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Carol Eunmi Lee 10/18/16 Natural Selection Natural An Adaptive Mechanism Selection Evolutionary Mechanisms Darwin Evolution acts through changes in allele frequency at each generation Genetic Drift Non-adaptive Migration According to Darwin, this happens via Mutations Natural Selection Adaptive Natural Selection (HeconsideredSelectiononly,andnot otherevolutionarymechanisms,suchas mutations,geneticdrift,etc.) Sources of Genetic Variation Mutation generates genetic variation Natural Selection Natural Selection acts on genetic or epigenetic variation in a population Epigenetic modification changes expression of genes Genetic Drift can reduce genetic variation Without genetic or epigenetic variation, Natural Selection cannot occur Title goes here OUTLINE (1) General Description of Natural Selection (2) Distinguishing between Phenotypic Plasticity (Acclimation) vs. Natural Selection (Adaptation) (3) Modes of Natural Selection (4) Natural Selection Violating Hardy-Weinberg Equilibrium 1 Carol Eunmi Lee 10/18/16 Darwin’s contribution: Natural Selection Population Speciation as a result of Natural Selection ■ Toomanyoffspringproduced ■ Limitedresourcesandcompetition Differentialfitness (survivalandreproduction) of differentheritable (genetically-basedinherited) phenotypes(NOTplasticphenotypes) becausesome arebettersuitedtotheenvironmentthanothers ■ Variationinapopulation NaturalSelectionleadstoà ADAPTATION ■ Betteradaptedindividualssurvive ■ Survivorsleavemoreoffspring ■ Thus,averagecharacterofpopulationisaltered NOTrandom,butdeterministic 8 Natural Selection Darwin ■ SO… The important point is that Natural Selection is all about who lives and who dies (and reproduces) “Population speciation” The important factor is: FITNESS 9 Darwin Darwin mutation Title goes here Selection favors 2 Carol Eunmi Lee 10/18/16 Selection on pathogens imposed AZT by Drugs (refer to Lecture 1) Darwin ■ Greater Fitness ■ ■ AZT(Azidothymidine)isathymidine mimicwhichstopsreversetranscription Mutationsinthereversetranscriptase geneofHIVarisessuchthattheenzyme canrecognizeAZT ThedrugsimposeSelectiononthevirus. Geneticvariation(generatedby mutations)allowsthevirustorespond toselectionandevolvedrugresistance Evolution of HIV resistance in Human Populations ■ ■ ■ ■ ■ Frequency shift in CCR5- D32 allele CCR5-Δ32 (or CCR5-D32 or CCR5 delta 32) is a mutant allele of the receptor CCR5, where the deletion of a 32 base pair segment makes the receptor nonfunctional Fr The allele has a negative effect upon T cell function, but appears to protect against smallpox and HIV HIV has no receptor to bind to and cannot enter the cell This allele is found in 14% of Europeans HIV can impose selective pressure for CCR5-Δ32, increasing the frequency of this allele in human populations (Sullivan et al. 2001) Amy D. Sullivan et al. 2001. The coreceptor mutation CCR5Δ32 influences the dynamics of HIV epidemics and is selected for by HIV. Proc Natl Acad Sci USA. 98: 10214–10219. Selection imposed by Transmission Rate on Virulence of HIV ■ ■ ■ Need to keep host alive long enough to get passed on to the next host (Evolutionary tradeoff between fast population growth and keeping the host alive) Selection on Virulence ■ High Transmission Rate: will select for High Virulence High Transmission rate : High Virulence (Can grow fast and jump to the next host; ok if host dies; genetic strain that grows faster will win) Low Transmission Rate : Low Virulence (More virulent strains would die with the host and get selected out; less virulent strain will win) 18 Title goes here 3 Carol Eunmi Lee 10/18/16 High Transmission Rate Selection on Virulence ■ Low Transmission Rate: will select