Biology 2970 Post Exam Material

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test

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test

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Epistatic Variance

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Non additive genetic variance at population level arising from interactions among genotypes at different loci

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Epistatic Variance

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Non additive genetic variance at population level arising from interactions among genotypes at different loci
- Medelian epistasis is necessary but not sufficient for epistatic variance

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Population genetics definition of evolution

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1. Change in allele or gamete frequency in the gene pool
2. fates of alternative forms of genes over space and time in a population

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Evolutionary forces in populations (defn)

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factors or processes that can change the frequency of an allele in a population

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Evolutionary forces in populations (examples)

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1. Mutation
2. genetic drift
3. gene flow
4. natural selection

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Mutation

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causes many small changes in a population

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Genetic Drift (defn)

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random changes in allelic frequency as a results of finite population size
- sampling error
- chance introduces variation
* decreases variation within a population (loss of alleles), increases variation between populations

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Genetic Drift Characteristics

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1. No direction
2. Cumulative Across generations
3. Strength ~ 1/2N (autosomal loci)
4. Causes loss of alleles from demes
3. Causes divergence among isolated genes

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Genetic Drift: It's Cumulative

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- Bigger deviations from initial gene pool become more likely with passing time

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Genetic Drift: Strength

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~1/2N
- bigger populations have smaller genetic drifts

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Genetic Drift: Loss of Alleles

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- If you lose an allele you need mutation to bring it back

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Genetic Drift: Mutation

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Mutation is the ultimate source of variation
* increases variation within a population and between populations

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Genetic Drift Characteristics

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1. No direction
2. Cumulative Across generations
3. Strength ~ 1/2N (autosomal loci)
4. Causes loss of alleles from demes
3. Causes divergence among isolated genes

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Genetic Drift: It's Cumulative

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- Bigger deviations from initial gene pool become more likely with passing time

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Genetic Drift: Strength

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~1/2N
- bigger populations have smaller genetic drifts

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Genetic Drift: Loss of Alleles

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- If you lose an allele you need mutation to bring it back

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Genetic Drift: Mutation

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Mutation is the ultimate source of variation

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Coalescence

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- loss of alleles = coalescence
- Take all copies of homologous DNA in population today and trace back in time to the ancestral molecule
- Rate of loss of alleles = 1/2N
- Time for 2 genes to coalesce = 2N generations
- time for all genes to coalesce =4N
** the smaller the population, the further back in time we have to go

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Rate of Loss of Alleles

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=1/2N

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Average time for TWO genes to Coalesce

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2N Generations

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Average time for ALL genes to coalesce

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=4N Generations

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Ideal population (things assumed)

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1. Constant size
2. even sex ratio
3. non-overlapping generations
4. mating random
4. no selection
5. fecundity Poisson distributed

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Fecundity Poisson distributed

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- statistic sampling measurement
- in ideal populations, u=sigma^2=2
- 2 offspring on average and variance = 2

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Effective Population Size

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Ne = size of an ideal population whose rate of [random genetic drift] equals that of the real population

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Inbreeding effective size

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= size of an ideal population whose rate of accumulation of identity by descent equals that of the real population

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Variance effective size

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= size of an ideal population whose rate of change of allele frequency equals that of the real population
- i.e. grasshopper in lab

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Bottleneck Effect

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A large population today had on or more generations of small size in the past
- violation of ideal population size [constant size]

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Founder Effects

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bottleneck coincides with a new geographic settlement

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Consequences of Founder events

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1. drastically alter allelic frequencies
2. Reduces overall genetic variation - decreases non-additive variance
3. Creates linkage disequilibrium

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Founder Event: Example

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- Salinas, Domincan Republican
- founded by a small number of individuals 7 generations earlier
- Girls became males at puberty
- single AA mutations --> low steroid reductase
- converts testosterone (which develops testes) to dihydrotestosterone (which forms external male genitalia)
- During development, there was not enough testosterone to make child look male
- puberty - high levels of testosterone and looked male
**usually rare, but in a small population, identity by descent increases and homozygotes produced***

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Evidence for Neutral Alleles: Fibrinopeptides

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*If evolutionary change is by natural selection, most specific and important aspects should evolve fastest
- Graph shows that the higher the functional density, the slower the rate of evolution
- Based on the fact that fibrinopeptides evolved the fastest, we can conclude that proteins that evolve more rapidly have less specificity in amino acids

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Unit Evolutionary Period

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(UET) - time needed for 1% of amino acid sequence divergence between homologous proteins
- Directly proportional to functional density

