Download Population Genetics 6: Natural Selection Natural selection Natural

Population Genetics 6:
Natural Selection
Natural selection
GENETIC
SUCESS
⎯→
VARIATION
 + DIFFERENTI

AL


 ⎯
This genetic prefix is important as the
variation must be heritable. Change in
this portion of the equation is undirected.
(undirected)
This has two components: (i) reproduction
and (ii) survival in a particular environmental
context. This portion provides a direction to
evolutionary change
EVOLUTION


For this part of the course,
we define evolution as change
in allele frequencies
(directed)
Natural selection explains adaptation
1
Natural selection
The conditions for natural selection:
1.  variation among individuals (mutation)
2.  replication (DNA, RNA, mitosis, meiosis)
3.  inheritance (Mendelian transmission genetics)
Fitness
2
Fitness: a measure of an organisms ability to survive and
reproduce. Fitness may be measured in relation to viability (the
probability of survival from fertilization to reproduction) and mean
fertility.
Relative fitness: measuring fitness by assigning a fitness value of
1 to the genotype with the highest absolute fitness.
Selection coefficient (s): the difference between the relative fitness
of the most fit genotype and the relative fitness of another involved
genotype.
Life is a struggle
3
Natural selection in action: HIV drug resistance
HIV/AIDS:
•  40 (±6million) million people worldwide (2006)
•  33 (±3million) million people worldwide (2007)
•  2 million are children (< age15); 90% in SubSaharan Africa
•  Two-thirds of infected people live in Africa
Growth:
•  2.7 million new infections in 2007 (3.0 in 2001)
•  >7,500 per day
•  45% of new infections are young people (15-25)
Toll:
•  > 20 million deaths since first case
•  3 million deaths in 2006
•  Death rate falling in developed countries since
1990’s
Data from NIH, NIAID, UNAIDS [2008 report]
4
5
New statistic (Zimbabwe):
Prior to HIV: Average lifespan = 60 years
Current:
Average lifespan = 36 years
6
HIV-1 genome:
7
Life cycle of HIV
8
Viral budding
A billion viral particles are
produced every day
Fusion inhibitors:
Inhibit the fusion of HIV
with target cell
membrane.
Administered by
injection
Non-nucleoside RT
inhibitors:
Nucleoside RT
inhibitors:
The newest class of HIV
drugs.
The first effective class of
antiretroviral drugs.
Bind directly to reverse
transcriptase and prevent
synthesis of DNA from
RNA template
They mimic A,C,G or T.
They incorporate
themselves into growing
DNA polymer and act to
disrupt the replication
complex.
Protease inhibitors:
These work at final
stage of virus life cycle.
They prevent proper
assembly and release
of mature HIV virus.
Example: AZT
9
Natural selection in action: HIV drug resistance
RT inhibitor treatment:
1. 
dramatic decline in HIV in patient
2. 
HIV grow to detectable numbers in a matter of days
⎯ completes life cycle in just 2 days
3. 
1-2 months patient has 100% resistant population of HIV
Resistance:
1. 
avoid incorporation of RT inhibitor
2. 
proofread and excise inhibitor
Note: most resistant strains have lower fitness in untreated individuals. Compensatory
mutations have been observed to evolve!
10
Concept map of evolution of resistance to RT inhibitors in HIV
Generation:
1
2
3
4
No drugs
5
6
7
Single drug therapy
High polymorphism
Low resistance
Low polymorphism
High resistance
Fitness in diploids
Evolutionary fitness is symbolized with W
Symbolism
Genotype
AA
Aa
aa
Phenotype
WAA
WAa
Waa
1
1
0.76
11
Fitness
Directional selection
1
0.8
0.6
0.4
0.2
0
WAA > WAa > Waa
AA
Aa
aa
Genotypes
Directional selection occurs when selection favors the phenotype at an extreme of
the range of phenotypes.
•  exerts pressure for FIXATION (frequency goes to 1)
•  imposes a direction on evolution
Overdominant selection
1
Fitness
0.8
WAA < WAa > Waa
0.6
0.4
0.2
0
AA
Aa
aa
Genotypes
Overdominant selection occurs when the heterozygote has a greater fitness than
either homozygote.
•  also called balancing selection or heterozygote advantage
•  maintains a stable polymorphism; acts against fixation
12
Fitness
Underdominant selection
1
0.8
0.6
0.4
0.2
0
WAA > WAa < Waa
AA
Aa
aa
Genotypes
Underdominant selection occurs when the heterozygote has lower fitness than either
homozygote.
•  yields an unstable equilibrium
•  also called apostatic selection or disruptive selection
Fitness in diploids
Genotype
Frequency
Phenotype
Symbolism for generation 0
AA
Aa
2
p0
2p0q0
WAA
WAa
aa
2
q0
Waa
Survival ratio: WAA : WAa : Waa
Genotype ratio:
p2WAA : 2pqWAa : q2Waa
Problem: the genotype ratios do not sum to 1.
13
Fitness in diploids
Normalize by dividing by the grand total after selection:
W = p2WAA + 2pqWAa + q2Waa
W = AVERAGE FITNESS
Normalized fitness:
W
W
AA and Aa and Waa
W
W
W
p 2 + 2 pq + q 2 = 1
p2
W
W
AA + 2 pq Aa + q 2 Waa = 1
W
W
W
Under HW:
With selection:
p1 = p2 + (1/2)2pq
( ) + (1/2)2pq ( )
WAA
p1 = p2 W
WAa
W
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Selection simplified…