for Low Virulence Ifthevirusislikelytomovetoanewhost,thefaster growing(andmorevirulent)strainislikelytoovertake theslowerstrainsand“win” ■ It’soktokillthehost,sincethechancesofjumpingto anewhostishigh ■ ■ NaturalselectionwillfavortheMOREvirulentstrain 19 Low Transmission Rate Ifthevirusisnotlikelytomovetoanewhostthe slowergrowing(andlessvirulent)strainislikelyto “win” 20 Evolution of Virulence ■ ■ It’snotoktokillthehost,sincethechancesofjumping toanewhostislow.Iftheviruskillsthehost,itwillkill itself ■ ■ NaturalselectionwillfavortheLESSvirulentstrain The direction of selection could change as the environment changes 21 22 Conceptual Confusions Selection vs. Plasticity Title goes here Trait variation is often assumed to be due to Adaptation, when the differences might be due to Phenotypic Plasticity or nonadaptive genetic causes 4 Carol Eunmi Lee 10/18/16 Not All Phenotypic Variation is due to Adaptation Phenotypicchangeandvariationcouldhaveother causes: – PhenotypicPlasticity:Changesthatarenotdueto geneticchanges,butduetochangesingene expression Nature vs. Nurture • Bothenvironmentandgeneticsaffectmany traits,butneedtoexperimentallyorstatistically separatethesefactors • How? – ChangesthatareGenetic,butNOTadaptive: • GeneticDrift: randomchance •LinkageandGeneticHitchhiking: Geneticchangesthatoccur becausethegenewasrightnexttoanothergeneonachromosomethat wasunderselection • Constraint:physicalorstructural(liketheSpandrels) Adaptation Requires Natural Selection Requires polymorphism in a population • Example:Common-gardenexperiment • Havingappropriatecontrols • Statisticallyassessingtheeffectofenvironment How can you tell if a trait evolved as a result of Adaptation (and due to Natural Selection)? (1)Thetraitmustbeheritable (2)Thedifferencesbetweenpopulationsare geneticallybaseddifferencesratherthaninducible differences(plasticity) MUST have an effect on Fitness Is a frequency (%) change in a population (3)Thetraithasfitness consequences(promotes survival,performance,andnumberofoffspring) There must be a Selective Force (Ifatraitevolvedduetogeneticdrift,linkageor pleiotropy,thechangeisgenetic,butmayconfer nofitnessadvantage) PhenotypicPlasticity Definition Acclimation (≠ Adaptation) • Differencesinphenotypethatagenotypeexhibits acrossarangeofenvironments,becauseofchanges ingeneexpression • Changesingeneexpressioncouldbecauseby environmentalcuesinstigatingsignaltransduction... changesingeneexpressioncouldalsobecausedby epigeneticmodifications • Sometraitswithaplasticcomponent:intelligence, height,temperaturetolerance,salinitytolerance, musclemass… Title goes here 1) Result of Phenotypic Plasticity 2) Not heritable (Not inherited) 3) Short term or developmental response within a single generation 4) Arises through differential gene expression or other regulatory mechanism rather than natural selection 5 Carol Eunmi Lee 10/18/16 Allele A1 Demo Allele A1 Demo Genetic Drift can interfere with Natural Selection ■ ■ ■ With Selection, what matters is the RELATIVE fitness of different genotypes Recessive deleterious alleles are harder to remove by negative selection because their phenotype is hidden in the heterozygous state ■ For instance, putting 1.0 and 0.9 is the same as putting 1000 and 900 for fitness values of genotypes However, dominant beneficial alleles are more difficult drive to fixation by positive selection, because they are dragging recessive alleles along in the heterozygous state ■ 31 32 Allele A1 Demo ■ ■ However, dominant beneficial alleles are more difficult drive to fixation by positive selection, because they are dragging recessive alleles along in the heterozygous state • Positive Selection: Selection favoring an allele or a heritable trait