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Fibrinopeptides

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* fibrinogen - inactive fibrin in blood stream
- at injury, converted to fibrin by fibrinopeptides
*fibrinopepties - spacer peptides that prevent formation of the clot, able to function with a wide variety of amino acids

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Functional Density of proteins

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proportion of amino acid sites that perform specific functions
- substrate recognition, active site for catalysis, ligand-binding, allosteric shift
* can only be performed by amino acids in specific sites

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General Functions of Proteins

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- charge, isoelectric point, solubility

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Synonymous sites

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- do not change the amino acid chain...due to "wobble" in genetic code

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Non-synonymous sites

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- a mutation in this site gives a change in a amino acid
- more f a functional consequence to a mutation

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Meta-population

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large population subdivided geographically into many local demes
* most mating occur within a local population, but sometimes individuals mate outside their local deme --> gene flow

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Evidence for Neutral Alleles: Beta Homoglobin Gene

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- Evolution rate for pseudo-beta is much higher than functional B
- natural selection is conserving alleles that are functional
- prevents harmful mutation
- all alternative genes evolved from duplicates
*DOES NOT reject the hypothesis that neutral alleles are invoked in evolution

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Gene Flow

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Movement of genes between demes

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Allelic Diversity

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*Units of Measure - allelic frequency
*Units of Variance - 2pq OR 1-[p^2+p(n)^2]
* categories - within or between

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Quantitative Phenotype

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*units of measure - norm of reaction, mean phenotype
* Units of Variance - units of measure squared
* Categories - gametic vs. environmental, additive vs. non additive, dominance vs. epistatic

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Gene Flow

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- Demes become more similar over time and eventually become the same
- No Evolutionary change occurs if the demes are the same
- Increases Genetic varaince WITHIN local populations and decreases variance BETWEEN local demes

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Migration

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* increases variation within populations, decreases between populations
OPPOSES GENETIC DRIFT

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Fst

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*measures the balance of gene flow to drift on a 0-1 scale
*0 = dominated by gene flow
* 1 = dominated by gene drift
* = (Ht-Hs)/Ht
Ht = between
Hs = within

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Calculation of Fst

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* Ht = heterozygosity expected by randomly choosing two genes from the TOTAL population = 2pq

*Hs = Heterozygosity expected by randomly choosing two genes from within a SUBpopulation = [2pq(1)+2pq(2)]/total pop

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Ht=Hs

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All demes have identical gene pools; all variation shared equally throughout species; gene flow dominates

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Hs=0

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No variation within demes; All variation exists as differences between demes' gene pools

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Ozarks

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- Has become a wetter region since the colonization by animals from the SW united states
- as a result of the increase in fragmentation, increase in genetic drift in certain regions (assuming no gene flow)
- if we could increase gene flow, we could increase diversity

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Grasshopper vs. Lizards in ozarks

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- Fst of grasshoppers is low compared to lizards because they can fly
- migration of lizards after the burning of the glades

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Fst of humans

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human populations have a surprisingly low Fst, rather homogeneous geographically
* 85% of variation is within
* 7% is between populations on same continent
* 7% between continents

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Isolation by Distance (Sewall Wright)

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*Fst
1. partial isolation only
2. most gene flow is between neighboring demes with genetic difference among populations being proportional to their geographic distances
- gene flow usually occurs within a deme or between neighboring demes
3. a new mutation can spread throughout the entire species even if no individuals move long distances
- each local deme is a "stepping stone" and genes can take many generations to cross such stepping stones
4. Best predictor of genetic differentiation among human populations is geographic difference

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Measure of Fst

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- pairwise distance measure - can use neighbor joining method [distance matrix method to construct a tree]

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Isolation by Distance (predictions)

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younger haplotypes have smaller geographic distributions located within the ranges of their ancestral haplotypes
*haplotypes have geographic distributions
i.e. Haplotype tree of Elephants

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Geographic range expansion

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*idea that opposes isolation by distance
*undergoes long distance expansion into uninhabited area
younger haplotypes can have geographic distributions well outside the ranges of ancestral haplotypes
i.e. mtDNA in humans

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x-chromosomal haplo-diploid locus

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- number of genes in pool = 3/2N
-average time to coalescence = 3N generations
*reflects gene flow and events in both males and females

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y-chromosomal paternal haploid locus

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- number of genes in pool = 1/2 N
- average time to coalescence = N generations
*reflects gene flow and events in males only
* good tool because there is less coalescence time

