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Queen's University
BIOL 206
Christopher G Eckert

Biology 206 Notes: Lectures 1-9 Lecture 1: Introduction to the Class Lecture 2: A case for evolutionary thinking – HIV Chapter 1 1. Biology of HIV/AIDS - Among the worst epidemics ever o Infected 65 M people, killed 25M ppl o Quantity and quality of life is reduced o Success of preventing the spread but infected rates still increasing in some areas – drugs users, third world countries - Caused by a retrovirus o Virion enters the host cell and the gp120 protein binds to CD4 and co-receptor (CCR5) on the immune cells, then the virion injects the host cell with the DNA and needed replication machinery (genome, reverse transcriptase and integrase) then the machinery replicates the genome o Integrase splices the genome into the host cell’s genome so that the host replicates it and then creates new virions to be passed on to other healthy cells o Reversed flow of genetic information – looking for how the treatment can disable the virus but not the host - Kills people by attacking the immune system o Doesn’t actually kill the person directly – people become more susceptible to other diseases because of AIDS o Finite capacity for replication by the T-cell lineages o Helper T cells are targeted o Host immune system contributes to immunodeficiency and the host dies of a 2 degree infection - Key point about infection: o HIV infects CD4 and CCR5 - CXCR4 on the naïve helper T cells o Naïve and memory helper T cells are long lived and are attacked by the virus, only the naïve T cells can make more helper T cells o Anti-bodies and killer T cells recognize the HIV viral protein epitopes o Reverse transcriptase is very error prone - Course of infection (3 Phases) o Acute: spike in viral load, death of immune cells with CD4 and stimulation of the immune system o Chronic: reduced viral load, immune cell recovery, but immune system stimulated, host is asymptomatic o AIDS: immune function is eroded by the chronic phase, host is prone to infection by bacteria and fungi, (no treatment – dies in 2-3 years) 2. Drug Resistance - Evolution by natural selection: o Phenotypic variation in a trait allows different receptors to arise – virus cant bind and is ineffective to the host o Genetic basis to phenotypic variation; Individuals vary in survival and reproductive success (fitness) and variation in the trait influences the fitness - Drug therapy o Variation in fitness among the virus genotypes can affect the type of treatment that needs to be developed o Is there a genetically based trait that influences the fitness during the treatment? o Azidothymidine (AZT)  AZT replaces the base thymine during reverse transcription and azide group blocks the reverse transcriptase  Is successful at first but then the cells got used to it and the virion evolved - HIV found a new formation that wouldn’t use the AZT and would only accept the proper base  The AZT is a short term drug bc it can only be used for 6 months- a year before the HIV evolves  Hiv changes the structre of the reverse transcriptase - Resistance Evolution o Variation: increased by the very high error rate of RT – highest mutation rate known o Population size: likelihood of a resistant genotype high in huge viral populations o The Trait: mutation in reverse transcriptase active site – convergent evolution 3. Evolution of virulence - What is the fitness of a pathogen? o Replication (virulence) : exploitation of the host cells leads to the host disease and death – the ability to replicate itself very successfully without using very much energy and surviving o Transmission: the ability of the pathogen to transmit its offspring to new hosts  Does a successful pathogen have to kill its host? Can it kill the host?  Is pathogen evolution short-sighted? Doesn’t seek long term gain?  Depends on the relation between the replication and the transmission - Thought: what aspects of an AIDS infection influence the virus fitness o Increase in the number of immune cells produced – higher chances of infection of the host cells - Epitope evolution during the chronic phase o A sequence change in the outer envelope of the gp120 protein o Increase in the viral load o Then the gp120 stops changing o Has the virus lost capacity to evolve further or has natural selection on the epitope relaxed? - Evolution of a more aggressive replication o Lab assay of viral competitive ability o Virions that target co-receptors (CXCR4) and reduced host capacity to make the immune cells - Virulence (replication) vs. Transmission: o Longer asymptomatic period = better chance of transmissions  The CXCR4 virus strains suffer low transmission but replicated more o Higher viral load in the host = better chances of transmission  Lower transmission of attenuated strains with mutant nef genes  HIV-2 less widespread than HIV-1 4. Resistance to HIV - Genetic basis for variation in latency & probability of infection o Latency: length of time in chronic phase  Hypothesis – is it caused by a variation in the co-receptor molecules? o 32 –base deletion in CCR5 sequence – tying to change the protein structure to combat the virus - deletion in the CCR5 also inhibits SIV  Hypothesis – the selection will increase the base deletion of 32 frequency where the HIV is most prevalent 5. Evolutionary origins of HIV - View lecture 4 section 4 – using trees Lecture 3: Evolutionary Patterns Chapter 2: 1, 2 Chapter 3: 1 – 4 1. Special Creation - Pattern of life’s history o Species don’t change through time o Created independently o Earth an species created recently - Process of creation o Separate and independent acts of creation by a supernatural designer o Separate acts of creation that are independent from each other 2. Change through time - Evidence from living species o Can see evolutionary change in bacteria and short-term organisms that grow at a rapid rates – high rates of mutation and change Vestigial organs: useless or reduced version of a structure that has an important function in one species but none in the reduced version species o many examples of vestigial organs in textbook o vestigialization of attractive traits after a shift to self-fertilization in flowering plants - Evidence from the fossil records o Fact of extinction: rich, stratified record of species that no longer exist – the fact that species became the losers in the race for fitness and died out o Law of succession: fossil and living species in the same region related and distinct from those in other regions - can see organisms that are related and are more fit than the ancestors o Transitional forms: trait transitions in the fossil record, not necessarily direct lines of descent - can see traits that have changed over time but are obvious to have evolved to form a better version of it 3. Common ancestry - Phylogenetic analysis: o “The tree of life” – can relate organisms to each other in phylogenetic trees based on looks, genotypes and differences o Ring species: that one species can turn into two – ex. The Siberian greenish warblers (bird) – they won’t interbreed with species in