1 Natural selection The conditions for natural selection: 1. - - PDF document

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Population Genetics 6: Natural Selection                               

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EVOLUTION SUCESS AL DIFFERENTI VARIATION GENETIC ⎯→ ⎯ + Natural selection

(undirected) (directed)

Natural selection explains adaptation

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Natural selection The conditions for natural selection: 1. variation among individuals (mutation) 2. replication (DNA, RNA, mitosis, meiosis) 3. inheritance (Mendelian transmission genetics) Fitness

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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

• f the most fit genotype and the relative fitness of another involved

genotype. Life is a struggle

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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 Sub-

Saharan 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]

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New statistic (Zimbabwe): Prior to HIV: Average lifespan = 60 years Current: Average lifespan = 36 years

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HIV-1 genome:

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Life cycle of HIV

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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: The newest class of HIV drugs. Bind directly to reverse transcriptase and prevent synthesis of DNA from RNA template Nucleoside RT inhibitors: The first effective class of antiretroviral drugs. They mimic A,C,G or T. They incorporate themselves into growing DNA polymer and act to disrupt the replication complex. Example: AZT Protease inhibitors: These work at final stage of virus life cycle. They prevent proper assembly and release

• f mature HIV virus.

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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!

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Concept map of evolution of resistance to RT inhibitors in HIV Single drug therapy No drugs

High polymorphism Low resistance Low polymorphism High resistance

Generation: 1 2 3 4 5 6 7

Fitness in diploids Evolutionary fitness is symbolized with W

Symbolism Genotype AA Aa aa Phenotype

WAA WAa Waa

1 1 0.76

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WAA > WAa > Waa

0.2 0.4 0.6 0.8 1 Fitness AA Aa aa Genotypes

Directional selection

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

0.2 0.4 0.6 0.8 1 Fitness AA Aa aa Genotypes

WAA < WAa > Waa Overdominant selection

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

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0.2 0.4 0.6 0.8 1 Fitness AA Aa aa Genotypes

WAA > WAa < Waa Underdominant selection

Underdominant selection occurs when the heterozygote has lower fitness than either homozygote.

• yields an unstable equilibrium
• also called apostatic selection or disruptive selection

Symbolism for generation 0 Genotype AA Aa aa Frequency p0

2

2p0q0 q0

2

Phenotype WAA WAa Waa

WAA : WAa : Waa Survival ratio:

p2WAA : 2pqWAa : q2Waa

Genotype ratio: Problem: the genotype ratios do not sum to 1.

Fitness in diploids

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W = p2WAA + 2pqWAa + q2Waa

Fitness in diploids

Normalize by dividing by the grand total after selection:

W = AVERAGE FITNESS

W W W W W W aa and Aa and AA Normalized fitness:

Under HW: p1 = p2 + (1/2)2pq With selection: p1 = p2(

)

W WAA

+ (1/2)2pq(

)

W WAa

1 aa 2 Aa 2 AA 2 = + + W W q W W pq W W p 1 2 2 2 = + + q pq p

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p1 = p(pWAA + qWAa) / W q1 = q(pWAa + qWaa) / W Selection simplified… OK, now we have the tools we need… 1. Deleterious recessive 2. Deleterious dominant 3. Overdominant 4. Deleterious recessive under partial dominance ⇐ Remember these.

Deleterious recessive

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Deleterious recessive

Our model Genotype AA Aa aa Frequency p0

2

2p0q0 q0

2

W 1 1 1 - s

We specify the fractional reduction in survival by the selection coefficient, s.

