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University of Toronto Scarborough
Biological Sciences
Maydianne Andrade

Lecture 16: Why do HIV treatments Fail? 11/25/2012 2:08:00 PM 1. AZT, looks a lot like thymidine but not thymidine  Reverse transcriptase molecule accidentally binds with AZT instead of thymidine, and AZT ends reverse transcriptase  Initially very effective, doesn‘t cure HIV just makes the concentration of virus loads in their blood and usually do not progress to AIDS as a result 2. Stopped working after six months: WHY?  HIV evolved resistance to AZT winin the body of a single host usually within 6 months—Resistance does evolve o Our bodies also need Thymidine so there is a certain dosage level of AZT that you cannot pass for a human, this dosage level needs to be exceeded after 6 months as more AZT is then needed to inhibit the HIV viruses o Mutation in HIV transcriptase makes it less error prone, and hence makes it less likely to mistake AZT for Thymidine o Due to natural selection (BLIND-not heading to goal that we want it to), HIV viruses with mutant reverse transcriptase reproduce at higher rate than normal virions o Eventually, most viruses present in body are resistant to AZT o To test whether this was actually happening they sequenced genes which showed that viral strains present late in treatment (mutant type) are genetically different from the ones present at the beginning of treatment (wild Type) 3. Why is it so effective at evolving resistance to most drugs  Considerably heritable variation o Has the highest mutation rate of any known virus as there is no error correcting enzyme; DNA polymerase corrects for us but there is no such thing for HIV; more than 50% of DNA transcripts carry at least 1 mutation o Genetic divergence from the original genes; genetic material changes in the epitopes (proteins that coat the outside of the HIV) that allow the T-cell to recognize them; shifts the proteins that your immune system uses to recognize HIV o Rapid Replication: during chronic infection 10- 100 mill new virions produced per day o Lot of variation and rapid replication increased probability of mutations beneficial to HIV in short time o Drug, then, is an agent of selection  Any variant that is resistant to anti viral drug produces more copies of itself than other strains Fig 1.14 4. What about vaccine? To reduce infection  2009, first vaccine that reduces risk of HIV infection o Didn‘t have much effect  Trial by a drug comp showed that Being vaccinated with HIV could increased probability of infection because people thought they were protected  Not possible because of the way that epitopes shift so quickly  Flu epitopes shift in a way that you can predict future shifts  Some mutations affect critical systems that make the entity viable—this is the approach/mind set that they have to figure out a vaccine  Recent efforts concentrate on ―conserved epitotes‖, the thing that is essential, that does not change, for HIV function th  October 18 2012 effective vaccine tested on lab rats 5. How to use understanding of Evolution to help individuals  Evolution can go and come back therefore Periodic shifts in selective environment: antibodies serves as the constant selective environment o Take individuals who take the AZT and get to a point where AZT is no longer effective as the mutatnt strand of HIV has developed. Take away the AZT immediately and then the mutant strand will not be as effective any more; pop of viruses that are adapted to AZT, then replication will decrease and may give immunes system time to rebound o Take away AZT, and use a new drug; now HIV is in a novel environment; periodic shifts in selective environment will give immune system time to rebound o Can you introduce AZT again? Yes enough time to remove the mutant AZT-HIV strand then using AZT again would be effective, only if given enough time  Simultaneously treat with multiple retroviral drugs o Mix or cocktail of drugs each targeting different stage of HIV cycle o Virion must carry multiple benefits to be resistance Fig 1.15 a o Eg HAART o Virus eventually adapts by 3 years so different mix must be used  HIV can quickly evolve resistance to drugs within the body of a single host 6. Why is HIV fatal (evolutionary causes)  Killing host means that virus dies with it so why is it fatal?  Virulence= tendency to cause disease in host  High virulence- rapid growth rate of virus leads to severe host illness and/or death  Low virulence- slow growth rate of viruses  leads to slow development of illness or little effect on host  HIV evolves to more virulent over time within the body of one host as it adapts to host and reproduces rapidly; due to selection for rapid replication inside the body of a host  By definition the most common strains of HIV will be those that infect the largest number of hosts  Therefore, does high virulence increase the number of host infected?  