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Coalescence of Mitochondrial DNA

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- expected coalescence time = N
- detects gene flow and events solely through females
- inherited as a maternal haploid

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Bantu and Yemeni example

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- Several centuries ago yemeni men sailed down to africa and married bantu women (Lemba peoples)
- analysis reveals that the Y chromosomal DNA shares more in common with Yemeni/Jewish ancestry
- mtDNA shows more in common with Bantu DNA

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Fishers Fundamental theorem of Natural Selection

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- rate of increase in fitness of a population at any time equals its additive genetic variance in fitness at that time (single locus model)
*heritable variance in fitness
*destroys variance in fitness (will act until it removes and reaches selection equillibrium

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Selective equillibrium

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= selective peak
- no additive variance in fitness
*selection moves a population toward a selective equillibrium

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Fitness

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1. Viability
2. Mating Success
3. Fecundity/Fertility
*average number of offspring produced by individuals of a genotype
*highly influenced by environment that an organism is in
...sufficient parameter for natural selection

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Natural Selection is not circular...

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- The environment is subject to change and thus, produces different results in the formation of organisms
i.e. PKU babies and Malarial selective peaks

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Viability

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=V
probability of individuals reaching adulthood

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Mating probability

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= C
probability of a genotype mating

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Average number of offspring

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= b

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Mathematical measure of fitness

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W = V * C * b

- different fitness for each genotype

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Converting fitness to frequency

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Divide fitness by average fitness of gene pool

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Does Evolution Occur?

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*change in allele frequency after 1 generation (p'-p) or (q'-q)
* Δp = paA/Wbar
Natural selection is an evolutionary force whenever p is not 0 or 1 (there is genetic variation), and when the average excess of an allele is not 0 (when there is heritable variation in a phenotype of fitness)

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Sign of Average excess

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tells us whether selection is increasing or decreasing a phenotype

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Evolution by Shifting Balance

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- interaction between natural selection, genetic drift and gene flow in a metapopulation causes it to explore adaptive peaks
*illustrated by the increase of the C allele in a deme by genetic drift and thus causes the drift to shift peak

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Evolution by Shifting Balance (cont.)

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1. Drift in demes can shirt average excesses of alleles for fitness (illustrated by calculations of S, A, C i.e. change in C allele frequency)
2. selection then directs a population toward a different peak
3. demes with highest peaks preferentially send migrants to other demes (gene flow --> allows demes with best genetic fitness to export alleles)
4. Entire metapopulation moves to a peak

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Three Phases of HIV infection

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1. Early phase (M-tropic) - CD4 and CCR5 recognition proteins on outside of macrophages are identified by M-tropic HIV
2. Middle Phase (Dual Cell Trophism) - also recognize CD4 and CXCR4 of T cells
3. Late Phase (T-Cell Trophism) - attack T cells

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Reverse Transcriptase

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- makes mistakes at a high rate
*makes double strand DNA from single strand RNA
* encoded for by the RNA of HIV

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dN/dS

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[number of non-synonymous substitutions by NS site]/[number of synonymous substitutions per synonymous sites]
*neutral alleles predict =1
* conservation selection <1
* directional selection >1
- permits evaluating the role of natural selection in the evolutionary history of a protein-coding region

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Expected N/S in pyrin locus

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2.6 (based on number of replacement sites)

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Evaluating Diseases on a Phylogenetic Tree

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If a disease reverses a selectively driven substitution (reversal to ancestral type) then it is probably associated with a disease because it is acting against natural selection

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neutral allele

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alternative sequences of homologous DNA that have no impact on any phenotype related to reproductive success

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Identity by Descent

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population genetic term for copies of homologous DNA that are identical because they were replicated from a common ancestral molecule in a previous generation without intervening mutation

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Role of population-genetic processes in Templeton's inferred history of human geographic genetic variation over past 1.7 million years

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Gene flow among human populations conforms well to a model of isolation by distance
following the initial expansion of humans out of Africa ~1.7 million years ago. Superimposed on
the pattern of isolation by distance are some additional long-distance expansions out of Africa,
and one backward expansion from Asia to Africa. Range expansion eastward from northeastern
Asia established human populations in the Americas relatively late in human evolutionary histor

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Selective Equilibrium

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= selective peak
no additive variance in fitness
*natural selection moves population towards selective peaks
*only occurs when Δp = 0 (no variance to act on)

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Viability

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*ability to survive in a given environment
In malarial regions: A/A and S/S is not as viable as A/S

In non-malarial regions: A/A and A/S are more viable than S/S

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Mating Success

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In PKU babies
1. if fed a low phenylalanine diet than they will develop normally and have a higher change of mating success
2. if they are not fed low phenylalanine diets, they have a lower chance of mating due to mental retardation

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Malaria/Anemia Phenotypes in A, S, and C genotypes

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A/A - neither
A/S - malarial resistance
S/S - anemia and resistance
A/C - Neither
C/S - Mild anemia and resistance
C/C - only resistance

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In non-malarial regions,what is the critical component of fitness?