Although, if recessive beneficial alleles are very rare they will take longer to fix because most will be in the heterozygous (rather than homozygous state) • Negative Selection: Selection disfavoring an allele or a heritable trait 33 SelectiononDominantvsRecessiveAlleles ■ ■ ■ Herron & Freeman Selection against recessive allele Set fitness of genotypes to: WAA = 1, WAa = 1, Waa = 1 – s (s = selection coefficient) Selection against dominant allele Set fitness of genotypes to: WAA = 1 - s, WAa = 1 - s, Waa = 1 (AA and Aa have same phenotype) Title goes here 34 SelectiononDominantvsRecessiveAlleles ■ ■ ■ What Happens? Selection against recessive allele In Allele A1, set fitness of genotypes to: WAA = 1, WAa = 1, Waa = 1 – s (s = selection coefficient) Selection against dominant allele Set fitness of genotypes to: WAA = 1 - s, WAa = 1 - s, Waa = 1 (AA and Aa have same phenotype) 6 Carol Eunmi Lee 10/18/16 SelectiononDominantvsRecessiveAlleles ■ Selection against recessive allele: ◆ ◆ Selection on Discrete vs Continuous characters ■ As recessive allele becomes rare, rate of its disappearance slows down As homozygote recessive allele becomes rare, most are in the heterozygous state and are masked from selection ◆ ◆ ■ ■ Selection against dominant allele: ◆ Whenphenotypesfallintodiscreteclasses,wecan thinkofselectionactingdirectlyongenotypes Dominant allele that is disfavored by selection is removed quickly from the population Suchdiscretetraitsareusuallycodedbyoneorafew genes(loci) Mendel’syellowvs.greenpeas However,whenphenotypesfallintoacontinuum, becausetheyareencodedbymanyloci,youwillsee changesinthedistributionsoftraits(nextslide) ◆ ◆ ContinuoustraitssuchasthoseDarwinexamined,beak shape,bodysize,haircolor,etc. suchtraitsarecalled“quantitativetraits” 38 Distribution of discrete versus continuous traits Frequency ina population Trait1 Trait2 DiscreteTraits:Traitsthatoccur indiscretecategories; Examples: Mendel’straits(green andyellowpeas,wrinkledand smoothpeas) (theseareencoded bysingleloci) Alsodiscretetraitsencodedby multipleloci:fingernumber, clutchsize Modes of Selection ContinuousTraits:Traitsthat varyalongacontinuum; (mosttraits) Examples:bodysize,height, IQ,bloodpressure,milk yield,fatcontent,feather color,beakshape,limb length,haircolor,etc... 39 DIFFERENT MODES OF SELECTION Directional Selection: Directional Selection Stabilizing Selection Disruptive Selection Selection favors an extreme phenotype and causes a shift in allele frequencies toward that direction Balancing Selection ■ Genetic diversity is reduced at the relevant loci (knock out maladapted genotypes) ■ Examples: ■ ■ ■ 41 Title goes here Drug-resistance in tuberculosis and HIV Agriculture: artificial selection for specific traits Sexual selection for a trait (e.g. for 42 bright plumage, peacock tail) 7 Carol Eunmi Lee ■ 10/18/16 Does sexual selection typically act on more on males or females? 43 Sexual Directional Selection: Pheasants Selection favors an extreme phenotype and causes a shift in allele frequencies toward that direction Unable to Reproduce 44 ■ Most of the males do not mate, so their genotypes (and phenotypes) are removed from the population à genetic diversity reduced at the relevant loci ■ The population shifts toward the extreme trait (e.g. plumage, body size, etc) zero 30+ Largevarianceinmale reproductivesuccess, withmanyproducing fewtonooffspring,and afewmalesproducing lotsofoffspring 45 Directional Selection on pathogens imposed by Drugs • In the presence of AZT, Natural Selection favors mutants that are resistant to AZT (blue, have (refer to Lecture 1) ■ ■ ■ 46 slow & careful enzyme) AZT AZT(Azidothymidine)isathymidine mimicwhichstopsreversetranscription Results in %change in