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This 27 page Bundle was uploaded by Anahit Ghaltaghchyan on Friday February 26, 2016. The Bundle belongs to EEMB 2 at 1 MDSS-SGSLM-Langley AFB Advanced Education in General Dentistry 12 Months taught by william rice in Winter 2016. Since its upload, it has received 25 views. For similar materials see EEMB2 in Electrical Engineering at 1 MDSS-SGSLM-Langley AFB Advanced Education in General Dentistry 12 Months.
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Date Created: 02/26/16
Evolution 02/09/2016 ▯ 2/9/16 ▯ ▯ 4103 LSB ▯ ▯ Intro to evolution ▯ Partitioning an organism into 2 parts ▯ ▯ Genotype= the organisms hereditary material, or set of genetic instruction, codes for many of the structure ▯ Phenotype= physical traits of an organisms representing the outcome of the expression of the genetic instructions in the genotype ▯ ▯ Phenotype must ▯ 1. secure raw material for growth and reproduction (g) ▯ 2. protection from enemies (p) ▯ 3. produce offspring (f=fecundity) ▯ ▯ thought experiment ▯ why? strip away al unnecessary complexity and focus on the process of evolution ▯ ▯ consider a hypothetical plant ▯ 3 assumptions ▯ 1. annual life cycle ▯ 2. asexual reproduction ▯ 3. entire phenotype coded by a single gene ▯ ▯ ▯ suppose we plant five different genotypes into a natural meadow describe the phenotype in terms of a resource budget pi diagram… has equal investment in all 3 function, or some kind of unequal distribution reflects tradeoff of energy, minerals, etc put into growth protection and fecundity. ▯ Looking at the type of seed with respect to the phenotype, summer plants, fecundity and fall seeds ▯ Multiply the summer plants number times the fecundity Growth specialist B- protection specialist C-fecundity specialist D- equal in all three phenotypes ▯ Analysis ▯ 1. does the population reproduce itself? Growth of population seen ▯ 2.each genotype reproduce itself? No, A, B, and C do not Gene pool- abstract assemblage of all genes in the population ▯ ▯ Gene pool observed through the gene frequency for generations 1 and 2. Divide the number of seeds by the total number of seeds for the pre and post ▯ ▯ ▯ 3. what is a good measure of the biological success of a genotype?? Darwinian fitness fitness- the number of genome copies an organs place into the generation o fall seed #/spring seed ▯ 5. supposed a new herbivore was introduced into the meadow so that the level of damage produced by herbivore was raised but only slightly? Which phenotype has highest fitness now? Favor E. fitness Is not an intrinsic quality of an organism. Context dependent. Depends on environmental demands ▯ 6. does any one attribute predominate fitness? No it’s the combo of the 3 relative to the environment ▯ 7. function of phenotype to be an effective gene transport machine to be a good transporter of your genes to the next generation ▯ 8. why can we conclude that organisms are designed to be good gene transport machines? Because those genotypes that code for phenotypes that transport more gene copies from generation to generation will eventually predominate within a population ▯ Natural selection- change sin the relative frequencies of different genotypes due to difference in the associated survival and fecundity of their phenotypes ▯ ▯ Do phenotypes evolve because they are good for species?? ▯ Misconception ▯ “cheater and altruism gene example”. Good for the individual but bad for the species some evolutionary geneticists consider phenptypes like you and be to be “throw away survival machines:” used by genes to transport themselves from one generation to the next? Sexual organisms do not reproduce themselves Do genes reproduce themselves? Yes. 99.99999%, aside from mutations Gameteszygotesphenotypes ▯ Genes potentially live fore ▯ ▯ Two ways to view genes and organisms? Organism based view- genes are blue prints Gene based- organisms are short lived vessels made and used by long lived genes o Transposable elements mostly ▯ ▯ Antagonistic p. Short telomeres =- protection from cancerous cells in early years, but more likely to die of heart disease and immune infections at old age ▯ MICROEVOLUTION-Evolution change that occurs