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*Viability
- A/A, A/S, C/C

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Relationship between A and C alleles in non-malarial environment

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- neutral alleles
- frequencies determined by genetic drift and mutation
*due to genetic drift, C allele will drift to high frequencies relative to A allele

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evolutionary forces that act on neutral alleles

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genetic drift and mutation

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Sign of Average excess

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indicates whether selection is increasing or decreasing a particular allele

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Why is Average Excess of Allele C 0 to begin?

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- low in frequency so will only be in heterozygotes
- heterozygote is unfavorable

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initial adaptive response to malarial environment

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- initial adaptive response to malarial environment mediated by natural selection is to Decrease A, increase S and leave C the same

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After initial adaptive response to malarial environment

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natural selection continues to decrease a, increase s, BUT no decreases C (aC = -.014)
*As pS increases, Average fitness increase and genotypic deviations of A/C and C/S become increasingly negative

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At Selective Equilbrium, What are the frequencies of the S and A alleles?

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A = 0.89
S = 0.11
*only broad sense heritability, no narrow sense with respect to fitness
* this is a polymorphic equilibrium --> maintains both alleles in population
*occurs because when S < .11, average excess of S is >0. Malarial resistance dominates average excess
* When S > .11, average excess <0 and anemia will dominate excess

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When S < 0.11

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Malarial resistance dominates average excess

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When S > 0.11

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Anemia Dominates average excess

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Balanced Polymorphism

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*produced by the selective equilibrium allele frequencies that are maintained by natural selection
*helped at A = .89 and S = .11

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Balanced Polymorphism

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*produced by the selective equilibrium allele frequencies that are maintained by natural selection
*helped at A = .89 and S = .11

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Two Possible responses to Malaria

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1. polymorphic equilibrium
2. monomorphic equilibrium
*two different selective peaks

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Polymorphic Equilibrium of Malaria

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S = 0.11
A = 0.89
*not the most desirable peak
1. the fittest genotype is eliminated
2. average fitness goes from 0.9 to 0.91
3. 20% of individuals have a relative viability of 1 and 80% have either anemia or malarial resistance

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Monomorphic Equilibrium

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C = 1.0
1. the fittest genotype is fixed
2. Average fitness goes from 0.9 to 1.3
3. 100% of the individuals have a relative viability of 1.3 and none have anemia nor malarial susceptibility

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Negative Correlation between C and S

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*most populations moved towards polymorphic eq.
* The lower the frequency of C, the higher the frequency of S and the closer a population moves towards the polymorphic peak

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Sincicium inducing

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causes cells to fuse with each other and clump
*measured in culture not in patient

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Replacements that cause SI viruses

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1. arginine or lysine at pos. 306
2. glycine at 306 and lysince at 320

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Different kinds of substitutions

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Interior intraspecific - persisted and gave rise to at least 1 descendent haplotypes

intraspecific (tip) - recently evolved

interspecific - fixed

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N-terminus of Cytochrome Oxidase

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- transmembrane protein
- relatively low functional density
- neutral allele
- does not disprove the null hypothesis

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C-Terminus of Cytochrome Oxidase

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- Higher functional density
- active site
- higher rate of silent mutations
- acting to conserve a sequence

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Neutral Alleles Model

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-role of natural selection in protein evolution
- if most of change is evolution of neutral alleles, primary role of selection is to weed out harmful mutations
- most of evolutionary change is neutral alleles
- selection acts to conserve function of the protein

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How is natural selection redefined in quantitative-genetic terms by Fisher's theory?

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heritable variance in fitness OR additive variance in fitness (accept nonzero average excesses of alleles for fitness)

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In quantitative genetic terms, how does natural selection destroy the conditions that give rise to it?

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Natural selection operates on heritable/additive variance in fitness and moves the population to a condition in which heritable/additive variance in fitness is zero