different locations, can tell by the different songs– north and south will interact but not east and west = speciation due to geographical constraints - Homology of Traits Homology: Similarity in position, structure, and evolutionary origin but not necessarily in function of a part of the organism – i.e. similar structure o Structural and developmental homology most consistent with the descent from the common ancestor o Molecular homology – huge amount of evidence arising from large scale genomic sequencing o Fundamental molecular evidence from the university of genetic code and pseudogenes and genetic flaws - Molecular homology of pseudogenes o Where the processed pseudogenes come from  Non-functional copies of normal genes that originate when processed mRNAs are accidentally reverse transcribed to DNA and inserted back into the genome at a new location – lack introns and promoters so they are recognized by the mother genes  They are inevitable – shared ones are most consistent with shared ancestry – can track their changes between organisms and ancestors and date them – the more mutations the older – can mutate without consequence to the organism 4. Mechanisms of change - The 4 evolutionary forces: Mutation: creates new genetic variation – alleles, loci, chromosomes Genetic drift: random fluctuation in the allele frequency in the population based on the demography Gene flow: mixing between populations to get new/different genes Natural selection: non-random changes in the allele frequencies – Darwin’s main mechanism of modification - Concept of natural selection inspired by the amazing results fo artificial selection o Crops, animals, pets, long term selection, experimental evolution (labs) o Example of the animals (chicken – dancing?  caused by a recessive loss of function mutation at a single locus – fibroblast growth factor 20) - Natural Selection: 4 testable postulates: o Do the individuals vary – phenotypic variation o Is some of the variation among the individuals heritable - can it be passed on to progeny? o Do the individuals vary in survival or reproductive success – the variation in fitness of the organism o Are the survival and reproduction non-random with respect to the phenotypic variation? – trait-fitness co-variation? Is reproduction non-random? - Example of Darwin’s finches in the Galapagos islands - Issues that complicate how the heritabilities are estimated o Misidentified paternity – females sometimes have extrapair sex – social dad isn’t real dad and they act like they are related o Conspecific nest parasitism – some birds lay their eggs in other’s nests and the social parent isn't related to the actual kids o Shared environments – the environment will be correlated to a phenotypic trait but there is no relation between the heritability of this trait o Maternal effects – differences in the nutrient stores and the hormonal contents of the eggs – from the mothers only – combatted by testing the heritability from the fathers Lecture 4: Evolutionary trees Chapter 4 1. Logic and terminology - How to read a tree: o Existing species are at the very end of the tree “most recent” - the dead ancestors are higher up and relate to the extant species o A node is a speciation event – new species created - An important aspect of the tree topology is the pattern of common ancestry - They imply evolutionary groupings Monophyletic – common ancestor and ALL the descendent taxa Polyphyletic – Derived from more than one common evolutionary ancestor or ancestral group and therefore not suitable for placing in the same taxon Paraphyletic –common ancestor or ancestral group, but not including all the descendant groups Synapomorphy – homologous trait that is shared in among the species and is similar because it was modified in a common ancestor Convergent evolution – occurs when the natural selection favors a specific trait or structure among different organisms as a solution to a problem present in their environments Homoplasy – convergence and reversal (=the reversal of a DNA sequence from the original sequence between 2 generations , i.e. the kid has the same gene as his grandpa but his dad is different) Synplesiomorphy – shared ancestral character state (not informative) Autapomorphy – unique derived character state (not informative) 2. Building trees - First – you need data o Best traits to use are homologous ones – character states that can be compared across taxa o Traits- morphological, behavioural, physiological, metabolic, ecological – deeper branches of an evolutionary tree or life can involve some very divergent taxa o DNA sequences provide useful data – solves problems with the homology (ACGT) but there are varying rates of change - Phenetic / distance methods o Phenetic methods – approaches based on the overall resemblance – superficial o They quantify the proportion traits or the character states shared between the two taxa o They calculate the index of similarity – converting the discrete character data (presence or absence of a nucleotide or morphological trait) into a distance value - what we did in the lab – calculating the number of differences in nucleotide sequences of a trait to determine how close they are - Cladistic methods and parsimony o Based on a trait by trait analysis: shared derived character states – synapomorphy (syn-shared, apomorphy –derived state), synplesiomorphy, autapomorphy o Only the synapomorphies can define the monophyletic groups o Always choose the most parsimonious tree – the easiest and most simple tree that makes sense - Outgroup analysis + parsimony: o Analysing the traits by who has what and who doesn’t o Example: looking at the color and structure of a flower – which ones have petals, color and how many leaves… o Rooting trees through the outgroup analysis indicated historical sequences – what came first and what developed through time - Cladogram – all of the tree – not showing the actual arrival of the species i.e. what time they arose - Phylogram – shows all of the tree and the times that the species came about – length of tree shows the rate/amount of evolution - Statistical methods: o Specify a mathematical model of the character state change – easier for DNA than morphology o Maximum likelihood: given the specified model of state change and a tree with a particular topology, how likely are these DNA sequences? (or other character states?) o Bayesian Analysis: what is the probability of this tree being correct given the model of state change and the DNA sequences? 