Transmission Rate Hypothesis: Natural selection favors increased virulence of sexually transmitted diseases when transmission to new hosts in frequent, and favors decreased virulence when transmission to new hosts is infrequent  Virulence involves reproductive trade off  High virulence: many virions/ml blood; rapid illness and death of host Cost to virus Benefit of virus Rapid illness and death of Many virons/ml blood  host decreased # copulations increased chance transmission before death of host at each copulation  Does High virulence increase # of hosts affected?  Depends on how quickly people change sex partners Frequent partner change Infrequent partner change Largest # host infected with Largest # host infected with HIGH virulence strain low virulence strain as has not spread to other individuals o Partner change, virulence form Rare Partner change, 2 new hosts are Low virulence infected before original host dies Rare partner change, Only 1 new host is high virulence affect as original host dies before changing to another partner Frequent partner 2 new hosts are changes, low virulence infected; individual lives pretty long before death Frequent partner 3 new hosts are changes, high infected virulence o If Measures are in place to reduce the amount of body fluids exchanged, even though within body of individuals hiv is still selected for high replication rates, at the level of the pop, characterists of the virus you expect to see is viruses with low virulence levels; viruses with which host can survive with for much longer periods of time o Hiv can out compete humans because of its rapidity of replication and high rate of mutations Lec 16 conclusion; voice recording: o Why is hiv fatal: 3 reasons  natural selection within the host favors rapid replication thus the virus becomes more virulent/more likely to cause illness  Selection of virus at level of population of the host  In a human pop where hiv is going from individual to individual there is another level of natural selection that affects what characteristics of HIV are most common at the level of the population of host  On avg in pop of humans how virulent is HIV?  Natural selection of virus in terms of moving between host  Virus with characteristics to affect largest # of hosts will be the one we will see in that population o Humans have not evolved resistance to virus  Why have humans not evolved resistance to the virus o 2 levels of selection:  selection inside body-rapid replication favored (to infect other cells in same host)  selection across the pop of hosts- max spread among hosts favored (to pass on to new hosts via body fluids) o Transmission Rate Hypothesis: Natural selection favors increased virulence of sexually transmitted diseases when transmission to new hosts in frequent, and favors decreased virulence when transmission to new hosts is infrequent Predictions:  Diff pops will have HIV strains with diff degrees of virulence depending on sexual/intravenous practices  Virulence will change as virus spreads to areas with sexual practices different from original source population o Human HIV co-evolution  Ways humans can combat HIV evolution:  changes in sexual and drug use (cultural, not evolutionary)  Can humans evolve to combat it? o Delta 32 mutation in CCR5 coreceptor- HIV cannot ener the cells  Function of Coreceptor: is critically important in allowing the HIV to bind to the tcell and create an infection cycle o People with delta 32 allele survive HIV infection much longer than people with wild type: eg if heterozygous for delta 32 allele, it takes much longer and can survive HIV for much longer time  Was there a random mutation that has increased the frequency due to the presence of HIV as a selective agent  Delta 32 allele present in 9%; close to 0% in Asians and Africans  Delta 32 mutation is most common in areas where HIV is relatively rare so cannot be an evolutionary response to HIV  2 hypothesis:  past selection by small pox or bubonic plague  genetic drift (founder effects) via Vikings  few individuals amongst Vikings carried this mutation and as Vikings had period of pillaging Europe (raping/leaving offspring behind); had high frequencies of this therefore left high frequencies of this trait  will delta 32 increase in frequency due to selection? save us from HIV  model: wild type individuals have fitness of 0.75; heterozygotes fitness of 0.75; delta 32 homozygoes mutatnts fitness of 1.0 as completely resistant to HIV; initial freq of CCR5 delta 32 allele= 0.2 as generation increases to 40 freq=1.0  in 40 generations, under selection of HIV, rapid increase delta 32 to point that it becomes fixed in human pops  But is it realistic? NO; scenario combines highest ever freq of delta 32 (0.2) and highest death rates (mortality)—highest selection in favor of the trait that expect to find in areas where death rates from are the highest (ex AFRICA)  In natural conditions:  Europe: wild type: 0.995; heterozygotes: 0.995; delta 32 homozygotes: 1.0; initial freq: 0.2; no change  Africa: wild type: 0.75; heterozygotes: 0.75; delta 32 homozygotes: 1.0; initial