the population, toward higher % of AZT resistant mutants Mutationsinthereversetranscriptase geneofHIVarisessuchthattheenzyme canrecognizeAZT ThedrugsimposeSelectiononthevirus. Geneticvariation(generatedby mutations)allowsthevirustorespond toselectionandevolvedrugresistance Title goes here 47 48 8 Carol Eunmi Lee 10/18/16 Directional Selection Directional Selection on a continuous trait 49 Directional Selection during Domestication ■ ■ ■ Corn Morphological differences between teosinte and maize Rapid evolution under intense directional selection for large and numerous kernals ■ • Has branching patterns like teosinte Selection by humans for a few regulatory genes (affecting transcription) Reduced genetic diversity in domesticated corn Genes selected for in Corn teosinte maize Hardy Weinberg revisited F1 Hybrid Teosinte Major morphological differences are due to directional selection on 5 genes Genes: • Teosinte branched1 (tb1): single mutation affects branching and inflorescence • Regulator of tb1 • tga glume (outer coating) reduction on chromosome X • teosinte – ~8-12 kernels F1 hybrid 8 rows, corn 20+rows Evidence for selection in 2-4% of genes, ~1200 genes Title goes here Maize with tb1 knocked out Generation 1 Generation 2 Generation 3 AA Aa aa 250 750 900 500 200 90 250 50 10 (1) Is this population remaining in HW Equilibrium from generation to generation? (2) What might be going on? 9 Carol Eunmi Lee 10/18/16 AA Hardy Weinberg revisited Generation 1 Generation 2 Generation 3 AA Aa aa 250 750 900 500 200 90 250 50 10 aa 0.40 0.60 0 Gen2 Freq of A (p) = 0.75 + (0.20/2) = 0.85 **Genotype frequencies deviated from expectations based on allele frequencies: freq of A is 0.5 in Gen1, so expect AA =0.25 at Gen2, 55 (2) What might be going on? Directional selection favoring AA? Hardy Weinberg revisited AA Aa aa 0.40 0.60 0 (1) Is this population in HW Equilibrium? NO (2) Are the HW expectations the same as the genotype frequencies above? NO (2) Are the HW expectations the same as the genotype frequencies above? Freq of A (p) = 0.40 + (0.60/2) = 0.70 Freq of a (q) should be = 1 - 0.70 = 0.30 Hint: Calculate the genotype frequencies from the # above, and then calculate allele frequencies. Use the allele frequencies to calculate HW expectations. 57 Stabilizing Selection ■ Selection favoring intermediate trait values ■ The average trait value stays the same ■ Genetic diversity is reduced at the relevant loci ■ Examples: Favors Freq of A (p) = 0.25 + (0.50/2) = 0.50 Freq of a (q) should be = 1 -0.50 = 0.50 **Allele and genotype frequencies are changing across generations: freq of A is increasing across the 3 generations (1) Is this population in HW Equilibrium? (3) What might be going on? Gen1 Freq of a (q) = 1-0.85 = 0.05 + (0.20/2) = 0.15 Hardy Weinberg revisited Aa 250 50 10 Gen3 - can do same calculations ***check if (a) alleles frequency changes across generations and (b) where allele frequency yields predicted genotype frequencies AA aa (1) Is this population remaining in HW Equilibrium from generation to generation? NO (1) Is this population remaining in HW Equilibrium from generation to generation? (2) What might be going on? Aa Generation 1 250 (freq = 250/1000) 500 Generation 2 750 (freq = 750/1000) 200 Generation 3 900 (freq = 900/1000) 90 First convert # of individuals to frequency of genotypes Based on HW expectations, freq of aa should = 0.3 x 0.3 = 0.09 aa is missing! aa might be a homozygous recessive lethal 58 à Negative selection acting against aa? Example of Stabilizing Selection Selection for an optimal number of eggs Selection for an optimal number of fingers Selection for optimal body size 59 Selection for optimal number of offspring Title goes here 