3. Testing trees as hypotheses - Phylogenetic Trees are hypotheses o They specify patterns of a common ancestry – none of them are written in stone and are always changing based on the new evidence that is found o An unresolved “node” is a polytomy o Conflicting trees get combined into a consensus tree - Parsimony trees are tested with bootstrapping: o For “k” traits – draw random samples with a replacement of the k traits and redo the tree (repeat several times to get more accurate trees) o What proportion of the trees exhibit each grouping? – ex: lobed –fin fished – 29 morphological traits - Maximum likelihood and Bayesian trees are tested statistically o Likelihoods computes and compared between the alternative trees - Ultimately all the phylogenetic hypotheses are tested by collecting and analyzing more data for more taxa o Morphology vs molecular o Mitochondrial vs nuclear DNA 4. Using trees - Phylogenetics now used widely in all areas of biology and medicine o Used from systems for classifying the diversity of life to the origins of disease – causing agents – where did HIV come from and how did it move among human populations? o Informative uses of phylogenetics include dating events that are poorly documented in the fossil records, analyzing the geographic distribution of species and studying co-evolution o Origin of HIV – from different possible ancestors – may have evolved and converged, may have originated in certain locations or different multiple locations – different types of HIV from different ancestors - Environmental genomics o Metagenomics = sequencing DNA belonging to unknown species collected from the environment and trying to classify them based on molecular genetics and trees o Especially useful for studying bacteria & fungi as most species aren’t cultured - Novel phototrophy in marine bacteria o Collected marine bacterioplankton in a tow and extracted DNA was subjected to a pulsed field electrophoresis to isolate large pieces of the DNA – cloned and put in library – found a gene for proteorhodopsin in a clone which codes for a trans- membrane proton pump o Then related the new gene to other rhodopsin genes from prokaryotes and eukaryotes  Generates ATP  energy to fuel biochemical processes o Light – powering Escherichia coli with proteorhodopsin  Proteorhodopsin (PR) increases the proton motive force (pmf) across a bacterial membrane  Is expressed in E coli hosts  The speed of eh E coli flagellar motor increases with pmf Lecture 5: Evolutionary Science vs. Creationism Chapter 2: 4 Chapter 3: 7 1. What is science? - Universally repeatable way of knowing o Poses hypotheses that make predictions amenable to testing are this falsifiable – asking questions about the world we live in s o A focus on how a result was obtained ensures repeatability and can be tested by anyone, anywhere o Peer review:  When studies are conceived the proposal in reviewed by other scientists  Before any results are published they are reviewed by other scientists  Granting agencies and refereed journals have high rejection rates o Ontological versus methodological naturalism – difference between running experiments and saying that it was magic – and running experiments and determining the true cause of a process: methodological scientists can believe in god outside the lab but in the lab there is no such thing as a supernatural force, ontological is to run an experiment with no such thing as supernatural force and saying that there is no god 2. What is creation science? - Young earth creationism o Institute for creation research  Duane Gish – defies evolution and fossils  Henry Morris – scientific creationist  Canada has a museum for it o Legal battles in the US over teaching it and evolution in schools (mostly in the south) - Intelligent design: a more scientific creation science o List of books by creationsists o Basically saying that God designed life to be evolutionary and that he watched from afar yatta yatta yatta o Darwin’s Black Box – being able to use evolution to see God’s plan o The wedge Manifesto – saying that evolution is making humankind less human – saying that we are slaves to biological processes – we are the difference between being civilized and spiritual and being animals o The Wedge strategy  General Goal • Nothing less than the overthrow of materialism and its cultural legacy – replace it with a theistic understanding of nature  General tactics • Scientific research • Legal action on school curricula • Publicity and opinion making • DISAVOW RELIGIOUS MOTIVATIONS o Irreducible complexity proves design – an irreducibly complex biochemical pathway – lots of stuff and communication in between the start and the end of a process – lots of intermediates  I mean a single system composed of several well-matched, interacting parts that contribute to basic function, wherein the removal of any one of the parts causes the system to effectively stop functioning o Irreducible complexity of the Blood clotting cascade  None of the cascade proteins are used for anything other than the formation of a blood clot  Duplication of other genes and subsequent selection yielded all the clotting factors  Clear genetic relations among the clotting factor genes  Basal organisms without the clotting cascade have the protein domains from which clotting factors evolved o Is intelligent design falsifiable?  Feature that strike us as having odd design might have been placed there by the designer for a reason, for variety, to show off, for some as-yet- undetected practical purpose or for some un-guessable reason – or they might not - Intelligent design isn't tested isn’t peer reviewed in scientific literature – it just gets published in books and radical theories by churches and stuff o No papers to this day actually testing ID - The Dover PA court battle o Quote on legal stuff - The war over public opinion o Biased media coverage o Coverage by reporters with little or no scientific training o Misconceived concern for balance or fairness – equal time implies equal evidence o Clear bias towards creationism by some media outlets 3. The rise of anti-empiricism - Blatant misrepresentation of evolutionary science in the media o Article saying dumb shit about evolution - Manufacturing doubt – telling people to ask their teacher and others who don’t know very much about the subject and them giving dumb answers - Inertia of doubt about evolution o Statistics – 45-50% don’t believe in evolution - Distortion and misrepresentation of science is increasingly common o People putting mass misrep. Of what scientists are saying – climate change example – all scientific papers say the same thing – why is there doubt? o Book – Merchants of doubt – why are scientists denying the truth??? Lecture 6: Mutation Chapter 5: 1 – 3 1. Sources of new alleles – Mutation and Recombination - Important background from 205 o Structure of the DNA o Replication, transcription, translation o Genetic code and its redundancy o Synonymous vs. nonsynonymous mutations o Chromosome structure and meiosis - Mutation accumulation experiments estimate the rate and effect of mutations o Start with an ancestral genotype o Create independent lines with single-individual descent o Minimize the mortality and selection o Measure the change in mean and variance of fitness across generations - Mukai mutation experiment on accumulation of mutations with fruit flies o Females carry the balancer chromosomes as there is no crossing over, a dominant marker and lethal recessiveness o Results show a mean line across generations and is equal to gene U times s, an increase in variance can estimate gene U and the misses are the lethals and the synonymous mutations o The individual replicate