Anderson Flashcards
What is the principle of maximum parsimony?
- simplest hypothesis
What kind of hypothesis do you always have for transmission genetics?
- genetic hypothesis
How is hypothesis testing carried out for transmission genetics?
- genetic hypothesis leads to prediction
- in some cases can use observed no.s to give idea of genetic hypothesis
- compare prediction with observed
What is a null hypothesis?
- diff between O and E no.s can be explained by chance alone
- no signif diff between O and E
What is P (p values)?
- probability of obtaining observed deviation, or even bigger, assuming null hypothesis correct
What gives a simple approximation of P?
- chi-squared
What does a p value of greater than 0.05 mean?
- no signif deviation from expectation at 5% level
- if did 20x, expect 1x to get deviation bigger, can accept null hypothesis
- no reason to reject it, can’t say its proven, just failed to prove it wrong
What does a p value of less than 0.01 mean?
- signif deviation from expectation at 1% level
- if did 100x and genetic hypothesis correct, only expect deviation 1x, so quite unlikely result just by chance
What does a p value of less than 0.05 mean?
- signif deviation from expectation at 5% level
Why is there a grey area for p values between 0.01 and 0.05?
- can’t just assume one thing if just below threshold and opp if just above threshold
- chi-squared only aid to thinking about signif, have to weigh up data biologically
Where are qualitative differences in phenotype found?
- in “conventional” Mendelian analysis
- prod by allelic variation at single locus
What are quantitative characters influenced by?
- usually several to many genes and env
- look at real pop (not in lab)
- several oligogenes or many polygenes
What is a polygene?
- 1 member of group of genes contributing to quantitative character, NOT group of genes
What is an oligogene?
- 1 member of group of genes, w/ fewer members but each are making bigger contribution
What is a QTL (quantitative trait locus)?
- section of DNA that correlates w/ variation in phenotype
Why is unlinked always the default hypothesis?
- simplest explanation
What are the 2 types of variation?
- continuous
- discontinuous
What is a meristic character?
- countable quality w/ integer values
When are genes said to act additively?
- when sub of 1 allele for another alters phenotype value by certain amount irrespective of other alleles present at same or other loci
What simplifying assumptions are made in additive model for polygenic inheritance?
- 3 genes
- each making same contribution
- no env contribution
What is the additive model for polygenic inheritance (EXAMPLE)?
- height of hypothetical plant controlled by 3 genes
- a1, b1, c1 each add 1cm
- a2, b2, c2 each add 2cm
- a1a1 = +2cm
- a1a2 = +3cm
- a2a2 = +4cm
- then to all of these:
–> b1b1c1c1 = +4cm
–> b2b2c2c2 = +8cm - no dominance, no epistasis
P1 x P2 = a1a1b1b1c1c1 (+6cm) x a2a2b2b2c2c2 (+12cm)
F1 = a1a2b1b2c1c2 (+9cm)
F2 = 8 phenotypes in ratio 1:6:15:20:15:6:1
What are the general features of the additive model for polygenic inheritance?
- F1 mean exactly intermediate between P1 and P2
- F2 mean same as F1
- variation greater in F2 than F1
- extremes in F2 correspond to P1 and P2
How do extremes in F2 correspond to P1 and P2 (additive model for polygenic inheritance)?
- for n genes proportion F2 as short as short parent = (1/4)^n
- which is a v big no.
- so unless no. genes v small or vast no. in F2 gen, then prob not going to see extremes
Why is scale transformation needed?
- common problem to find non-normal distributions = skewed distributions
- not a big problem just need to define quantitative character in way that will fit, eg. log(score)
- makes curve much more symmetrical so maths will now work for it
What are the components of total phenotypic variance (VP)?
- = genetic (VG) added to environmental (VE) component
What is heritability in the broad sense?
- H^2 = VG/VP
What does broad sense heritability show?
- indicates proportion of phenotypic variance attributable to genetic variation
- property of particular pop in particular env
- not good predictor of success in selective breeding
- only part of VG is due to additive effects of gene
Why is only part of VG due to additive effects of gene?
- VG = VA (additive component) + VD (dominance component) + VI (interaction/epistasis component)
What is the range of values broad sense heritability can have, and what does a value of 1 mean?
- 0 to 1
- 1 means all variance due to genetic component
Why dont VD and VI operate in way modelled?
- 2 interacting alleles separated in mitosis
- so interact w/ other alleles when fertilised
- could decrease superiority due to diff allele combo, so inherently unpredictable
What is narrow sense heritability, h^2?
