Heterozygote advantage: cystic fibrosis
CFTR gene
(Bars indicate frequencies of
different loss-of-function mutations
across the gene -- lots!)
CFTR protein: Cystic fibrosis
transmembrane conductance
regulator
‘Homozygote’ recessive: cystic fibrosis; susceptible to Pseudomonas
aeruginosa lung infection; early death.
• Loss-of-function allele frequency: ~2-5% in Europeans
• ΔF508 (70%), plus ~1000 other loss-of-function haplotypes identified
Heterozygotes are protected against Salmonella typhi cell infiltration in the
gut: 86% fewer bacteria.
Across 11 European countries, severity of typhoid outbreaks is correlated
with frequency of ΔF508 in the next generation.
(But not all high-frequency disease alleles reflect heterozygote advantage)
1
Methods for documenting natural selection:
1. Longitudinal studies: follow a group of individuals for some
or all of their lives; observe variation in phenotypes and fitness
e.g., Darwin’s finches
Methods for documenting natural selection:
1. Longitudinal studies: follow a group of individuals for some
or all of their lives; observe variation in phenotypes and fitness
e.g., Darwin’s finches
2. Experimental manipulation (transplants, mark/re-capture, etc.); look for
associations between phenotypes and fitness in different environments
e.g., guppies; positive frequency-dependent selection with Müllerian mimicry
2
Methods for documenting natural selection:
1. Longitudinal studies: follow a group of individuals for some
or all of their lives; observe variation in phenotypes and fitness
e.g., Darwin’s finches
2. Experimental manipulation (transplants, mark/re-capture, etc.); look for
associations between phenotypes and fitness in different environments
e.g., guppies; positive frequency-dependent selection with Müllerian mimicry
3. Comparison among age classes. Look for shifts in phenotypes.
e.g., metal tolerance in grass
Methods for documenting natural selection:
1. Longitudinal studies: follow a group of individuals for some
or all of their lives; observe variation in phenotypes and fitness
e.g., Darwin’s finches
2. Experimental manipulation (transplants, mark/re-capture, etc.); look for
associations between phenotypes and fitness in different environments
e.g., guppies; positive frequency-dependent selection with Müllerian mimicry
3. Comparison among age classes. Look for shifts in phenotypes.
e.g., metal tolerance in grass
4. Long-term studies of trait distributions (over many generations)
e.g., Darwin’s finches
Better for detecting directional selection than stabilizing
3
Methods for documenting natural selection:
1. Longitudinal studies: follow a group of individuals for some
or all of their lives; observe variation in phenotypes and fitness
e.g., Darwin’s finches
2. Experimental manipulation (transplants, mark/re-capture, etc.); look for
associations between phenotypes and fitness in different environments
e.g., guppies; positive frequency-dependent selection with Müllerian mimicry
3. Comparison among age classes. Look for shifts in phenotypes.
e.g., metal tolerance in grass
4. Long-term studies of trait distributions (over many generations)
e.g., Darwin’s finches
Better for detecting directional selection than stabilizing
5. Environmental perturbations
e.g., antibiotic resistance, pesticide resistance, Galapagos droughts
Methods for documenting natural selection:
1. Longitudinal studies: follow a group of individuals for some
or all of their lives; observe variation in phenotypes and fitness
e.g., Darwin’s finches
2. Experimental manipulation (transplants, mark/re-capture, etc.); look for
associations between phenotypes and fitness in different environments
e.g., guppies; positive frequency-dependent selection with Müllerian mimicry
3. Comparison among age classes. Look for shifts in phenotypes.
e.g., metal tolerance in grass
4. Long-term studies of trait distributions (over many generations)
e.g., Darwin’s finches
Better for detecting directional selection than stabilizing
5. Environmental perturbations
e.g., antibiotic resistance, pesticide resistance, Galapagos droughts
6. Correlation between environment and phenotype
e.g., clover cyanogenesis clines; caveat: correlation is not necessarily causation
4
Assumptions of Hardy-Weinberg equilibrium:
1. Random mating (panmixia)
A1
A2
A1A1 A1A2 A2A2
p2 + 2pq + q2
2. Infinite population size (no sampling effects)
3. No migration (gene flow)
4. No new mutation
5. No segregation distortion (meiotic drive)

6. No natural selection: all genotypes have
equal survival/reproduction
Hardy-Weinberg assumptions:
1. Random mating
2. Infinite population size (no sampling effects)
Genetic drift
— effect in small populations (bottlenecks, founder events)
— effect on isolated populations of a species
3. No migration (gene flow)
4. No new mutation
5. No segregation distortion
 6. No natural selection: all genotypes have
equal survival/reproduction
5
Hardy-Weinberg assumes that genotype frequencies in the
next generation are exactly the products of allele frequencies
in the parental generation (no sampling effect).
p2 + 2pq + q2
A1A1
A1A2
A2A2
Pool of gametes:
A1
p = 0.6
A2
q = 0.4
Probability that a genotype is:
A1 A1 = (0.6)(0.6) = 0.36 = p2
This is only true for an infinite population size.
Example of genetic drift:
Population size = 2 individuals
A1A1 and A1A2 p=0.75, q=0.25
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Example of genetic drift:
Population size = 2 individuals
A1A1 and A1A2 p=0.75, q=0.25
A1
A2
A1 A1A1 A1A2
1) From one mating, probability
of producing an A1A1 offspring
is 0.5
A1 A1A1 A1A2
2) Probability of producing two A1A1 offspring in a row is:
(0.5)(0.5) = 0.25
3) So if the population size remains the same in the next
generation (N=2), there’s a 25% chance that the A1 allele will be
fixed and the A2 allele lost altogether after only 1 generation.
(p= 1.0, q=0)
e
gen
ra t
io n
s
a ll
e le
q
fre
ue
nc
y
1
0
7
Genetic drift will
ultimately cause the
fixation of one allele and
loss of the other.
Loss of genetic variation
e
gen
ra t
io n
s
ra t
io n
s
a ll
e le
q
fre
ue
nc
y
1
0
Genetic drift will
ultimately cause the
fixation of one allele and
loss of the other.
Loss of genetic variation
e
gen
a ll
e le
q
fre
ue
nc
y
1
0
Probability of fixation is
determined by the initial
allele frequency.
Differential loss of rare alleles
8
Smaller populations = stronger genetic drift.
Two ways to think about this:
1) Probability of fixation of a newly arisen allele in a diploid population:
e.g.,
a) N = 5 inds. (2N =10 alleles)
Probability of fixation = 1/2N = 1/10 = 0.10
vs.
b) N = 500 inds. (2N =1000 alleles)
Probability of fixation = 1/2N = 1/1000 = 0.001
2) Average time to fixation if a newly arisen allele does become fixed:
~4N generations
(you don’t need to know the derivation!)
Simulations (genetic drift, selection, interaction):
http://darwin.eeb.uconn.edu/simulations/simulations.html
Try these on your own too.
9
Genetic drift simulations, recap:
Allele frequencies fluctuate randomly, and eventually
one allele will become fixed. This effect is inversely
correlated with the size of the population.
Genetic drift can potentially override selection and lead
to the loss of a selectively favored allele.
Founder Effect -- The principle that the founders of a new colony
carry only a fraction of the total genetic variation in a population.
Bottleneck -- Instances in which populations are greatly reduced in
size for one or more generations.