on a time scale of a few to 100’s of generations ▯ ▯ Common perception of evolution- a process that is impeccably slow, involving the transition of simple life form to complex forms like mammals ▯ ▯ Many evolutionary biologists study evolution to understand the present rather than trying to decipher biological history ▯ Many evolution ▯ ▯ Ex. HIV. Causing AIDS, the latter stages of HIV. 23,000000 people infected in 1996, and now its 36900000. About half do not know that they have aids 34 mil killed ▯ ▯ 3 epidemics among heterosexual men and women in sub sahara Africa o Botswana 38.8% Europe among homosexual men and IV drugs Newer epidemic among heterosexual men and women Most will die in less than 15 years ▯ ▯ The life cycle of HIV Virus ▯ ▯ 2 RNA chromosomes reverse transriptase 2 RNA chromosomes ▯ ▯ ▯ cell needs Cd4 protein and CCr5 cofactor (door knob) NEEDS BOTH TO ENTER ▯ Infection starts with the virus fusing with the membrane of the cell. ▯ ▯ (door) cd4+ helper T cell DNA version of virus chromo Translation to make reverse transcriptase protein Assembles and release of daughter virus to find other cells with Cd4 and ccr5 to enter Pathology of HIV virus does not kill directly kills cd4+ helper T cells which are critical parts of our immune system opportunistic infections and cancers ultimately occur and kill you o fungal pathogens o viral pathogens o bacterial pathogens etc ▯ time course of HIV infection ▯ ▯ number of cd4 and helper T cells threshold, one drops below 200, trouble infection usually lasts 10-15 years initially decline due to killing of ccd4 helper cells by virus, rebound and increase due to successfully responding to infection and killing most infection virus population then drops linearly. Decline due to evolution by the remaining virus about 10 years, passes the critical value of 200, and AIDS symptoms begin ▯ ▯ AZT- first drug to help stop aids. But was unsuccessful because of the evolution taken place by the virus AZT acts at the spot where RNA is converted to DNA (very start of cycle) Base analog that mimic thymine during reverse transcriptase of the HIV chromosome ▯ ▯ ▯ ▯ Normal reverse transcription RNA is exposed to pool of DNTp’s Reverse transcriptase reverses RNA to DNA ***normal reverse transcription of ssRNA to ssDNA*** ▯ When AZT present AZT acts like thymine and is considered a DNA nucleotide along with ACT and G RNADNA At one spot, the AZT acts in place of the T, and the polymerase reaction is terminated Premature termination of the reverse transcriptase process ▯ ▯ ▯ Only works for 1-3 years, but has no effect after that due to the HIV evolution inside the body of the patient ▯ Evolves to discriminate thymine. To reject AXZT and selectively use T instead ▯ ▯ Why so rapid? ▯ Mutation rate of HIV virus is a million times higher than in humans. Much more mutagenic ▯ Also 1000 times higher than influenza RNA virus ▯ ▯ Generation time of HIV is only 2.5 says so HIV has 140 generations in each year of infection ▯ So HIV can evolve rapidly due to short generation time, high mutation and large population size. ▯ in 10 years, the HIV gene evolve the same extent as human genes have evolved in the last 1,000,000 years very dangerous because evolve so quickly ▯ no simple drugs like AZT can stop on HIV infection ▯ ▯ How does HIV adapt to human immune system The same way it adapts to AZT ▯ Infection gets responded to by human immune system to decimate extant HIV genotype. Generates selection for HIV virus to hide from the immune system, to create new proteins which are not recognized by our immune system. New genotype of HIV evolve and accumulate ▯ We have a Pool of formant cd4 and helper T cells, waiting for signal to clone themselves ▯ HIV system responds to new HIV genotypes by recruiting new types of helper T cells (that were previously present since birth but inactivated until simulated by pathogens proteins) ▯ BUT HIV counter responds by evolution ▯ ▯ ▯ Fact: Early on HIVs high mutation rate permits it to persist at low levels by its continued evolution of new genotypes to keep 1 step ahead of the immune system ▯ ▯ ESCAPE hypothesis The number of evolving HIV genotypes increases with time So the immune system must combat ever