freq 0.01; no change even though there is selection very much favoring delta 32  Evolutionary theory:  Can explain many characteristics of HIV:  Resistance to treatment  Lethality  Suggest best way for society to fight HIV is by selecting for reducing virulence (safer sex, safer drug use)  Rapid evolution of HIV= vaccine or drug is ineffective in the long term  However once infected we no longer talk about selection at level of pop but at level of host:  Suggests best way for an individual to fight HIV is by slowing the ―within-host‖ evolution of resistance  Change selective environment periodically  Use a cocktail of drugs Lecture 17: Quantitative Genetics and Heritability 11/25/2012 2:08:00 PM 7. Genes are the source of proteins, proteins come together to make certain phenotypes 8. Internal factors affect the production of proteins; genes interact with each other, which can occur directly or via the production of proteins which together have to be together to make a phenotype 9. Quantitative traits: characterists for which pheontypes show continuous variation among individuals (eg height)  Traits are determined by environment and many mendelian genes at many loci with small effects (actually the case for most traits)  Focuses on: phenotypes, and heridability, statistical properties of population traits (mean, variance)  Genes basis of trait is not the same as heritability of trait 10. Example of quantitative trait which is affected by both genes and environment  Yarrow (Achileea)  Took the plants and reared them in three different environments: different elevations along a mountain  How variation in phenotype of the plant resulted in the genotypes and from the different environments which they were reared  Variation across environments across ONE genotype,  Variation across genotypes for ONE environment  Therefore plant form (height, #stems) varies with both environment (elevation) and genotype  Hence we can conlude from this experiment that genes and environment can work together to affect variation in phenotype  Most phenotypes are affected by genes and environment; very common for quantitative traits 11. How do we study evolution of these traits when we usually don‘t know which loci control quantitative traits  Quantitative genetics: provides us with tools for measuring and tools for predicting  Tools for measuring: heritable variation in traits (HERITABILITY), differences in lifetime reproductive success (intensity of selection)  Tools for predicting: effect of selection on phenotypic trait value (evolutionary response to selection) how do we expect phenotypes to change given the heritability of the trait and intensity of selection that we have measured 12. Heritability= extent to which phenotypic differences are due to differences in genes underlying those traits  Focuses on differences and causes of differences between individuals  To what extent do differences in environment have an effect and to what extent do differences in genes have an effect, which one has biggest effect on trait in given environment because that will tell us something about how likely it is that that trait can respond to selection  The bigger the relative effect of genes on a given trait the stronger the response to selection  Higher herability, the more likely that there will be change in the next generation as individuals will inherit genes from their ‗successful‘ parents  Broad sense heritability= fraction of total variation in trait that is due to variation in genes 13. Is a trait heritable? Do offspring tend to look like parents? (when we control for variation due to environment; based on simply genes)  Bigger the effect of genes, bigger the response to selection: in other words if genes have a bigger effect on the trait then selection will change not it will not for offspring  What portion of phenotypic variation (total variation in trait) VP is due to genetic variation o VP= VG+VE  Different types of genetic variation o VG= VA+ VD o VA additive gentic variation: differences among individuals due to cumulative (additive) effects of genes  Contribution of each allele to phenotype is independent of other alleles  Help us to predict how offspring will look like based on what parents look like o VD: Dominance Genetic variation  Differences among individuals due to interactive effects of genes eg dominance, epistasis  Effects of alleles on each other, within locus across loci  Hard to predict if look at one allele how much allele will contribute to final phenotype because that will depend on genetic environment it is in  Will make offspring phenotype less predictable from parental phenotype  Use AG: isolate because this is the type of variation that shows similarity between parent and offspring; heritability depends on additive genetic variation underlying variation in traits o AG: loosely means offspring looking like average of parents  Additive genetic variation (no dominance) two alleles rr a white flower and RR a red flower, then Rr is resulted which