lines are getting more and more different from each other o Introducing variance in the populations - increasing and decreasing in fitness depending on the mutations present o Rate of mutation - increase in the variance of the mutations - Mutation accumulation with direct sequencing of the DNA o The worm - C elegans o Selfing o 50 independent lines for 396 generations of no selection o Sequences 10kbps of nuclear DNA o Found 17 indels and 12 point mutations  Means that there are approximately 2.1 mutations per genome per generation - Mutation rate can very within and between species o MA experiment for 200 generations with 3 species and 2 strains per specie o Showed a decline in fitness varied among the species and varied among strains for 2/3 spp o Update of the Baer et al. MA lines – 2 spp, 2 strains/sp, several lines/strain, 50 generations, millions of bp of DNA sequenced o No difference between the species or strains - Other work reveals broad variation in the mutations due to DNA error repair o Variation in DNA polymerase accuracy in bacteriophages o There is a trade-off between accuracy and replication speed of RNA virus polymerase o Mutation in the genes are responsible for the mismatch repair increae mutation rates in E. Coli, Salmonella and C elegans o E coli with elevated mutation rates have high fitness in novel environments - Effect of mutations o Most mutations affect the organism negatively and decrease the fitness of the organism o Good mutations take time to take place o Expect a spectrum of effects – lots of neutral o New mutations are bad but mild  created a single insertion mutation at a random locations and compared the growth rate to control (without insertion)  E coli – significantly different than zero (exp 1 & 2) 2. Gene duplication - Two mechanisms of gene duplication o Retrotranscription – reverse transcription of a processed messenger RNA – no introns, poly-A tail, far from original o Unequal crossing over – mistake during meiosis – one chromosome gains DNA and another loses it (introns, no Poly-A, tandem repeat) - Misalignment – the first step o Happens most frequently when there are too many tandem repeats and the genes arent really sure where to line up along the tandems o Tandems = repeats --> misalignment--> tandems--->misalignment - How often does gene duplication occur? o Lynch and Conery: compared genomes of 9 species of eukaryotes - not very often (at all) – 0.01 duplications per gene per million years - one genome per 10 000 years o Cheng et al.: compared human and chimp genomes 2.7% of genome is duplication in one species but not the other - Fate of duplicate genes o Silenced – pseudogenes - mutation o Repurposed - selection o Same function – dosage increase favored by selection o Two types of homologous genes  Paralogues: diverging within species  Orthologues: diverging between species - Example: Haemoglobin o Duplicated human globin genes and pseudogrenes, occur on 2 chromosomes (2 evolutionary lineages) and locations of introns and exons line up o Haemoglobin = 2 subunits, expression of different loci varies during the development - Duplicated gene families are common o 30% of the AA must be identical bw two genes to be considered part of the same gene family 3. Chromosome mutations - Translocations: movement of DNA between non-homologous chromosomes o Reciprocal: even exchange of material  change of the direction of the chromosome in the crossover – turned around  1/500 human newborns – carriers have a higher risk of unbalanced chromosomal translocations in their gametes o Robertsonian: fusion of 2 acrocentric chromosomes near the centromere  1/1000 have fused 13/14 – no phenotype but have a higher risk of unbalanced genes  fusion of two chromosomes that break off where you lose genetic material  Unbalanced gametes from the parent with the genetic defect - Wide variety or detrimental chromosomal translocations in humans o View picture in lecture 6 of different combinations of genes and their effect - Chromosomal inversions prevent crossing over during meiosis o Allows the linkage of alleles at different loci within the inversion – “supergenes” o Polymorphic inversion well-known in fruit flies due to polytene chromosomes o Chromosome gets flipped around and prevents crossover bc the gene sequence doent match up anymore - can create super genes o Comparing sequenced genomes and polytene maps yields complex picture of the genome rearrangements among the drosophilia species - Chromosomal inversions may play a role in adaptations o Parallel clines of Estimated inversions of D. subobscura in two regions where it was introduced- both are the same – they developed the same mutations – why? 4. Polyploidy - Polyploidy happens through the production of unreduced gametes o Polyploidization may seem unlikely o Polyploidy liable to result in speciation o Sets the stage for massive gene silencing and repurposing o Ancient polyploidization events in early vertebrates, fish and plants o Taxa often tolerate extreme env. through slow growth Autopolyploidy: within a species – duplication of the set of chromosomes Allopolyploidy: hybridization between species – uneven number of chromosomes – more common o May hinge on rare events o Selfing increases the likelihood of the event to occur o The triploid block o As common as point mutations - Example of the mutation mechanism – get four diff types of gametes with a diploid and a tetraploid - triploids are often fertile to some extent and can therefore be a bridge rather than a block in the evolution of polyploids Lecture 7: Genetic Variation Chapter 5: 4 Chapter 6: 1 1. Meiosis and recombination - Existing alleles are reshuffled in different combinations – you get a variety of genotypes o Allele: distinct DNA sequence at a locus o Genotype: combination of alleles at all loci o Syngamy: union of gametes – making a babay o Recombination: crossing over between homologous chromosomes and independent assortment of non-homologous chromosomes - Lots of variation in recombination potential among species o Wide variation in base chromosome number – different species have different number of chromosomes – prevents specie crossing – some exceptions o Wide variation in chiasma frequency among mammals, increases with the lifespan and is higher in domesticated species 2. Types of genetic variation? – discrete vs. continuous variation - Discrete phenotypic variation often caused by a single locus polymorphism – i.e. variation that varies in intervals is caused by a single locus that has different forms o Dominance = 2 phenotypic classes o Co-dominance = 3 classes  Heterozygotes distinct so allele frequencies can be estimated – can see the differences between the alleles superficially - Continuous variation is caused by variation at more than a single loci o Height of 20 years olds – controlled by many different loci/factors – get a continuous variation of height – and approaches a statistical normal distribution o Can be described with means and standard deviations - Continuous variation is explained by simple extensions of Mendel’s Laws o 2:1:1 for Aa, AA, aa