10 Carol Eunmi Lee 10/18/16 Disruptive Selection Disruptive Selection ■ Selection favors the extremes ■ Genetic diversity is increased (favor novel beneficial alleles; knock out alleles that code for intermediate traits) ■ Can lead to formation of new species ■ Examples: ■ ■ ■ ■ Balancing Selection ■ Balancing Niche Partitioning (Specialization on different resources, food) Differences in habitat use Will discuss more in lecture on Speciation Sexual selection for different traits (blue birds mate with blue, red birds mate with red)—intermediate colors selected against (on discrete or continuous traits) Balancing Selection ■ Selection is a generic term to refer to any type of selection that acts to maintain genetic variation in a population ■ There are different mechanisms: Fluctuating selection, selection favoring heterozygote (overdominance), frequency-dependent selection, etc. ■ Examples: ■ ■ ■ Selection for heterozygotes (sickle cell anemia, and cystic fibrosis) Selection for different traits in different environments Selection for different traits at different times (fluctuating selection) Overdominance: Selection favoring the heterozygote Generation 1 Generation 2 Generation 3 Generation 1 Generation 2 Generation 3 ■ ■ ■ Genetic diversity is maintained in a population in this case because the heterozygote maintains both alleles ■ Example: Sickle Cell anemia An Example of one mechanism: Generation 1 Generation 2 Generation 3 In this case, allele frequencies (of A and a) do not change. However, the population did go out of HW equilibrium because you can no longer predict genotypic frequencies from allele frequencies Title goes here ■ Overdominance: Selection favoring the heterozygote aa 0.25 0.20 0.10 For example, for p = 0.5, the HW expected p2 = 0.25, but in Generation 3, the observed p2 = 0.10 aa 0.25 0.20 0.10 64 Overdominance: Selection favoring the heterozygote Aa 0.50 0.60 0.80 Aa 0.50 0.60 0.80 Balancing Selection An Example of one mechanism: AA 0.25 0.20 0.10 AA 0.25 0.20 0.10 63 Balancing Selection ■ An Example of one mechanism: ■ 65 AA 0.25 0.20 0.10 Aa 0.50 0.60 0.80 aa 0.25 0.20 0.10 Why is this NOT stabilizing selection? In Stabilizing Selection, genetic diversity decreases as the population stabilizes on a particular trait value (a multilocus quantitative trait, like body size, height, clutch number, finger number, intermediate 66 color –typically of a multilocus nature) 11 Carol Eunmi Lee 10/18/16 Sickle cell anemia Sickle cell anemia example of balancing selection ■ ■ ■ Reducedabilityofredbloodcellstocarryoxygen (mutationinHbSgene,makesdefectivehemoglobin protein) HAHA:homozygous,noeffectsofdisease(sicklecell anemia) ■ HAHs:heterozygotes,suffermildeffects ■ HsHs:homozygous,usuallydiebeforereproduction ■ ■ In the absence of malaria, which genotype would be favored? Which mode of selection would be acting? 68 Sickle cell anemia When Malaria is present HAHs advantage: red blood cells with abnormal hemoglobin tend to sickle when infected by parasite and are culled out ■ When Malaria is not present, AA advantage: US African Americans: 91.26% H A H A ; 8.54% H A H s ; 0.2% H s H s ■ ■ With malaria, balancing selection favors the heterozygote ■ Without malaria, directional selection favors HAHA 69 When Malaria is present HAHs advantage: red blood cells with abnormal hemoglobin tend to sickle when infected by parasite and are culled out With malaria, balancing selection favors the heterozygote because of increased malaria resistance, even though oxygen carrying capacity is lowered Example from Africa: 73.7% HAHA; 24.3% HAHs; 2% HsHs ■ In the presence of malaria, which genotype would be favored? Which mode of selection would be acting? 