is pink  Every allele contributed by parent changes the pop of offspring by one unit  At high rates of R being produced higher rates of RR will result; generation will eventually be completely red  Dominance genetic variation o Now RR is dominant over rr therefore Rr is red and not pink 14. Narrow sense Heritability h^2 (never take sq root of it) this is what we mean when we say heritability in evolutionary terms  What proportion of total phenotypic variation is due to these additive effects  Fraction of total variation that is due to additive genetic variation  Ranges between 0 and 1, if 0 then trait is entirely determined by environment, if 1 the trait is entirely determined by genes 15. Ways of measuring heritability  Parent offspring regression o How much do offspring resemble parent o Measure of the amount of variation in parental trait due to additive genetic variation o Must control any variation due to parents and offspring sharing common environment o X axis mid parent height and y axis mid offspring height o Get the slope of this relationship and heritability is equal to this- slope of parent-offspring regression o Measure of extent to which a change or variation of parents is related to a change in offspring o BUT: parents may resemble offspring due to similar genotype OR similar ENVIRONMENT o To measure heritability accurately we have to control for environmental effects o Ex: might be short because of genes but could also be short due to diet (poor diet); parents feed you the same way they were fed hence you also inherit their diet styles o Control for environment= isolate generation  Strategies:  Ensure offspring and parents have different environments (eg cross fostering/adoption (animals) or reciprocal transplant (plants)  Ensure all offspring have same environment eg common garden experiments 16. Example of cross fostering experiment: heritability of beak depth  Established foster parents; swap out offsprings so that offsprings were raised by parents that were not their own; compared biological parent to biological offspring slope value (heritability due to genetics) was very high 0.98  To check that this high value was real, they said that if its so high then the value for the effect of environment on heritability should be very low: compared how similar foster parents are to foster offspring; very low effect of environment -0.18  Therefore can conclude that similarity is due to underlying genetic similarity rather than environmentally-induced similarties  Could have raised birds in a common place instead: common garden experiment 17. Twin studies:  monozygotic twins reared apart Identical genotype, different environment—how similar are they as adults o Jack Yufe raised Jewish in Caribbean; Oskar Stohr raised catholic in Nazi Germany (monozygotic identical twins, adopted apart) o Lots of similarities in personalities—heritability of personalities  compare similarity of monozygotic twins to similarity of dizygotic twins o Monozygotic: 100% genetic similarity  Same genes, same environment o Dizygotic: 50% genetic similarity  Different genes, same environment o If heritability is high, monozygotic should be more similar to each other than dizygotic: mono have more genes in common o Heritability low: amount of similarity/dissimilarity should be the same in monozygotic and dizygotic because it is the similar environment that is affecting the trait Lecture 18: Heritability Continued 11/25/2012 2:08:00 PM  Mistakes of Heritability o Heritability is NOT a FIXED characteristic of a trait  Instead, Heritability is specific to a particular population in a particular environment  Mathematical explanation: If the amount of variation induced by environment changes (VE) (even if VA underlying trait remains the same), then h^2 (heritability) has to change in order to respond to the change in VE  h^2=VA/VP = VA/ (VG+VE) o Eg: What is the heritability of skin color among Caucasians in Vancouver?  Fact: sun exposure is the largest environmental determinant of skin color  Vancouver winter-hardly any sun, rains all the time; summer- is quite sunny  Aussume: random varation in how much time people spend outdoors (tanning) when it is sunny (VE)  Winter: VE is low; therefore predict that heritability is high as they are inverse variables  Summer: VE is high; therefore predict that heritability is low  Depending on where trait developed you can have high or low heritability for that trait o Error 1: if all members of a pop have the same trait value that trait is highly heritable  Error because if there is no variation in the trait then the trait is not heritable o Error 2: heritability is a fixed value for a particular trait  Error because heritability is not a fixed characteristic of a trait; heritability of a trait is specific to a particular population in a particular environment (as was seen in the example about the Vancouver weather variation and skin color) o Error 3: heritability tells us whether differences between populations are due to differences in genes or the environment  Does heritability tell us something about the source of differences between populations?  