and the pattern grows as you get more types of allele combinations with the more loci - Environmental variation (V ) complicates the correspondence between the phenotypic E distribution and genetics o No Ve = no change, a little more V – get more than one possible curve, they mesh together are there are more and more Environmental factors that contribute 3. How much genetic variation? – Natural Populations contain much genetic Variation - Classical school – most individuals have normal “wild type” allele at most loci o T.H. Morgan and H.J. Muller - Studied Drosophilia in the lab o Wild type alleles predominate + rare mutations o High levels of homozygosity o Evolutions waits for the mutational variation o Selection acts on mutations in isolation - Balance School – individuals differ at most loci – lots of allelic variation o T. Dobzhansky & EB Ford - Studied fruit flies in natural populations o No such thing as a wild type allele o High heterozygosity o Evolutions waits for an environmental change o Selection atcs on standing variation and alleles at different loci selected in concert - Evidence of Standing genetic variation from artificial selection experiments o Example: selection for oil content in corn seeds – started at university of Illinois in 1896  Rapid initial response - Compelling evidence cane with the advents of electrophoresis in the 1960s o Protein electrophoresis : proteins migrate thru the gel depending on the charge, size and shape of the molecules – basically how it works o It detects amino acid differences that alter the proteins o Estimates of the heterozygosity from hundreds of species – but most individuals have less than 1 allele at many loci o There is a wide variation of the loci among species in all the groups – in the world there is A LOT of genetic variation - DNA sequencing now provides a more direct measure of genetic variate o Example: sequence variation in 30000 disease causing alleles at the cystic fibrosis locus 4. Mendelian mechanics in populations - Mendelian inheritance yields predictable transmission of alleles between generations o Predictability allows formulation of math models to study evolutionary change o start with a null model – nothing interesting is going on  random mating between diploids, no selection, very large population size, no substantial immigration/emigration - Random mating between diploid individuals o Consider a locus with two possible alleles  Freq (A) = p, freq (a) = q  p+q=1  AA= P Aa= H aa= Q  P+H+Q=1 p=P+H/2 q=Q+H/2 o Genotype frequencies: Male AA Aa aa Female AA Aa Aa - Hardy Weinberg Equilibrium dictates assembly of genotypes from alleles o Genotype frequencies always for to the equilibrium regardless of the initial frequencies o H-W equi achieved by a single round of random mating o Allele frequencies (p and q) DO NOT CHANGE between the generations o If genotypes not at HW eq. the something interesting is going on o READ 6.1 o There are a set of assumption for the HWE – if they are violated then interesting phenomenon is occurring:  Random mating, no environmental factors, no mutation, no drift and no gene flow - For every set of allele frequencies there is a set of expected genotype frequencies o Note that the 2pq or expected heterozygosity is a useful measure of genetic diversity - HW eq. ealisy generalised to loci with more than 2 alleles o Locus with k alleles – A1, A2, A3… o Frequncy of allele A = p o Binomial expansion of p = 1 (P1+p2+p3…) o Freq. of AA homozygote – p^2 o Freq. of AA heterozygote = 2PP o Overall freq. of homozygosity = sum of p^2 o Overall freq. of heterozygotes= 1-sum of P^2 - CHALLENGE QUESTION o Copy from the lecture slides Lecture 8: More HWE and Introduction to Selection Chapter 7: 7 Chapter 6: 1 – 3 1. Mating system s – Deviations from Random mating violate the HWE - Inbreeding: reduces the freq. of heterozygotes o AAxAA / aaxaa / AaxAa– gives only AA / aa / 2:1:1 individuals - What does full selfing do to the proportion of heterozygotes? o Freq of heterozygotes is reduced by one half each generation o Increases the number of homozygotes in the population - The degree of inbreeding quantified by the inbreeding coefficient ( F ) o F =pr(that 2 alleles in an ind. at a particular locus are “identical by descent” – IBD) o Distinguish the IBD from an identical in state – calculate with pedigree – mom and dad give ½ of the alleles – use probability laws to calculate (multiplication) o Tables: from chronic (long term) inbreeding – F tends towards 1, mixed outbreeding and inbreeding – 0>F>1, Fe=s/(2-s) - where s= fitness of the allele, lethal=1 (H = Aa) - You can estimate the inbreeding coefficient (F) from a pedigree o Using the pedigree – looking at the generations and the possible gametic outcomes from the parents o Example: inbreeding of the eckerts – o Inbreeding depression: decline in fitness with inbreeding – post natal and pre reproductive survival in humans – recessive alleles have higher chances of being expressed due to high homozygosity - Difference between inbreeding and assortative mating o Inbreeding = related and have the same genotype o Assortative = not related but have similar phenotypes/the dominant phenotype expressed and still get heterozygosity 2. General selection model - Natural Selection has 4 testable postulates: o Do individuals vary? – phenotypic variation, do they look different from each other? o Is some of the variations among individuals heritable? – can they inherit the different variations of the phenotypes? o Do individuals vary in fitness and reproductive success? – are there stronger and weaker versions of the allele, how well can they make babies? o Are the survival and reproduction random with respect to the phenotypic variation? –trait – fitness co-variation – are the two factors independent from one another? - Natural selection at a single locus o Is there more than 1 allele at the locus? – genotypic variation o Do genotypes vary in fitness? Fitness variation - Natural selection causes changes in allele frequencies between generations o Recall the formulae for p and q o Now: 3. Directional selection - Directional selection o This is where one allele is favored over the other – look at the frequencies of the alleles – has it increased, decreased or no change? o One allele confers higher fitness and the other lower fitness (s) o Dominance dictates the genotypic fitnesses o Calculate the (1) population mean fitness, (2) frequencies in next generation and (3) change in allele frequencies (Δp, Δq) - The rate of evolutionary change depends on the expression of alleles o Rate of change depends on the strength of selection (s) and the genetic variation (pq) o Recessive alleles take a lot of generations to become very frequent o A dominant or co-dominant allele becomes very frequent very rapidly but the dominant one need more time to get close to 1 but spiked in less generations and the co-dominant allele takes less time to reach max frequency but needs more generations to spike - Graph - Properties of directional Selection o Favored allele eventually goes to fixation- finds maximum point of