67 Sickle cell anemia ■ BUT... When Malaria is present HAHs advantage: red blood cells with abnormal hemoglobin tend to sickle when infected by parasite and are culled out ■ The homozygous wild type HAHA is disfavored because resistance to malaria is low The homozygous mutant HsHs is disfavored because it is 70 lethal Hardy Weinberg problem using actual data ■ ■ ■ 71 Title goes here 1 in 5000 individuals have sickle cell disease and are homozygous for the sickle cell hemoglobin (HsHs) What are the expected genotype frequencies of the HAHA, HAHs, and HsHs genotypes in the population? What are the frequencies of HA and Hs alleles? 72 12 Carol Eunmi Lee 10/18/16 ■ Detecting Selection ■ ■ RNA Codons (1) So, how does one detect Natural Selection in a population? Many types of tests The challenge is distinguishing natural selection from signatures of Genetic Drift Simplest Test: Ka/Ks Test Nonsynonymous substitution rate Synonymous substitution rate In the case of amino acids § Mutations in Position 1, 2 lead to Amino Acid change § ■ Ks is used here as the “control”, proxy for neutral evolution ■ Synonymous substitution rate ■ ■ ■ A greater rate of nonsynonymous substitutions (Ka) than synonymous (Ks) is used as an indication of selection (Ka/Ks >1) Substitution rate: out of all the possible number of mutations, how many fixed Summary Ka/Ks Test Nonsynonymous substitution rate = 1 Need coding sequence (sequence that codes proteins) ■ (1) Ka Ks > ■ Mutations in Position 3 often don’t matter § = Ka > Ks 1 (1)OftheevolutionaryforcesthatcandisruptHWEquilibrium, NaturalSelectionistheonlyonethatisadaptive In the absence of selection, you’d expect Ks = Ka, and for Ka/Ks = 1 (2)Selectionoccursthroughdifferentialreproductionwhichis NOTrandom A greater rate of nonsynonymous substitutions (Ka) than synonymous (Ks) is used as an indication of positive selection (Ka/Ks >1) (3)Naturalselectionrequiresgeneticvariationuponwhichitcan act If Ks > Ka, or Ka/Ks < 1, that would suggest purifying selection, that selection might be preserving amino acid composition Title goes here (4)Therearedifferentwaysinwhichselectioncanact(favoring theextremes,orheterozygotes,orunidirectional) 13 Carol Eunmi Lee 10/18/16 The following are numbers of red, pink, and white flowers in a population. Concepts Natural Selection Fitness Directional, Stabilizing, Disruptive Selection Balancing Selection Selection on dominant vs recessive alleles (A1A1) Red (A1A2) Pink (A2A2) White Generation 1: 400 200 400 Generation 2: 600 100 300 Generation 3: 500 0 500 1. Is the population above in Hardy-Weinberg Equilibrium? (A) Yes (B) No (C) Yes in the first generation, but No in the third generation (D) No in the first generation, but Yes in the third generation 2. What are the frequencies of alleles and genotypes at Generation 3? (A)A1: 0.50, A2: 0.50 A1A1: 0.25, A1A2: 0.50, A2A2: 0.25 (B)A1: 0.65, A2: 0.35 A1A1: 0.60, A1A2: 0.10, A2A2: 0.30 (C) A1: 0.50, A2: 0.50 A1A1: 0.50, A1A2: 0, A2A2: 0.50 (D) 3. In the previous example (from question #1), what might be going on? (A) Genetic Drift (B) Balancing Selection (C) Recombination (D) Directional Selection (E) Disruptive Selection (but, rare for single locus trait) A1: 0.50, A2: 0.50 A1A1: 0.25, A1A2: 0, A2A2: 0.25 Answers: 4. What would Darwin say? (A) Genetic drift is also an important evolutionary force that occurs through random survival and reproduction (B) Individuals pass alleles onto their offspring intact (inheritance is particulate) 1B 2C 3E 4D (C) Selection acts on genetic variation such as Mutations (D) Selection acts on differential fitness of individuals that vary in heritable traits in a population (E) Evolution occurs at the level of the individual Title goes here 14