Hypothetical example: you observe that people from Vancouver have fairer skin that people from Los Angeles on average  Both have high heritability for skin tone  Does this mean that the difference in average skin tone of people from Vancouver versus California is due to genetic differences (additive genetic variation) between the populations?  NO!it is due to an environmental difference…think of the 007 picture when he went to los Angeles after living in Vancouver- he became darker but he is still the same person therefore cannot be a genetic diff  One likely hypothesis to why there is still high heritability is because it is sunnier in los Angeles than in Vancouver thus Los Angeleans are darker skinned on average  in this case diff b/w populations mainly due to VE despite high heritability within each population and avg diff between the two  heritability does not tell you anything about the cause of differences between populations  Ex 2: Yarrow: same seeds planted in different environment giving different heights of same plant this variation is all due to environment as genetics are kept constant o Why bother to measure heritability: allows prediction of whether selection on a trait in a given population will cause trait to evolve 18. Evolutionary response to selection  Magnitude and direction of change in trait for offspring (R)  This depends on heritability (h-extent to which parental phenotype predicts offspring phenotype) and selection differential (S-magnitude and direction of selection) 19. It is profitable to select on trait with highest heritability—farmers do this to increase their profit 20. Heritability and Bell Cure Fallacy: Heritability and racial differences  The bell curve: Intelligence and class structure in American life o Came out 1994, discussion of heritability of intelligence (IQ), socioeconomic, social factors, and race o Concludes that racial differences in IQ are due to hereditable differences in intelligence among races o Brought about argument that it was a waste to nurture children from areas such as the getto (from african American races) as environment will have no effect on intelligence levels, therefore enrichment programs and having healthy meals before school were a waste o Jhon Rushton- Dept Psychology Western Ontario claimed to use a gene based evolutionary theory to explain patterns of intelligence between races  Heritability of IQ and book The Bell Curve o Most populations heritability of IQ is 0.40-0.80; it is heritable o African American average IQ is 15 points lower than average IQ of European Americans o The book, the Bell cure questions whether this difference mainly due to differences in environment or genes?  Bell Curve Approach: o Argues that the difference is too big to be due to environment therefore conclude that IQ is heritable, environment causes unlikely, genetic differences cause of racial difference in IQ  Background: o No debate that IQ is affected by the environment during development o At the time, African and European Americans basically form separate populations with diff environments  Huge differences between environments in these two pops: ex child poverty and low birth weight o Avg IQ of Africans were lower than Europeans  They assumed heritability of IQ in each group is about 60% (range is between 0.4 and 0.8 so is a reasonable assumption)  Imagine what curve would look like for each group if genetic variation was removed; o Assume heritability= 0.6 for IQ so reduce variation in each curve by 60%; essentially removing Additive variation (VA) still having same diff between avg IQ scores o Leaving behind only variation due to environment within each population as you have shaved off variation due to genetics o X-axis that was once labled IQ scores, is replaced with quality of environment influencing intelligence o Then conclude that the difference in quality of environment influencing intelligence is insufficient to yeild a 15 point difference in IQ score o Then conclude that difference must be mainly due to genetic differences between the races  Problems with Herrnstein/ Murray o You cannot just trip off 60%, Where to trim 60%: alters average  Evenly from each side of distribution (H&M)  From one Tail? Which one? Same trim for both distributions? o How an you separate genetics and environmental effects? o Heritability does NOT define the proportion of a trait value that is due to genetic effects  You cannot do this. It is like saying you are 7 ft tall and 4 feet of that is due to genes but 3 ft is due to what your parents fed you o Basic misunderstanding about heritability o Despite heritability within each population cannot conclude difference between populations is mainly due to genetic differences  These are different populations with different environments 21. Is the IQ difference mainly due to differences in environment or genes?  