frequency o Change is fastest when the s is large and p=q o When a favorable allele is dominant – strong selection is required for many generations before it fixates o Favorable recessive alleles take a long time to fixate and are rare o Selection of the allele is most rapid when the allele is co-dominant o The fitness of a genotype is derived from the fitness and the expression of the phenotype o The population mean fitness is increased when the fitness of one allele is increased in the population Lecture 9: Other Models of Natural Selection Chapter 6: 2 – 3 1. Directional selection revisited - One allele confers the highest fitness – therefore natural selection veers towards a high frequency of this allele - In vitro demo of directional selection against a recessive lethal o Dawson 1970 – textbook figure 6 -16; evolution of the flour beetle in labs – experiment showing that the frequency of a lethal recessive allele decreases dramatically over time and evolution slows as the allele becomes more rare o Recessive lethal alleles at two loci I and Sa – initially all the populations were heterozygous (+/I or +/Sa)  How fit are heterozygotes for the two loci?  The I allele is recessive or nearly so  The Sa allele is partially expressed in a heterozygote o Questions with Populus (comp program online) MIDTERM #1 CUTOFF 2. Over- and under-dominance – selection can favor Combinations of alleles - Over-dominance: the heterozygote advantage o Population reaches a stable equilibrium allele frequency (p* and q*) o Populations return to p* when they are perturbed away from it o Always tends towards 50/50 - stable equilibrium o Stability will happen when delta-q is zero - things will stop changing and stability will increase when the change is zero o When sp=tq, it reaches stability, Equilibrium is reached when Δq=0, sp=tq, p=(t/s)q o The equilibrium p* depends on the relative size of the selection coefficients – s and t - Kuru disease: box 6.4 in text o Transmissible spongiform encephaolopathy like CJD o Killed many fore people of papua new guinea in the 1950s o TSEs caused by prion protein PrP – cell surface protein that directs the development, especially in nervous tissues – mutations in the PrP cause misfolded proteins and is heritable o PrP knockout in mice prevents the TSE o TSE is also transmissible by a vector or by the misfolded protein o TSE in the fore is linked to mortuary feasts (cannibalism) – more frequent in women than men because of the customs (only girls eat it) o Immunity to TSE linked to a change in AA #129 (VM) – scientists genotyped 140 young females (cant have been exposed) + 30 older females o Can use two sets of observed frequencies as before selection and after selection to estimate the relative fitness of MM MV and VV o General Selection Model: o Calculate the fitness of the homozygotes to heterozygotes to see the effects - Experimental proof of overdominance (OD) o Mukai and Burdick o Fruit flies and two alleles – viable (V) and lethal (L) – started with all VL o f(V) didn’t go to fixation but tended towards p* - matches the OD selection with s=0.265 and t=1. Definitive proof – started with f(V) or 0.975 - Underdominance: the heterozygote disadvantage o The trend of these alleles is to disappear because even if they are not dominant – the heterozygotes no longer can show the phenotypic allele - Experimental test of under-dominance: o Foster et al. – figure 6.19 o Simulated under-dominance with fruit flies using compound chromosomes o Initial freq. was very high and then decreased rapidly over time/with generations 3. Frequency-development – when fitness of a Genotype varies with its frequency - Negative frequency – dependence - Negative frequency dependence leads to a stable polymorphism o For a co-dominant locus, the equilibrium occurs when p2 = 2pq=q2 or when p=q o If A is dominant then the eq. is when p2+2pq=q2 OR p=0.29 and q=0.71 o When would this type of selection occur?  During predation – a new tactic or search image  Pathogens – rare genotypic immunity  Mating – female choice selection, selfing incompatible…  Resource use – rare consumer enjoys more resources - Negative frequency dependent selection in scale-eating cichlids o Morph freq. fluctuate around 0.5 o Handedness: single locus, 2 alleles (RL) with R dominant to L o Evidence of disassortative mating - Negative frequency – dependent selection in tristylous populations o Plant – has three different types of stamen and pistil forms o Mating between the morphs only o Rare morph enjoys male fitness advantage over other morphs o Equal morph frequencies in populations at equilibrium o Lythrum salicaria  24 popns with initially skewed morph frequencies  Sampled over 5-year interval  Morph frequencies moved closer to equilibrium in 17 populations o Graph: shows the morph evenness of the populations sampled – moved towards equilibrium after some time passes - Negative frequency-dependent selection deceptive orchids o Dactylorhizia sambucina  Purple/yellow polymorphism within populaitons  Flowers are very showy but offer no rewards  Bumble bees tend to avoid the unrewarding flowers (WHY does it have it then)  Set up experimental populations in natural habitat  Quantified male and female fitness of each plant o Experimental results  Relative fitness of yellow morph on the y axis  Male fitness (pollinia removal) declines with freq (Y)  Female fitness (2 diff measures used) also declines with freq (Y)  Equilibrium should be where fitness of yellow Is the same at the fitness of purple so predicted values = 61%, 69%, 72%  The observed frequency is 69% - Positive frequency-dependence leads the unstable polymorphism o The fitness of a genotype increases with its frequency o Unstable equilibrium at p=q o As soon as p is larger than q, then the dominant allele goes to fixation o As soon as q is larger than p, then the recessive allele goes to fixation o This phenomenon is hard to study (takes a lot of generations to see the effects) o When does this mode of selection occur?  during mullerian mimicry (=A distasteful species evolves to resemble another distasteful species. Both gain increased protection, because predators learn to avoid the common pattern more quickly.) o What other modes would cause this? Directional selection - Positive frequency-dependent selection and Mullerian mimicry o Convergence on a common phenotype by a group of distasteful prey species (one dangerous dude copies another dangerous dude) o Mutual benefit of sharing warning signals results in positive frequency- dependent selection o Shared aposematic (=pattern that indicates scary or danger or poison) phenotype enjoys enhanced survival as it increases in freq o An unusual aposematic phenotype does not enjoy the mullerian advantage – want to have something easy to develop (takes less energy) or something effective and practical o Mimicry with several “co-models” can generate geographically divergent selection - Mimicry in Heliconius butterflies o Mimetic rings often consist if unrelated species o striking convergent evolution - Experimental analysis of selection on colour in Mullerian