- h^2 = VA/VP
- good predictor of success, as focusses on VA (1 component of VG)
How can estimation of narrow sense heritability be used in selective breeding?
- test effect of selection on pop involved
- choose best by taking from above certain point in distribution = truncation point
- mean of offspring will be higher than original mean
How is realised heritability (h^2) and its components calc, and what does a positive value mean?
- response to selection / selection differential
- response to selection = mean of offspring - original mean
- selection differential = mean of parents - original mean
- +ve value shows trying to increase phenotypic score (-ve means opp)
How can narrow sense heritability be estimated using a graph?
- DIAG*
- plot mean of offspring against mid parent value
- slope gives h^2
- for some characteristics (eg. egg prod) may need to use regression of offspring on 1 parent, so h^2 will be 2x slope
What are the typical values of h^2 and what do they mean?
- high (>0.5) –> more than half contributed by VA
- medium (0.2-0.5) –> still a signif contribution by VA
- low (<0.2)
What is the breeders equation?
- response to selection = h^2 x selection differential
What are the limits of selection?
- not poss to improve phenotypic scores indefinitely by cont selection, as favourable alleles may all approach fixation
- -> mostly makes use of existing genetic variation, VA will decrease, so if VE stays same then h^2 will also decrease
- selection for 1 trait may lead to correlated response in another trait affecting fitness (eg. selection for extreme size often leads to loss of fertility, so problem maintaining pop)
- inbreeding depression
How is selective breeding diff to natural selection?
- over short period of time (few gens)
How does inbreeding depression occur as a result of selective breeding?
- picking ‘best’ encourages inbreeding
- increased freq of deleterious recessive alleles, as having 2 copies becomes more likely
What is a solution to inbreeding depression?
- select 2 lines (may have inbreeding)
- cross them
- hope recessive alleles complement each other and gen F1 hybrid w/ superior phenotype
How can genotype and environment interact?
- superiority of 1 genotype over another may not be maintained in all envs
- DIAG*
Why does a heritability of 0.7 for maize height not indicate that 70% of height of each plant is determined by genes acting additively and 30% by environment?
- means 70% variance in maize height in typical pop, due to genetic variation for genes acting additively
- 30% due to diffs in envs experienced by diff plants and interactions between alleles
If h^2 for maize height = 0.7 and h^2 for ear length = 0.17, is it true that genes are more important in determining height than ear length?
- no
- deletion of relevant genes for either character might be lethal
- both important to us, ear length could have undergone more selection so even be more important
If heritability for maize height is 0.7, is it true that there is little scope for increasing height by changing env?
- no
- high heritability indicates diff in envs experienced by individuals in typical pop contribute less to overall variance in genotype
- may still be scope for great improvement w/ env quality, unpredictable from heritability
Does high heritability for maize height indicate if 1 pop has high higher av score than other that it must carry superior genes?
- no
- could only conclude this if know envs identical and even then change in env could reveal diff norms of reaction
How is heritability in humans diff?
- heritability calcs assume env varies independently of genotype
- but family members share similar genes and envs
- regression of offspring on parents shows familiarity rather than heritability (shown by slope)
How does heritability vary for twins raised together?
- dizygotic and monozygotic twins share similar env to approx same extent
- but dizygotic twins share only 50% of genes
- so diffs in degrees of similarity between monozygotic and dizygotic twins may be attributed to genes
What is concordance?
- way of comparing degree of similarity between twins
What is a threshold trait?
- DIAGS*
- can plot threshold against liability
- there is a threshold liability
- liability influenced by genes and env
OR
- plot freq against no. predisposing alleles
- threshold zone where may or may display phenotype
- then disease where they will defo show phenotype
How can H^2 be calc for twins (assuming MZ and DZ share env to same extent)?
- 2 (tMZ - tDZ)
- where tMZ = phenotypic correlation of monozygotic twins and tDZ = phenotypic correlation of dizygotic twins
How are quantitative genes identified in humans?
- can’t do controlled crosses which allow detection by linkage to marker
- eg. originally RFLPs (restriction fragment length polymorphisms)
- eg. now SNPs (single nucleotide polymorphisms)
- DIAG*
What does QTL mapping involve?
- taking 2 lines where can follow many marker genes
- prod F1
- then F2 or backcross w/ parent (comparing homozygote w/ heterozygote)
- then need method to recognise 2 distributions are signif diff
What happens if the QTL and marker recombine, and what does this show about out ability to detect QTLs?