p1 = p(pWAA + qWAa) /
W
⇐ Remember these.
q1 = q(pWAa + qWaa) / W
OK, now we have the tools we need…
1. 
Deleterious recessive
2. 
Deleterious dominant
3. 
Overdominant
4. 
Deleterious recessive under partial dominance
Deleterious recessive
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Deleterious recessive
Our model
Genotype
AA
Aa
aa
Frequency
p 02
2p0q0
q 02
1
1
1-s
W
W = p2(1) + 2pq(1) + q2(1-S)
We specify the fractional reduction in
survival by the selection coefficient, s.
(average fitness)
W = p2 + 2pq + q2- Sq2
W = 1- q2S
(average fitness, simplified)
Deleterious recessive
q1 = q(pWAa + qWaa) / W
By substitution …
q1 = q(p(1) + q(1- s)) / 1- sq2
q1 = q(p + q - sq) / 1- sq2
2
q1 = q(1 - sq) / 1- sq
2
qt+1 = qt - Sqt / 1- sqt
2
The per generation change in
allele frequency due to
selection against a
deleterious recessive trait
16
Deleterious recessive
Dark form
Peppered moths in polluted environment
Light form
Genotype
AA
Aa
Frequency at birth
p2
2pq
aa
q2
Fitness
1
1
1-s
Let p = 0.06 and q = 0.94
Change in recessive allele frequency over time
(in generations)
1
Frequency of a allele
Biston betularia:
Dark allele (A) is dominant
Light allele (a) is recessive
In polluted environment, the light
allele is deleterious
0.9
s = 0.33
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
One empirical estimate of s =
0.33
1
4
7 10 13 16 19 22 25 28 31 34 37 40 43 46 49
Generations
Directional selection for
dominant allele
Deleterious recessive
Change in recessive allele frequency over time under different intensities of negative
selection
1
s=0
s = 0.01
Frequency of a allele
0.9
0.8
0.7
0.6
s = 0.1
s = 0.5
s = 0.9
0.5
0.4
0.3
0.2
0.1
0
1
26
51
s < 0.5
76
101
126
151
176
201
226
251
Generations
17
Deleterious dominant
Fitness
Recall: Directional selection
1
0.8
0.6
0.4
0.2
0
WAA > WAa > Waa
AA
Aa
aa
Genotypes
Directional selection occurs when selection favors the phenotype at an extreme of
the range of phenotypes.
•  exerts pressure for FIXATION (frequency goes to 1)
•  imposes a direction on evolution
18
Deleterious dominant
Peppered moths in restored environment
The model
Genotype
AA
Aa
aa
Frequency
p 02
2p0q0
q 02
1-s
1-s
1
W
Biston betularia:
Dark allele (A) is dominant
Light allele (a) is recessive
q − sq + sq 2
q1 =
1− s 1− q2
(
In clean environment, the dark
allele is deleterious
)
Directional selection for the
recessive allele
Deleterious dominant
Change in frequency of dominant allele under different intensities of negative
selection
1
Frequency of A allele
0.9
s = 0.05
s = 0.1
s = 0.2
s = 0.5
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
1
9
17
25
33
41
49
57
65
73
81
89
97
Generations
Note: At one site in northwest England the frequency of the dark form of the Peppered Moth
declined from 0.94 in 1961 to 0.11 in 1998.
19
Recall: Overdominant selection
1
Fitness
0.8
WAA < WAa > Waa
0.6
0.4
0.2
0
AA
Aa
aa
Genotypes
Overdominant selection occurs when the heterozygote has a greater fitness than
either homozygote.
•  also called balancing selection or heterozygote advantage
•  maintains a stable polymorphism; acts against fixation
20
Overdominance (Balancing selection)
The model
AA
Aa
p 02
2p0q0
1 – s1
1
Genotype
Frequency
W
q1 =
aa
q 02
1 – s2
q − s2 q 2
1 − s1 p 2 − s 2 q 2
Let s look at an example: s1 = 0.3 and s2 = 0.1
Overdominance (Balancing selection)
Let s1 = 0.3 and s2 = 0.1
Stable equilibrium resulting from overdominant selection
1
Frequency of a allele
0.9
0.8
Stable polymorphism:
q = 0.75
p = 0.25
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
1
7
13
19
25
31
37
43
49
55
61
67
73
79
85
91
97
Generations
What happens to this polymorphism during speciation?
21
Overdominance (Balancing selection)
MHC locus:
Virus infected cell
•  Major histocompatibility locus
Antigen
presenting
receptor
•  4 mega-base region of the genome
•  Encodes antigen presenting receptor proteins
TCR
T
Class I
Class II
Class III
The MHC locus on human chromosome 6
Killer
cell
Overdominance (Balancing selection)
ARS
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MCHBh
MCHAh
MCHAch
MCHBch
Overdominance (Balancing selection)
6 mya: Human – chimp speciation
9 mya: MHCBh - MHCBch
14 mya:MHCAh - MHCAch
Trans-species polymorphism !
Deleterious recessive under partial dominance
The model
Genotype
AA
Aa
aa
s = selection coefficient
Frequency
p 02
2p0q0
q 02
h = degree of dominance
1
1 - hs
1–s
W
h = 0 : dominance is 100%, recessives hide in heterozygotes
h = ½: dominance is 50%, additive models for phenotypic effect
q1 =
q − hspq − sq 2
1 − 2hspq − sq 2
23
Deleterious recessive under partial dominance
Effect of partial dominance on the change of the recessive allele
frequency under negative selection
1
Frequency of a allele
0.9
Partial
Dominance:
h = 0.5
s = 0.33
0.8
0.7
0.6
0.5
Full Dominance:
h=0
s = 0.33
0.4
0.3
0.2
0.1
0
1
4
7
10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58
Generations
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