populations o Color polymorphism in Heliconius cyndo alithea o Different morphs seen to mimic two other species o All 3 species are distasteful (dangerous) o Experiment = released both morphs of the dangerous butterfly and two other co- models (high density and a low density experiment for both) o They suffer bird predation o Mark-recapture analysis - Design and Results o Mean life expectancies  C=14 days, E=5 days, s=0.64  but at a high density, C= 17 days, E = 16 day o interpretation: at high density, the predators encounter rare, distasteful morph enough to learn to avoid??? - Assortative mating between H. cyndo alithea color morphs o Might strong PFD selection ultimately generate selection for assortative mating by color? o Tested 115 males in 1644 courtships o Preference index = want white o Y males prefer Y females and W males had less preference o But does it occur in nature – genetically, data says not yet - Selection model round-up Model Variation in fitness Fitness differences Stable equilibrium? between… constant? Directional Alleles Yes No (Fixation) Over-dominance Genotypes Yes Yes Under-dominance Genotypes Yes No (unstable at p=q) Negative frequency- Genotypes No Yes dependent Positive frequency- Genotypes No No (unstable at p=q) dependent Lecture 10: Random Evolutionary Processes Chapter 7: 2 1. Sampling error in populations: Sampling error underlies Random Evolutionary processes - Random biases are expected when the sample sizes are small o Analogies: coin flips, roll the dice, bag of marbles, o Probabilities of bias decreases as sample size increases - Sampling error is purely random o Sampling error does not favor one outcome over another (e.g. one allele over another) o Individual outcome unpredictable but the outcome of a group of events can predicted - Several processes in natural populations result in sampling error o Founder effects: sampling a small number of genotypes from a source population o Population bottlenecks: population crashes to low numbers then regrows (could be from natural disasters) o Genetic drift: during random mating, alleles are “sampled” to form progeny (chapter 7, figures 10,11,12) o for each of these, understand where the sampling error occurs 2. Founder effects - Founder effect requires two conditions o FIRST: new population established from a small number of colonists o SECOND: allele frequencies among the colonists not representative of population from which they came - Probability of losing an allele via FE o Say source population if at hardy – Weinberg equilibrium  f(AA) = p2 f(Aa) = 2pq f(aa) = q2 2 n o probability of only an A allele among ‘n’ colonists = (p ) 2 n 2 n o probability that n colonists have only one allele or the other = (p ) + (q ) - ‘R’ examples - shows the probability an allele going to fixation depending on the frequency of the allele in the source population o Higher the frequency of the allele the higher the probability it will fixate - Founder effect can ‘change’ allele frequencies, with long lasting effects o Example: porphyria variegata = inherited error in heam synthesis (vampire disease?) o Common among white south Africans – Afrikaaners (1/250) o Rare in the Netherlands and surrounding Africa (1/100000) o Dutch afrikaaners arried in SA in 1652 on one ship. o 50% of the current population have 20 names traceable to that ship o 1/3 white SA descended from 40 founders o  8000 cases of PV traceable to one married couple back then - Serial founder effect in silvereye o Naturalists documented colonization of islands off Australia (n=20-200) o Assay 6 microsatellite loci for birds caught in mainland and island sites o Compounded founder effect: ML to NI – diversity decreases in the island popualtions - Founder effect vs Genetic Drift o Founder effect: Source populaiton Founders New population N Growth o Genetic Effect: gametes zygotes t t+1 N N Meiosis Mating Mortality 3. Genetic Drift – causes random fluctuations in allele frequencies - Random fluctuations cause allele to be lost from populations o Fluctuations are RANDOM o No change in AVERAGE allele frequencies o Continues until each allele remains in EACH population o Probability of loss = 1 – initial frequency - Degree of random fluctuations larger in smaller populations o Graphs:  show the frequency of allele for 100 generations in N populations  trend varies for each population – fixation reaches different points for each population  could lose one allele or the other its random - Dgree of random fluctuations larger in smaller populations o Recall: diversity (H=2pq) maximized when p=q=0.5, THEREFORE drift reduced diversity o Reduction of heterozygosity: - VIEW GRAPHS 7-15 in textbook p 240 o MAKE SUMMARY - Sewall Wright – some biologist dude - Demonstration of genetic drift in fruit flies – p242-245 - 1Buri (1956) established 107 populations, each with 8M and 8F - Eye color marker locus (bw /bw) - Started with equal allele frequencies (p=q) - Kept the population size at 16 or 19 generations - Scored the genotype freqs - Then at gen 19 – the bw75 allele was lost in 30 populations and was fixed in 28 4. Theoretical concept of Effective Population Size (N )e - Census size (N) ≠ Effective size (Ne) o Census N = a group of conspecifics clustered in space and isolated from other such groups o Ne = size of an ideal population that would lose H at the same rate as the actual population observed o Ne = an ideal populations in which every parent has an equal chance of contributing to every progeny - Ne reduced by anything that causes variance in progeny production among individuals o Example: Ne = 4NmNf/(Nm + Nf) - R example : o Shows the graph of effective population size and the proportion of males in the population o Trend indicates that as the population size increases, the number of males is reaching/balancing out to 50% - Population size correlates with genetic diversity in 4 plant species o Note positive correlations between N and genetic variation o Concept of Ne has become central to conservation biology and wildlife management o In situ conservation o Ex situ conservation o View figure 7-19 in textbook GIVE SUMMARY Lecture 11: Gene Flow Chapter 7: 1 1. Gene flow in theory - Gene flow is a simple genetic mixing process o Alleles flow from one population to another by migration - Simple process = pretty simple basic mathematical theory o pR= Frequency of A allele in Recipient population o pS= frequency of A in source population o m = proportion of recipient population made up of new immigrants each generation o pR’ = (1-m)* R + m p S o Δ pR= p R - pR= m(p S p R o When is equilibrium reached?  when does Δ p =R0?? - Two events required for gene flow o Gene movement  Movement of individuals (dispersers, seeds, spores)  Movement of their gametes (pollen, sperm in water)  Do not confuse with seasonal migration o Gene Establishment  Survival in new location  Successful reproduction in new location  Reduced if new location differs from source location (maladaption) 2. Measuring gene flow - Distribution of dispersal distances probably ‘leptokurtic’ o Most move short distances, a few very long distances o How to measure??  