more new HIV genotypes with time Eventually the immune system is overwhelmed and cant catch up ▯ HIV is a devastating disease because of its enormous evolutionary potential ▯ ▯ RAPID evolution of pests and bacteria to pesticides and antibiotics ▯ Pesticide resistance- data from Illinois farms from house flies ▯ DDT lethal dose vs time plot(1940-1951) Lethal dose when flies were naïve to the pesticides, but over the next few years it started to take more and more DDT to kill the flies Same type of microevolution cause all forms of pesticides and herbicides to have a limited period of usefulness if they were used at large scale of extended periods of time Pesticides usually are useful for a generation or a generation and a half at most ▯ Antibiotics Data from Shigella (caused Dysentery) 15 years same type of pattern ▯ 15 years ago a strain of staff bacteria was isolated from a hospital that was resistant to virtually all known antibiotics ▯ ▯ reducing unnecessary use of antibiotics slows the evolution of resistance new antibiotics must continually be discovered to keep ahead of the pathogens in this arms race between pathogen evolution and medicine ▯ influenza pandemics ▯ ▯ deaths in the US vs time number of people killed increases over time ▯ ▯ molecular data ▯ each pandemic is due to the evolution of a radically new viral genotype ▯ how do the radically new viral genotypes evolve so fast ▯ has to do with farm animals. Most influenza strains originate in wild birds and spread to farm animals through birds which ultimately reaches us ▯ double infection generated hybrid virus immune system of human population ahs no cross reaction antibodies which leads to a pandemic ▯ HYBRIDIZATION generates a quantum jump in evolution creating a pandemic Hybrid virus carries new virulence genes to which the human population is naïve ▯ ▯ POLIO Why prevalent in some areas and not others? Vaccines- made via microevolution SERIAL PASSAGES- infecting chickens to the virus and the virus gets adapted to the chicken Loses ability to infect our nerves 3 doses provides about 99% immunity cant spread to unvaccinated cannot evolve oral polio vaccine, 3 doses about 95% immunity spread to unvaccinated evolution back to wild virus is 1/750000 patients in developed countries, injection is possible and polio virus has been irradiated in developing countries o Injection is NOT feasible.. so oral vaccine must be used. Because of politics ▯ 2003 nigerian politicians cancelled its polio vaccine program because of rumor that vaccination was rumored to be a western plot to sterilize muslims ▯ previously vaccinated chlldren shed live sttentuated virus into the water systems due to low sanitation ▯ many thousands of unvaccinated children were infected and despite the low reverse evolution rate wild type virus eventually re emerge ▯ WIL TYPE virus has higher Darwinian fitness.. selection ▯ Spread ▯ ▯ This will only happen when a a large part of the population is unvaccinated since the reverse evolution is so slow ▯ ▯ PERSPECTIVE ▯ ▯ Major epidemics last 4000 years first- Egypt- bubonic plague or influenza next Greece- typhoid or typhus Rome –measles or small pox, about 5 million killed Small pox again in Rome Bubonic plague 25 million in Rome Bubonic plague in Palestine Black plague in Europe 100,000,000 within 5 years Most recent in AIDS FAR more common. Time interval getting shorter and shorter ▯ 30% of Europe destroyed by black plague ▯ many died within 3 days of infection ▯ ▯ closest relative is a harmless soil bacteria ▯ Yersinia pseudotubercolosis ▯ The only difference is two additional plasmids, which converted it to the lethal human pathogen Yersinia pestis ▯ Quantum change ▯ ▯ Can we reconstruct the evolution of the black plague? ▯ Cemeteries allow us to go back in time. DNA is still around in bones ▯ About 50 bp, too small for reliable PCR analysis ▯ But readily sequenced and assembled via second generation DNA sequencing ▯ ▯ 103 bp difference between ancient bacterial genome sequence and current bacterial genome sequwnce can recombine to form the bacteria of the black plague ▯ genome wide genetic association studies: cemeteries ▯ ▯ Evolutionary phylogenetic tree of plague bacteria ▯ ▯ Estimated common ancestor of all extant Yersinia pestis (molecular clock estimate is AD 1282 very close to bubonic plague time) ▯ ▯ Major human infectious disease Malaria Cholera Anthrax Aids Dengue fever Using next generation DNA sequencing we can now watch Can now estimate when they crossed over to other animals and humans Changing the way we think about evolution ▯ SARS ▯ Severe acute respiratory syndrome ▯ Started in china, rapidly spread within a few months the genome was sequences ▯ ▯ The SARS rapidly evolved during the extremely short epidemic ▯ ▯ Now MERS-middle east respiratory syndrome from bats to camels to humans Ebola in Africa and spread. Evolutionary analysis is unknown for sure ▯ Phylogenetic analysis The evolutionary history of groups of organisms. Summary of relatedness among groyps ▯ Tree- a graphical summary of relatedness that described the patterns among lineages ▯ Taxon- a group of genetically related organisms, such as populations, species, genera, families etc ▯ Clade- a group of taxa derived from a common ancestor ▯ ▯ Basic forms of jargon ▯ Depicts relatedness of taxons G,X,T,F,Q, and E ▯ Branches- line of descent leading to some other point of the tree ▯ Root-common ancestor equally related to all the organisms in the tree ▯ Nodes- branching points on the tree(speciation) Denotes a common ancestor to distal taxa ▯ TIME IS ONLY CRUDELY REPRESENTED ▯ Can have more sophisticated trees ▯ ▯ Polytomy-unresolved branching Cannot tell who is more closely related ▯ Example of phylo tree ▯ Q: can a dentist spread AIDS to his patients? The CDC used evolutionary genetics to answer ▯ Data The dentist: a sample of RNA from his HIV virus(of the dentists) o Taxa- different populations of the same HIV virus Out-group: HIV RNA sequence from Africa o A taxon that is indisputably more distantly related to all other members of a group of taxa Locals: HIV RNA sequences from 4 AIDS patients unnasociated with the dentist (L1, L2 L3 L4) Patients: HIV RNA sequences from 7 patients with AIDS that visited the dentist? ▯ African sample-good outgroup ▯ Patients from dentist next ▯ 4 locals (that never went to the particular dentist) ▯ dentist and rest of his patients under one node ▯ 1. HIV from florida cluster together, away from Africa ▯ 2. clearly two of the patients did not get HIV from the patients ▯ 3.but the rest of the patients may have gotten HIV from the dentist ▯ ▯ mapping an informative character onto the tree ▯ HIV high risk behavior (Y or N) Promiscuous, unprotected sex The two patients not part of the common theme had unprotected sex Have a clear defined dental clade o Group of taxa that are all derived from a common ancestor ▯ How are phylogenies determined from the data? ▯ -intuitive way (does not always work) group taxa according to phenotypic similarities 2 reasons why not satisfactory approach 1.convergence- unrelated groups evolve similar phenotypes independently homologous trait-those that evolved originally in the same ancestor and were then passed on to all descendent taxa. Evolve once in a common ancestor and is passed on.2. o 2. Reversals- related taxa are no longer shared. Homologous trait found in common ancestor is lost in one or both taxa o COLLECTIVELY CALLED HOMOPLASY o Homoplasy Phenotypic siimlarty among distantly related taxa OR Phenotypic dissimilarity among closely related taxa Can think of phenotypic noise- that reduce or increase phenotypic similarity among taxa ▯ Idea slope of phenotypic similarity and evolutionary relatedness would be 1.0 but in real life, scattered about line is due to homoplasy ▯ ▯ In summary- constructing phylogenic trees based on phenotypic similarity alone is error-prone because of homoplasy ▯ As an alternative wil will use cladistics analysis of traits to construct Phylo trees. Need to focus on what traits to use ▯ ▯ What characters should we use to construct phylogeny? ▯ 3 major factors ▯ ▯ 1. must be homologous traits ▯ 2. must minimize homoplasy the traits must diverge among taxa but rarely lead to convergence and reverals. For example- fur color is not a good trait, but presence of feathers us a good trait (occurs once and passed on with high fidelity) ▯ 3. many independently evolving