W = p2(1) + 2pq(1) + q2(1-S) (average fitness)

(average fitness, simplified)

W = p2 + 2pq + q2- Sq2

W = 1- q2S

Deleterious recessive

q1 = q(pWAa + qWaa) / W q1 = q(p(1) + q(1- s)) / 1- sq2 q1 = q(p + q - sq) / 1- sq2 q1 = q(1 - sq) / 1- sq2 qt+1 = qt - Sqt

2 / 1- sqt 2

By substitution …

The per generation change in allele frequency due to selection against a deleterious recessive trait

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Deleterious recessive

Peppered moths in polluted environment

Dark form Light form Genotype AA Aa aa Frequency at birth p2 2pq q2 Fitness 1 1 1 - s

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49

Generations Frequency of a allele

s = 0.33

Change in recessive allele frequency over time (in generations)

Biston betularia: Dark allele (A) is dominant Light allele (a) is recessive In polluted environment, the light allele is deleterious One empirical estimate of s = 0.33 Directional selection for dominant allele

Let p = 0.06 and q = 0.94

Deleterious recessive

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1 26 51 76 101 126 151 176 201 226 251 Generations Frequency of a allele s = 0.1 s = 0.5 s = 0.9 s = 0 s = 0.01 Change in recessive allele frequency over time under different intensities of negative selection

s < 0.5

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Deleterious dominant WAA > WAa > Waa

0.2 0.4 0.6 0.8 1 Fitness AA Aa aa Genotypes

Recall: Directional selection

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

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Deleterious dominant

Peppered moths in restored environment

The model Genotype AA Aa aa Frequency p0

2

2p0q0 q0

2

W

1 - s 1 - s 1

( )

2 2 1

1 1 q s sq sq q q − − + − =

Biston betularia: Dark allele (A) is dominant Light allele (a) is recessive 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 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1 9 17 25 33 41 49 57 65 73 81 89 97

s = 0.05 s = 0.1 s = 0.2 s = 0.5

Generations Frequency of A allele

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.

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0.2 0.4 0.6 0.8 1 Fitness AA Aa aa Genotypes

WAA < WAa > Waa Recall: Overdominant selection

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

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Overdominance (Balancing selection)

The model Genotype AA Aa aa Frequency p0

2

2p0q0 q0

2

W

1 – s1 1 1 – s2

2 2 2 1 2 2 1

1 q s p s q s q q − − − =

Let’s look at an example: s1 = 0.3 and s2 = 0.1

Overdominance (Balancing selection)

Stable equilibrium resulting from overdominant selection

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1 7 13 19 25 31 37 43 49 55 61 67 73 79 85 91 97

Generations Frequency of a allele Stable polymorphism: q = 0.75 p = 0.25

Let s1 = 0.3 and s2 = 0.1 What happens to this polymorphism during speciation?

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Overdominance (Balancing selection)

T

Killer cell Antigen presenting receptor TCR Virus infected cell

MHC locus:

• Major histocompatibility locus
• 4 mega-base region of the genome
• Encodes antigen presenting receptor proteins

Class I Class III Class II The MHC locus on human chromosome 6

Overdominance (Balancing selection)

ARS

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Overdominance (Balancing selection)

6 mya: Human – chimp speciation 9 mya: MHCBh - MHCBch 14 mya:MHCAh - MHCAch MCHBh MCHBch MCHAh MCHAch 6 mya: Human – chimp speciation 6 mya: Human – chimp speciation 9 mya: MHCBh - MHCBch 14 mya:MHCAh - MHCAch MCHBh MCHBch MCHAh MCHAch

Trans-species polymorphism !

Deleterious recessive under partial dominance

The model

Genotype AA Aa aa Frequency p0

2

2p0q0 q0

2

W

1 1 - hs 1 – s

2 2 1

2 1 sq hspq sq hspq q q − − − − =

s = selection coefficient h = degree of dominance h = 0 : dominance is 100%, recessives “hide” in heterozygotes h = ½: dominance is 50%, additive models for phenotypic effect

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Deleterious recessive under partial dominance

Generations Frequency of a allele Effect of partial dominance on the change of the recessive allele frequency under negative selection

0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 52 55 58

Partial Dominance: h = 0.5 s = 0.33 Full Dominance: h = 0 s = 0.33