Mark-recapture  Telemetry  Other tracers  Marker genes  Experimental plots o How to capture the tail - Long-distance gene flow via pollen o Well-studied stand of Sorbus domestica in northern Switzerland o 167 reproductive individuals +1183 progeny o Genotyped at 9 microsatellites + paternity analysis o 33% progeny self-fertilized o Avg outcrossing distance = 1.2 km, max = 16km o Note the rare long-dist gene movements o ~10% of progeny not assigned to any pollen-bearing tree (longer distance immigrants?) - Gene flow over longer distances and longer times inferred from genetic structure o When populations are genetically differentiated, we know that gene flow has not homogenized them o Degree of genetic differentiation measured using FsT which is an extension of the inbreeding coefficient F and HWE o Recall F is the reduction of Hobserved compared to that expected at HWE (where H = 2pq) - Calculating FST o Consider 3 populations that differ in allele frequency o If the individuals mated randomly across all populations  all p = 0.5 , HWE at a large scale o Calculate 2pq for each popn  A = 0.5 B= 0.42 C=0.42 mean: 0.45 o If F = 1-Hobs/Hexp o Then FST = 1 – 2pqmean2pmeanmean= 0.1  this is the genetic differentiation among the populations o Max FST = 1, Min FST = 0 - Interpreting FST o If populations differ in allele frequency the FST>0 o If populations have different alleles then F=1 o Fst is usually measured with genetic markers o Statistical analogs of Fst can be calculated with DNA sequence data or even data on morphological differentiation among populations - Massive panmixia, Fst = 0?? o Wirth and Bernatchez 2001 Nature o European eel Anguilla Anguilla o Catadromous spawner o One mass spawing site = saragasso sea o Leptcephali carried on north atlantic currents back to Europe o Widely expected that Fst = 0 o Sampled 13 sites in the north atlantic, Baltic and Mediterranean sea o Genotyped 611 eels at 7 microsatellite loci o Fst = 0.0017, low but P = 0.0012 (not zero) o Genetic structure or sampling error? o Coastal distance correlates positively with pairwise genetic distance between sites o Indicates true population differentiation o Explanations  Geographical variation in breeding time  >1 spawing site 3. Interactions with other processes – Gene flow interacts with other evolutionary processes - Gene flow versus genetic drift o Drift increases divergence - Gene flow reduces divergence ( counter active forces) - Little bit of gene flow = big effect of Fst o Why is it Nm in the denominator? - Gene flow can interact with selection o Facilitate adaptation through selection  Introduce new advantageous mutations from one population to another o Oppose adaptation through selection  gene flow between ecologically different populations may introduce maladaptive alleles  natural selection in small populations may be stalled by swamping gene flow from larger nearby populations o Striking geographic variation in color and color pattern in the king snake (lampropeltis triangulum) - Maladaptive mimicry in kingsnakes o Harper and Pfennig in 2008 nature o L. triangulum elapsoides seems a batesian mimic of the venomous coral snake o But the mimic has a much larger geographic range than its toxic model o Model and mimic co-occur in yellow zone (florida/south of southern states near florida) = sympatry o mimic occurs without the model in the green zone (southern states near florida) = allopatry o assayed snakes from many sites for 3 mitochondrial genes (mt DNA) – 5 nuclear microsatellites (nuccDNA) o estimated gene flow = Nm from sympatry to allopatry o why different between mtDNA and nuccDNA? o King snakes less mimetic in allopatry than sympatry (a,c) o Degree of mimic declines with increasing distance from the sympatry zone (d,e) o Predator attacks on mimetic phenotypes increase with increasing distance from zone of sympatry - Crypsis in lake erie water snakes o King and Lawson 1997 o Nerodia spiedon occurs on L erie shores and islands o Mainland snakes are banded – island snakes are plain o Colour pattern is controlled by a single locus – banded is dominant o Unbanded young more cryptic on island rocks than banded - might selection favor unbanded snakes on islands o Scored snakes for banding phenotype (A = unbanded) on OH and on Mainland + 3 island groups o Mark-recapture survival estimates: unbanded > banded on islandsunW = 1,bW = 0.84) o Populations unbanded: islands > mainland , remote islands > near-shore islands o Why aren’t all island snakes unbanded? o How much gene flow from mainland to islands? o Assayed 7 polymorphic allozyme loci o Nm (mainland islands) ~13 o N ~ 1300, therefore m~0.01 o View Box 7.2 in textbook – READ Lecture 12: Genetic Diseases Chapter 6: 4 1. Diversity of Genetic Diseases - Single-gene diseases: common, diverse and cause much loss of life o Human genome has approximately 20000genes o WHO estimates that 10000 monogenetic human diseases o Frequency of monogenetic diseases are 1/100 at birth o In Canada, monogenetic diseases account for 40% of hospital pediatric care o Categories include: dominant, recessive, x-linked o Most genetic diseases exceedingly rare o View table in lecture slides for examples of diseases o Most have a frequency of 1/10000 o Many are undiagnosed - Monogenetic diseases not always monogenetic o Cystic fibrosis – most common monogenetic disease o Recessive loss-of-function mutation on chr. 7 o CFTR: cystic fibrosis transmembrane conductance regulator = cell surface receptor protein expressed in mucus membrane of lungs and intestines o CF patients susceptible to pseudomonas aeruginosa infections, leads to lung damage o Now known that CF phenotype modified by alleles at several other genes: MUCI, TNF, TGFBI, CFMI, NOSI o Somewhat polygenic – have a main locus and modifier loci o If a mutation reduces fitness, then why does it persist in a population? why doesn’t directional natural selection reduce its frequency to zero? 2. Mutation – selection balance: Using the directional selection model to predict human disease - Dynamics of a recessive disease allele o Situations where the s is very strong is often phenotypic selection o Selection is trying to get rid of the disease alleles but mutation provides a constant supply AA Aa Aa WA WAa Wa 1 1 1-s o Change due to selection: o Change due to mutation o These two equations balance each other when  We want this equilibrium So you get - Dynamics of a recessive disease allele o Solve the equation to get the equilibrium frequencies of affected genotypes and the frequency of the disease allele o Start by assuming that q is very small (~0) o Mutation rate over the selection coefficient o Compared to a recessive mutation, a dominant disease allele will occur at a lower frequency and affect more individuals AA Aa Aa WA WAa Wa a 1 1-s 1-s - Dynamics of a dominant disease allele Qe + He = 2(µ/s) - Recessive versus Dominant alleles µ = 105 Recessive Dominant s = 0.9 Allele μ μ frequency q= q= s √ s = 0.0033 = 0.00011 Frequency f (q)=μ f (q)=2μ of affected s s individ
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