Manipulate environment: a cross-fostering experiment  Children from both races rear all of them in European American environment/ African American environment  If Differences are due to environmental curves should overlap, one curve for both groups  If differences are du to genetic diffrences, a change in environment would have no effect and you should still see two different distinct lines  Variable results: data goes in both directions; suggests strong environmental effect, and suggests genetic effect 22. Problem: is the treatement (environment) of cross fostered or common garden children actually identical? Will children in Europe treat an African American child the same way…probably not, hence this type of data collection may be unreaible 23. Examine the stability of difference  Prediction: racial differences genetic o IQ difference should be stable over time and across populations  Prediction: racial differences environmental o IQ differences should decrease with enrichment or changes in social practices/nutrition Lecture 19: Response to Selection 11/25/2012 2:08:00 PM 24. Selection:  Natural Selection: differences in average reproduction of different phenotypes in a population  Examples of different phenotypes o Green or red snakes: qualitative—different traits  Fixation, loss, maintenance  How does allele frequency change with selection (population genetics) o Longer or shorter tails: quantitative—different trait values  How does mean and variation in trait change with selection (quantitative genetics) 25. Measuring Selection:  Approach: compare the mean value of trait x in population before and after selection  Selection Differential (S): difference in mean trait value between successful breeders (parents) and whole population  S=P*-P  P*= mean trait value in parents  P= mean trait value in whole population  S > 0 selection favors increase in trait value  S < 0 selection favors decrease in trait value  S=0 selection favors mean trait value  Direction of selection =sign of ‗S‘  Strength of selection= magnitude of ‗S‘, mag of S is high selection is stronger than when mag S is low  EXAMPLE: artificial selection on mouse tail length Population of lab mice: total mice-30 o Select only 1/3 of mice to breed; 10 mice with longest tails o How does the mean trait value change in the next generation? Look at babies of individuals that were bred o Evolutionary response to selection ®: difference in mean trait value in offspring of successful breeders versus offspring of whole population o ®= O*- O o O*= mean trait value in offspring of breeders o O= mean trait value of all potential parents‘ estimate mean trait value of population before selection—if no selection, assume no evolution then HW & no change in trait vlalue expected  Only expect evolutionary change if trait under selection is heritable therefore we need to include heritability  All variables can be seen in regression format  Slope= h^2= rise/run  H^2= O*-O/ P*- P  H^2= R/S  R=(h^2)(S)  Extent and direction of change in offspring ® depends on magnitude and direction of selection imposed on their parents (S) where that quantity is adjusted by extent to which parental phenotype predicts offspring phenotype 26. Case Study: selection by pollinators:  Alpine skypilots: live in alpine meadow and tundra  Very different in these two habitats  Timberline: narrow, ―skunky‖ smell, short stems  Turndra (further north): flowers 12% larger, sweet smell, long stems  Differences caused by co-evolution of plant and most common pollinator in each habitat?  Timberline: key pollinator-flies (like rotting things)  Tundra: key pollinator- bumblebees (like sweet smell)  Thought pollinators imposed differences  Hypothesis: original population was at timberline, and pollination was done by flies  After seed dispersal (when glaciers shifted) new population was moved to tundra where bumblebees did the pollination; did selection for shape, color and smell of flowers  Must measure: extent to which parental phenotype predicts offspring phenotype; magnitude and direction of selection imposed by bumblebee pollination; and from these you can calculate the response to selection and estimate the extent to which these population changes could have happened just through selection 27. Procedure:  Population= small flowered timperline plants (hypothesized ancestral population)  Measure flowers (144 plants) collect seeds  Geriminate seeds in lab, plant seedlings at RANDOM locations in parent‘s habitat (randomize any effects of environment)  Measure flowers of mature offspring (7 years later)  Couldn‘t tell which was the father but was able to distinguish maternal flowers as those were the ones she was holding o Slope of offspring vs midPARENT= h^2 o Slope of offspring vs ONEparent= (h^2)/2 o h^2= 2(one-parent slope) o slope was 0.5 o h^2= 2(0.5)=1.0 o 1 is not possible as scatter was considerable o Through statistical analysis, she concluded that flower size is heritable but ranges from 0.2
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