- reduce the diff in phenotypic score between homozygotes for marker alleles
- so ability to detect QTL determined by magnitude of effect by QTL on phenotypic score, and extent of recombination between marker and QTL
What does finding QTLs through linker-based analysis req/involve?
- large no. markers distributed across all chromosomes, at least every 5-10cM (can be done easily)
- test each maker for signif diff between av phenotype scores for 2 homozygotes
- or in practise usually homozygote and heterozygote in backcross
- log10 (prob of obs result if QTL assoc w/ marker / prob of obs result if QTL not assoc w/ marker)
What does identifying a QTL actually show?
- doesn’t identify gene
- just region around markers where think gene making contribution
- don’t know if more than 1 gene, but no tendency for QTLs to cluster together, distributed throughout genome
After a QTL identified, how is the gene identified?
- fine mapping
How is fine mapping carried out?
- for each marker showing signif diff, gen and compare lines that are isogenic except in region of suspected QTL and recombinant in this region
- congenic = isogenic (nearly)
- want flanking markers DIAG
- genotype recombinants prod to find COs (tells us CO is in QTL) DIAG
- look specifically at chromosome in region where we know QTL is
- can identify gene if narrow region down to 1 or a few genes
What has been used instead of linkage analysis in humans?
- GWAS
How is GWAS carried out for human diseases?
- range of DNA markers around genome, up to half a mil SNPs
- looked at many SNPs and got statistical analysis essentially equivalent to chi-squared –> log10 (P)
- null hypothesis is no assoc between marker and phenotype
- can’t use 5% level as looking at so many SNPs, so need v low probability threshold
- assoc clear if SNP is in QTL
- otherwise detection of QTLs dep on LD
How can SNPs be used to detect nearby QTLs is assoc studies?
- linkage disequilibrium
What is linkage equilibrium, and when is it expected?
- state where random assoc of alleles at any 2 loci
- expected in infinite pop w/ random mating and no selection
If allele freqs for A, a, B, b are p1, p2, q1, q2 respectively, what haplotype freqs will be gen by random assoc of alleles of 2 genes, and why is this true even if genes are linked?
- fAB = p1q1
- fAb = p1q2
- faB = p2q1
- fab = p2q2
- haplotypes gen by meiosis in wide variety of genotypes, so parental combos in 1 meiosis will be recombinants in another
- DIAG*
What is linkage disequilibrium?
- non random assoc of alleles at 2 loci
- deviation form linkage equilibrium
In linkage disequilibrium, what is D?
- deviation from linkage equilibrium
What is the range for D?
- can be +ve or -ve (but eg. if more fAB then there is less fAb, as same no. A alleles in pop)
- min = 0
- max = Dmax and depends on allele freqs and particular pop
How can you calc D?
- D = fAB - (fA x fB)
OR - D = (fAB x fab) - (fAb x faB)
What does it mean if D>0?
- fAB, fab greater than expected at eq
- fAb, faB less than expected at eq
- Dmax would correspond to pop in which fAb or faB reaches 0
- so Dmax = min | (fA x fb) , (fa x fB) |
What does it mean if D<0?
- fAB, fab less than expected at eq
- so Dmax = min | (fA x fB) , (fa x fb) |
Why can’t we directly compare D values?
- max value varies, so don’t know if we have small or large value
How can D values be compared?
- use normalised value of D
- D’ = D / Dmax
- range is 0-1
What is an alt measure of D?
- correlation coefficient (r^2) = D^2 / fA x fB x fa x fb
- range is 0-1
- NOT equal to D’
How can linkage disequilibrium arise?
- most commonly new mutation
- mutant allele initially assoc w/ particular allele of each closely linked polymorphic locus
- assoc breaks down as recombination assoc mutated allele w/ all poss alleles of linked genes
- decay of LD for 2 loci depends upon recomb in double heterozygotes
How does linkage disequilibrium decay?
- for 2 loci dep on recombination in double-heterozygotes
- exponential over pot many gens
- rate of decay dep on recombination rate (r) between loci
- new value of D in next gen: D1 = D0 (1-r)
- new value of D after t gens: Dt = D0 (1-r)^t
- bigger R gives lower values on graph DIAG
What is req for a Manhattan plot for GWAS?
- need large no. samples for affected/unaffected (typically >10,000)
- need large no. markers –> ≈ 13x10^6 common SNPs, in practise ≈ 5x10^5 TAG SNPs
What is the missing heritability?
- many QTLs still to be discovered
- lots of VG not accounted for by things we can test for, believe there are many genes which have a small effect and can’t measure this
What are haplotype blocks?