characters to help encounter the nose of homoplasy ▯ ▯ major types of characters ▯ 1. molecular data (usually DNA, RNA or proteins_ ▯ 2. gross phenotypic data (bones, teeth, behavior ) ▯ ▯ making a phylogenetic tree ▯ ▯ cladistics approach identifies monophyletic groups on the basis of shared derived characters called synapomoprhies o syna- homologous traits passed on to derived lineages outgroup- a taxon that is indisputably most distantly related to all other members of a group of taxa but as closely related to the other group members as possible ▯ ▯ ex- insects as outgroups ▯ taxa of interest-fish, amphibians, reptiles, birds mammals ▯ traits- closed circulatory system, vertebrae, notochord, greater than 2 chambered hearts, endotherm(heat body), scales or fur on legs, feathers, lactation ▯ ▯ create a trait matrix’ ▯ when homoplasy is present, then the tree that produces the minimal amount of homoplasy is the best tree ▯ ▯ pholgenies are hypothesis- best fir with the available data using molecular data as traits to construct a phylogeny for taxa O,A,B,C O is the outgroup O ATTCTGACT A ATGCTGTCT B ATGCTGTCG C ATGCTGACT Positions 3, 7 and 9 are variable (therefore, informative) Molecular data: Major problem producing homolasy are. If a base changes there’s 1 25% chance of changing back to what you were before. 1. Reversal 2. Convergence 3. Multiple hits 4. Saturation ▯ foe example- we will start with a simple triplet codon sequence in an ancestor ▯ DNA sequence of common ancestor ▯ AAA splitting into lineage 1 and lineage 2 ▯ Mutations- divergence/no homoplasy, divergence and homoplasy Multiple hit= homoplasy. We can only observe present, extant sequences, not past sequences. Only one bp divergence can be observed yet two occurred. Hidden change- homoplasy form Saturation (0% similarities)=homoplasy ▯ ▯ Genetic distance trees also occur. Based on how closely related different taxa are genetically. Vertical lines=common ancestor. Measured how far each taxa has diverged from its previous taxa ▯ ▯ ▯ Phylogenomics- constructing phylogenetic trees based on very large numbers of genes, or ideally based on whole genome sequences ▯ ▯ ▯ ▯ Mitochondrial genes- several thousand copies per cell, thousand times more copies of each mitochondrial gene per cell compared to nuclear gene ▯ ▯ In humans, most silent mutations are selectively neutral ▯ Silent site divergence between species estimates time. ▯ ▯ ▯ ▯ Basic evolutionary genetics ▯ Hardy Weinberg equilibrium ▯ ▯ 1986 a groups of men were identified who were HIV- despite long history of unprotected sex with HIV+ men ▯ -no detectable hiv antibodies present a combination of molecular and evolutionary genetics provides a partial aswer based on CCR5 coreceptor molecular analysis indiated 2 of them were homoxygous for th same loss of function allele at the CCR5 locus; called delta CCr6= broken(deleted CCR5) ccr5 is trans membrane protein found in cd4+ helper t cell receptor hiv virus has 2 forms M form- found only during early infection T- form- found later along with the M form Cd4 foor ccr5 door knob Hiv cannot enter without ccr5 (no doorknob) Immune to M form. Not T form MICE STUDY Ccr5 have white blood cells that enter nervous tissues less well encephillitis. Rapid death normal mice nearly all survived from the infection ▯ in humans individuals lacking ccr5 are much more susceptible to infection by the west nile virus ▯ ▯ extrapolating test tube data to nature ▯ Scientific method ▯ 1. observation ▯ 2.hypothesis ▯ 3. prediction ▯ 4. data (test of prediction) ▯ 5. modify hypothesis to confirm test results if needed ▯ start process again ▯ ▯ goal- to reach the status of theory. No longer can be invalidated ▯ theory is a conclusive endpoint after a long and exhaustive testing process ▯ ▯ ▯ 2 large samples of people from n Europe separated into uninfected (antibody-) and infected (antibody +) for HIV vs proportion of delta ccr5 allele. Demonstrates advantage for the broken ccr5 allele. Frequency of delta ccr5 genotypes is higher in uninfected individuals ▯ again, separate into the infected and uninfected individuals ▯ ccr5 homozygous ▯ ccr5 heterozygous ▯ delta ccr5 homozygous ▯ ▯ again seen higher frequency of ccr5 