
In Nearly Neutral Theory, _____ overpowers _____ in small populations
Drift overpowers selection in small populations
What are the types of selection at the molecular level?
- Purifying, or
- Directional
What tests can detect an excess of favourable mutations in the genome?
- Tajima’s D
- Fst Based Tests
- HKA Test
- dN/dS ratio tests
- Macdonald-Kreitman test
What is the time to fixation, for neutral mutations?
4N
What is the effect of population size on neutral mutations?
Neutral mutations are highly sensitive to population size
What is the time between new mutations that fix, for neutral mutations?
u-1
What is a neutrality test?
A statistical method aimed at rejecting a model of neutral evolution
What is the neutrality hypothesis?
- Strongly deleterious mutations are immediately eliminated from the population
- If this is the only type of selection, then the only mutations that segregate in the population are neutral
What are the other assumptions of the neutrality hypothesis?
- The efficacy of selection depends both on s and on the effective population size Ne
- Selection efficacy is reduced when multiple selected alleles segregate in the population: Interference
What is selective sweep?
A new beneficial mutation will rise in frequency (prevalence) in a population
As selected mutations increase in frequency, they tend to _____ _____ in the neighboring region where neutral variants are segregating.
Reduce variation
What is fixation?
Allele rise to 100% frequency
What is the signature of a selective sweep?
Reduced genetic variability around the selected gene
What is a frequency spectrum?
A count of the number of mutations that exist in a frequency of xi = i/n; for i = n - 1, in a sample of size n
What is Tajima’s D?
Difference between two measures of nucleotide diversity,
- Average number of polymorphic mutations, pi
- Number of segregating mutations, Theta
How to get the average number of polymorphic mutations, pi?
Sum the totals from tables and divide the number of comparisons
e.g. (10+6+3+1)/10 = 2
How to get the number of segregating mutations, theta, (number of polymorphic sites)?
Number of sites where differences are found
e.g. 4
How to calculate Tajima’s D?
-Substract average number of polymorphic mutations (pi) with number of segregating mutations (Theta)
d = pi - theta
-Divide d by the standard deviation to get D
How to interpret the value of Tajima’s D?
- Negative Tajima’s D: excess of low frequency polymorphisms
- Neutral expectation is that pi = Theta; D = 0
- Balancing selection is expected to give a positive D value
_____ _____ tend to produce significantly negative values of Tajima’s D
Population expansions
_____ _____ tend to produce significantly positive values of Tajima’s D.
Population bottlenecks
What is dN/dS ratio test?
dN = rate of nonsynonymous substitution per nonsynonymour site
dS = rate of synonymous substitution per synonymous site
dN/dS < 1: deleterious replacements
dN/dS = 1: neutral replacements
dN/dS > 1: beneficial replacements
What is the hypothesis for McDonald-Kreitman test?
All mutations are neutral
All dN/dS polymorphic sites should equal for dN/dS fixed differences
What is the alternate hypothesis of McDonals-Kreitman test?
Replacements are favoured
Favoured mutations fixed quickly, so dN/dS polymorphic < dN/dS fixed
What is McDonald-Kreitman test about?
- If evoultion of protein is neutral, the percentage of mutations that alter amino acids should be the same in all lineages being compared
- If all mutations are neutral, all should have the same probability of persisting
- So, dN/dS among polymorphisms should be the same as within fixed differences