Founder effect:
Bottleneck:
10
Founder effect (humans):
e.g., Ellis-Van Creveld syndrome
<1 of 60,000 live births worldwide
~5 of 1,000 Amish births
11
(PNAS 99: 8127-8132, 2002)
6 microsatellite loci
(noncoding variation):
Silvereye (Zosterops lateralis)
Bottleneck (humans):
Population of Pohnpei descended from 20 survivors of 1775 typhoon
Congenital achromatopsia:
<1 out of 30,000 people worldwide
~8% of people on Pohnpei
~30% are carriers (heterozygotes)
12
Even if lethal, the deleterious allele frequency declines slowly:
e.g., deleterious recessive allele (N=100): q= 0.2 vs. q=0.1
p2
2pq
0.64
64
q=
q2
0.32
32
(0.5)(32)
96
= 0.167
Decline by 0.033
Bottleneck:
0.04
4
p2
2pq
0.81
81
q=
q2
0.18
18
(0.5)(18)
99
0.01
1
= 0.091
Decline by 0.009
~10-30 northern elephant seals, now >175,000
No variation in 24 allozyme loci (Bonnell and Selander 1974)
(2000)
13
Bottleneck:
~10-30 northern elephant seals, now >175,000
No variation in 24 allozyme loci (Bonnell and Selander 1974)
(2000)
Pre-bottleneck: 5 different genotypes from 7 samples
Post-bottleneck: 2 genotypes from 155 samples
Consequences of genetic drift on genetic diversity
Loss of genetic variation:
A) # alleles/locus (through fixation)
# polymorphic loci (through fixation)
— differential loss of rare alleles (limits evolutionary response)
14
Consequences of genetic drift on genetic diversity
Loss of genetic variation:
A) # alleles/locus (through fixation)
# polymorphic loci (through fixation)
— differential loss of rare alleles (limits evolutionary response)
B) Heterozygosity, 2pq = 2p(1-p):
e.g., p = 0.5: 2p(1-p) = 2(0.25) = 0.50
p = 0.2: 2p(1-p) = 2(0.16) = 0.32
Consequences of genetic drift on genetic diversity
Loss of genetic variation:
A) # alleles/locus (through fixation)
# polymorphic loci (through fixation)
— differential loss of rare alleles (limits evolutionary response)
B) Heterozygosity, 2pq = 2p(1-p):
Average loss of heterozygosity
from genetic drift per generation:
[
1
Ht1= Ht 1 2N
]
e.g., for N=50 inds, and Ht = 2(p)(1-p) = 0.5,
e.g., p = 0.5: 2p(1-p) = 2(0.25) = 0.50
p = 0.2: 2p(1-p) = 2(0.16) = 0.32
Ht1 = 0.495
1% loss in heterozygosity per generation for N=50
15
Effects of genetic drift on multiple populations within a species
For multiple finite populations, all with allele A1 at frequency p, we
expect that a proportion p of the populations will be fixed for A1
Effects of genetic drift on multiple populations within a species
For multiple finite populations, all with allele A1 at frequency p, we
expect that a proportion p of the populations will be fixed for A1
e.g., If A1 allele frquency is p= 0.67, expect 2/3 of populations to
become fixed for A1:
Expect 2/3 of the
populations to become
fixed for A1,1/3 to be
fixed for A2
e.g., In each population,
p = 0.67, q = 0.33
t
16
Effects of genetic drift on multiple populations within a species
107 populations, 19 generations
8 males, 8 females per
population per generation
bw75/bw75
bw75/bw
bw/bw
bw75/bw
Started with all
heterozygotes (eye color,
co-dominant alleles)
Genetic drift effects:
Fixation/loss in each population
Proportion of populations
with bw75 fixed = bw75 frequency
at the start of the experiment
Genetic divergence
of populations
Buri (1956)
bw75/bw75
Recall:
bw75/bw
bw/bw
Average loss of heterozygosity
from genetic drift per generation:
[
1
Ht1= Ht 1 2N
]
17
Loss of heterozygosity over successive generations
[
Ht1= Ht 1 -
1
2N
]
1
2N
]
N=16
N=9
Rate of loss of heterozygosity fits a population of N=9, not N=16!
Loss of heterozygosity over successive generations
[
Ht1= Ht 1 -
N=16
N=9
Census
population
size
Rate of loss of heterozygosity fits a population of N=9, not N=16!
Ne: effective population size: the size of an ideal population
that produces the level of genetic drift observed in a real population
Here, Ne = 9, where genetic drift is measured as loss of heterozygosity
18
Reasons why Ne < census population size
1. Variation among individuals in contribution to the next generation
— unequal sex ratios (e.g., 1 male, 15 females)
— fitness variation (viability, mating success, fecundity)
2. Fluctuations in population size (Ne predicted by harmonic mean)
3. Overlapping generations
19