- genome effectively divided into blocks where v high amount of linkage diseq
- COs tend to occur at recombination hotspots
- so SNPs in GWAS identify haplotype blocks, in which linkage diseq maintained over many gens
- TAG SNP used as proxy for whole block, as CO unlikely to occur w/in block
- DIAG*
What are the most common diploid model organisms?
- Drosophila
- mouse
- C. elegans
- Arabidopsis
Why can’t simpler organisms like E. coli be used as models for human disease?
- too far from humans to be useful
What is the problem w/ using diploids as model organisms?
- difficult to detect and therefore isolate recessive mutations
What are the common features of model organisms?
- easy to culture and cross
- short life cycle
- many progeny
- easy to mutagenise
- small genome (not as important now seq cheaper and easier, but small still easier to analyse)
Why are model organisms more commonly used once they have become well established?
- genetically well characterised
- eg. genome seq, genetic map
- “genetic tricks”
How is life cycle length an important factor in selecting an approp model organism?
- yeast shortest so may be best choice if approp
- but Drosophila still short comp to mice and humans
- and mice short comp to other mammals, if need mammalian model
What are genetic tricks?
- to specifically exploit biology of organism
- diff for each organism, but may be used for same purposes
Why is Drosophila used as a model organism?
- 1 of best characterised diploid organisms
- small and easy to culture
- short life cycle
- prod 10s of progeny
- undergoes complete metamorphosis, have imaginal discs = structures identifiable in larvae, recognisably diff from laval cells which aren’t in adults
Where are polytene chromosomes commonly found?
- Drosophila
- eg. salivary glands of larva
What are polytene chromosomes and how are they formed?
- repeated rounds of rep in absence of division
- each chromosome may undergo up to 10 rounds of rep, giving up to 1024 DNA molecules arranged side by side
- homologous chromosomes undergo somatic assoc, so total no. DNA molecules packed in parallel can be up to 2048
- some seqs undergo fewer (7-8) rounds of rep, particularly ribosomal (rDNA) and heterochromatin
What is the structure of polytene chromosomes?
- centromeres assoc at chromocenter, which is made up of centromeric heterochromatin
- so complete chromosome complement of interphase cell visualised as 5 long arms (X, 2L, 2R, 3L, 3R) and 1 stump (4)
- Y chromosome not visible, as heterochromatic, under replicated and present w/in chromocenter
How can regions of Drosophila genome be identified w/ high res?
- banding patterns in polytene chromosomes
- 5000-6000 dark bands, alt w/ light interbands
- much more banded than humans
How have cytological maps been correlated w/ linkage map?
- rearrangement breakpoints can sometimes be assoc w/ mutations that occur when breakpoint disrupts a gene
How are inversions CO suppressors?
- small inversions may inhibit pairing of homologues in inversion heterozygote –> forms bubble so chromosome can’t twist DIAG
- larger inversions allow formation of inversion loop (where COs can occur), but inversions lead to duplications and deletions so CO products inviable
- pericentric and paracentric inversions also lead to duplications and deletions, so CO products inviable
What are the features of a ClB chromosome?
- CO suppressor –> inversion
- recessive lethal mutation (ensures balancer homozygotes automatically removed from pop)
- Bar eye -> dominant visible mutation (so can track chromosome in crosses)
How is a ClB stock maintained?
- DIAG*
- cross female ClB/WT w/ male WT
- prod:
- -> female Bar eyed
- -> female WT (removed after each gen)
- -> male w/ ClB (DIE)
- -> male WT
How can the ClB chromosome be used to isolate recessive lethals on the X chromosome?
*DIAG* Cross 1: - cross female ClB/WT w/ male mutated test chromosome - prod: --> female Bar eyed --> female WT --> male w/ ClB (DIE) --> male WT
Cross 2: (new mutation on test chromosome)
- INDIVIDUALLY cross Bar eyed female progeny from cross 1 w/ male WT
- prod:
- -> female Bar eyed
- -> female WT
- -> male w/ ClB (DIE)
- -> male w/ mutated test chromosome (DIE if new recessive lethal)
- so looking for absence of males from progeny of individual femals
How can the ClB chromosome be used to isolate autosomal recessive lethals?
(typically 3 step process)
DIAG
Cross 1:
- balancer stock females (w/ dominant marker) x mutagenised males
- progeny of interest have balancer chromosome from mother and mutagenised test chromosome from father (identified by dominant visible)
Cross 2:
- individual cross 1 progeny females x male balancer stock
- prod multiple progeny carrying same test chromosome and the balancer
Cross 3:
- cross heterozygotes for same test chromosome
- prod:
- -> homozygous for ClB (DIE)
- -> heterozygotes for ClB and test chromosome (form self maintaining balanced lethal stock, heterozygous yet pure breeding)
- -> homozygotes for test chromosome (if new recessive lethal then DIE)
What was the aim of the Heidelberg screens?