homozygous in infected, and higher delta ccr5 frequencies in uninfected ▯ ▯ all supporting evidence ▯ more and stronger evidence that the delta is protective for aids, ▯ ▯ more : look at delta ccr5 genotype within the sample of infected individuals do not fit expectations based on a null mode of no natural selection ▯ ▯ provides observed vs expected ▯ ▯ NULL MODELS: we will calculate the expected % by constructing a null model that assumes that no natural selection is acting ▯ ▯ Observation: most multicellular organism cycle between a short lived haploid state and a long lived diploid stage ▯ ASSUMPTIONS important ▯ 4.NULL MODEL- NO EVOLUTIONARY FORCES OPERATING. No mutations, selection, migration and sampling error ▯ 5. random mating ▯ ▯ mapping zygote pool to adult pool ▯ Alleles A1A1 ▯ A1A2 ▯ A2A2 ▯ By assuming a null model, the alleles are kept constant in the zygote and adult transition ▯ ▯ Finding probabilities of A1, and A2 based on the combination of heterozygous and homozygous alleles ▯ ▯ Probability of 2 independent events is the product of the two probabilities ▯ ▯ Make random mating tables ▯ ▯ Haploid gametes adult gametes ▯ Turns out A1A1 probability is P^2 ▯ A1A2 is 2PQ ▯ And A2A2 is Q^2 ▯ ▯ Binomial square principle ▯ ▯ Map expected vs observed ▯ ‘hardy Weinberg expected values represent a null model of what nature would look like in the absence of any evolutionary forces operating ▯ turns out POOR FIT ▯ so delta ccr5 is at least partially protective ▯ ▯ 3 predictions showing that delta ccr5 is protective of AIDS ▯ ▯ ▯ ▯ PERSPECTIVE ▯ effects of random mating inbreeding (mating between close relative more than by chance) measured by the inbreeding coefficient F ▯ sib sib mating F=0.5 ▯ parent offspring F=0.5 ▯ uncle niece/ aunt nephew= 0.25 ▯ first cousins =0.125 ▯ second cousins=0.03125 ▯ ▯ inbreeding increases homo and reduces hetero ▯ brother sister mating can increase the probability of rare recessive alleles from 1 in in a million to 1 in 4/ ▯ most hereditary diseases are recessive mutations ▯ ▯ westemark effect- people who live in close domestic proximity during the early childhood became desensitized to later sexual attraction ▯ ▯ inbreeding prevents the dilution of wealth in families. Political enemies ▯ fitness is determined by weighted average of each allele ▯ still assume random mating ▯ natural selection is on phenotypes produced by the genotypes ▯ PRIME=Next generation ▯ Gene pool selection p’ and q’ ▯ q’= 1-p’ ▯ ▯ ▯ w* hoomo 2 A1A1 ▯ hetero 1.8 ▯ homo 1.8 A2A2 ▯ ▯ allele average usually less than 1. Not true for genpytpe ▯ ▯ allel goes to 100% is called fixation ▯ would take 2.5 millenia. 2500 years due to our long generation time ▯ ▯ *if evolution is slow, then how did ccr5 delta rule to a frequency of 9% in northern Europe? ▯ Answer: not certain. Good hypothesis- recent evidence indicates that another virus also uses the ccr5 receptor to enter cells The virus that causes smallpox Perspective- are we evolving now Human hat map. Single nucleotide polymorphisms keeps growing Partial selective sweep. Drag surrounding SNPs to higher frequencies, not just the beneficial mutation. Haplotype mutations become less common. Length of haplotype is lessened Haplotype diversity vs time looks like a negative exponential, but then goes back up Most new beneficial alleles are not shared among the geographic groups, but there is overlap Reproduction genes always evolve rapidly More geneti beneficial mutations occurred in Africans. No population bottleneck. Small numbers of Asians and Europeans migrated out of Africa Rate of adaptive evolution in humans is changing over time, and began when agriculture started growing Due to growth in population Number of new mutation increase Fixation probability exponential growth ▯ ▯ Blue eyes- very recent selective sweep ▯ Manhattan plot ▯ Selective sweep- light skin evolved in Europeans ▯ Produces smaller and more dispered melanosomes ▯ ▯ Can natural selection stop the accumulation of fatal mutatinons in the gene pool? No ▯ Harmful recessive mutations accumulate to a frequency of about 1/100/ ▯ Natural selection cant keep out not shown prior to the 1%
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