Population Genetics 6: Natural Selection Natural selection GENETIC VARIATION DIFFERENTI AL SUCESS EVOLUTION + ⎯ ⎯→ This genetic prefix is important as the This has two components : (i) reproducti on For this part of the course, variation must be heritable. Change in and (ii) survival in a particular environmen tal we define evolution as change this portion of the equation is undirected . context. This portion provides a direction to in allele frequencie s evolutiona ry change (undirected) (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 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] 4
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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 Nucleoside RT Protease inhibitors: Fusion inhibitors: Non-nucleoside RT inhibitors : inhibitors : These work at final Inhibit the fusion of HIV The first effective class of The newest class of HIV stage of virus life cycle. with target cell antiretroviral drugs. They prevent proper membrane. drugs. assembly and release They mimic A,C,G or T. Bind directly to reverse Administered by of mature HIV virus. injection transcriptase and prevent They incorporate synthesis of DNA from themselves into growing RNA template DNA polymer and act to disrupt the replication complex. 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 5 6 7 No drugs Single drug therapy High polymorphism Low polymorphism Low resistance High resistance Fitness in diploids Evolutionary fitness is symbolized with W Symbolism Genotype AA Aa aa Phenotype W AA W Aa W aa 1 1 0.76 11
Directional selection 1 W AA > W Aa > W aa 0.8 Fitness 0.6 0.4 0.2 0 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 0.8 W AA < W Aa > W aa Fitness 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
Underdominant selection 1 W AA > W Aa < W aa 0.8 Fitness 0.6 0.4 0.2 0 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 Symbolism for generation 0 Genotype AA Aa aa 2 2 Frequency p 0 2 p 0 q 0 q 0 Phenotype W AA W Aa W aa W AA : W Aa : W aa Survival ratio: p 2 W AA : 2 pq W Aa : q 2 W aa Genotype ratio: Problem: the genotype ratios do not sum to 1. 13
Fitness in diploids Normalize by dividing by the grand total after selection: W = p 2 W AA + 2 pq W Aa + q 2 W aa W = AVERAGE FITNESS W W W Aa aa AA Normalized fitness: and and W W W 2 2 p 2 pq q 1 + + = W W W 2 2 AA Aa aa p 2 pq q 1 + + = W W W p 1 = p 2 + (1/2)2 pq Under HW: + (1/2)2 pq ( ) With selection: p 1 = p 2 ( ) W Aa W AA W W 14
Selection simplified … p 1 = p ( p W AA + q W Aa ) / W ⇐ Remember these. q 1 = q ( p W Aa + q W aa ) / 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 15
Deleterious recessive Our model Genotype AA Aa aa Frequency p 0 2 2 p 0 q 0 q 0 2 W 1 1 1 - s We specify the fractional reduction in survival by the selection coefficient, s . W = p 2 (1) + 2 pq (1) + q 2 (1- S ) (average fitness) W = p 2 + 2 pq + q 2 - S q 2 W = 1- q 2 S (average fitness, simplified) Deleterious recessive q 1 = q ( p W Aa + q W aa ) / W By substitution … q 1 = q ( p ( 1 ) + q ( 1 - s ) ) / 1 - sq 2 q 1 = q ( p + q - sq ) / 1 - sq 2 q 1 = q (1 - sq ) / 1 - sq 2 2 / 1 - sq t 2 q t +1 = q t - S q t The per generation change in allele frequency due to selection against a deleterious recessive trait 16
Deleterious recessive Peppered moths in polluted environment Dark form Light form Genotype AA Aa aa Frequency at birth p 2 2 pq q 2 Fitness 1 1 1 - s Let p = 0.06 and q = 0.94 Change in recessive allele frequency over time (in generations) 1 Biston betularia : 0.9 Frequency of a allele s = 0.33 Dark allele (A) is dominant 0.8 0.7 Light allele (a) is recessive 0.6 0.5 0.4 In polluted environment, the light 0.3 allele is deleterious 0.2 0.1 0 One empirical estimate of s = 1 4 7 10 13 16 19 22 25 28 31 34 37 40 43 46 49 0.33 Generations Directional selection for dominant allele Deleterious recessive Change in recessive allele frequency over time under different intensities of negative selection 1 s = 0 0.9 s = 0.01 0.8 Frequency of a allele 0.7 0.6 s = 0.1 0.5 s = 0.5 s = 0.9 0.4 0.3 0.2 0.1 0 1 26 51 76 101 126 151 176 201 226 251 Generations s < 0.5 17
Deleterious dominant Recall: Directional selection 1 W AA > W Aa > W aa 0.8 Fitness 0.6 0.4 0.2 0 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 0 2 2 p 0 q 0 q 0 2 W 1 - s 1 - s 1 Biston betularia : Dark allele (A) is dominant Light allele (a) is recessive 2 q sq sq − + q = ( ) 1 2 1 s 1 q 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 0.9 s = 0.05 Frequency of A allele 0.8 s = 0.1 0.7 s = 0.2 0.6 s = 0.5 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 0.8 W AA < W Aa > W aa Fitness 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 Genotype AA Aa aa Frequency p 0 2 2 p 0 q 0 q 0 2 W 1 – s 1 1 1 – s 2 2 q s q − 2 q = 1 2 2 1 s p s q − − 1 2 Let ’ s look at an example: s 1 = 0.3 and s 2 = 0.1 Overdominance (Balancing selection) Let s 1 = 0.3 and s 2 = 0.1 Stable equilibrium resulting from overdominant selection 1 0.9 0.8 Frequency of a allele Stable polymorphism: 0.7 q = 0.75 p = 0.25 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
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