- saturate genome and isolate mutations for all genes that could be mutated
- diff systems for isolating mutations on diff chromosomes
How is Drosophila eye colour determined?
- DIAG*
- 2 pathways
- 1 prod brown, cn mutation in this causes cinnabar eyes
- 1 prod bright red, bw mutation in this causes brown eyes
- both pathways together cause WT red eyes
- blocking both pathways gives white eyes
What was the strategy for screening recessive lethal mutations on chromosome 2?
- DIAG*
- used Cy (curly wings) as dominant visible on balancer chromosome and dominant temp sensitive mutation on normal chromosome
Cross 1:
- cross female w/ balancer and normal chromosome w/ Ts w/ males homozygous for bw and cn
- prod:
- -> curly wings, red eyes
- -> normal wing, red eyes (IGNORE)
Cross 2:
- cross F1 male progeny INDIVIDUALLY w/ female balancer and normal chromosome w/ Ts
- prod:
- -> homozygotes for balancer (DIE)
- -> curly wings, red eyes (heterozygotes for bw and cn)
- -> balancer and normal w/ Ts (DIE at high temp)
- -> test and normal w/ Ts (DIE at high temp)
Cross 3:
- cross Cy//m, bw, cn w/ normal//m, bw, cn
- prod:
- -> 1 homozygote for balancer (DIE)
- -> 2 curly wings, red eyes = Cy//m, bw, cn (new balanced lethal stock)
- -> 1 normal wings, white eyes (or DIE if new recessive lethal)
When screening for recessive lethal mutations on chromosome 2, why did cross 2 have to be done a particular way round?
- RFs vary between males and females
- Drosophila extreme eg. of this –> no COs in males
- wouldn’t matter in other species
What are mice useful for?
- large scale mutagenesis screens poss using balancer stocks
- balancers engineered in ES cells using Cre-loxP tech
What is the overall strategy for engineering balancers in mice, using Cre-loxP tech?
- introduce 2 loxP sites sequentially, in opp directions, at defined positions on chosen chromosome in mouse ES cells
- Cre transiently expressed on transfected plasmid to cause inversion as result of recombination specifically between loxP sites
Why does CreA provide an advantage in determining breakpoints?
- can decide where want breakpoints to occur for inversions, instead of at random
- DIAG*
How is the targeting vector inserted into chromosome? (gen mouse balancer chromosomes)
- DIAG*
- targeting vector has 2 regions of homology w/ chromosome at desired inversion breakpoint
- targeting vectors designed to disrupt and inactivate gene at each target site, therefore creating recessive lethal genotype that’s assoc w/ balancer chromosomes
What are the components of targeting vector? (gen mouse balancer chromosomes)
- DIAG*
- Neo = selectable marker in ES cells
- loxP = future inversion breakpoint
- 5’ HPRT = half selectable marker in ES cells (3’ HPRT in other vector, 2 halves arranged so recombination between loxP sites will gen complete HPRT gene w/ loxP site as intron) –> allows selection for ES cells w/ successful inversions, as HPRT expression allows recombinants to grow in selective medium (HAT)
- Ag = dominant visible marker in mice
What is the structure of a blastocyst, into which ES cells are injected?
- DIAG*
- trophectoderm forms outer ring = gives rise to placenta etc.
- ES cells injected into ICM (inner cell mass)
What is a chimera?
- individual from more than 1 zygote
How do we generate and identify transgenic adult mice heterozygous for engineered balancer chromosome?
- cross chimaera (ccaa and CCAA) w/ albino (ccaa)
- prod albino and agouti (CcAa) in unknown ratio
- w/in agouti progeny 1:1 ratio of balancer chromosome (lighter tails and ears) to normal agouti
What is the gene pool?
- sum total of breeding pop genomes
How is the freq of an allele calculated?
- eg. for freq of A (=p)
- no. of A alleles / 2N
- where 2N is total no. copies of that gene in gene pool
- p will also = freq A homozygotes + 1/2 all poss heterozygotes for A
How can H-W be proved?
- let fA = p ; fa = q ; p+q=1
- assume p, q same in males and females (reasonably in most cases, can prove w/o just req extra step)
- Aa x Aa –> p^2 + 2pq + q^2
- if consider freqs of matings between diff genotypes then see freqs of 3 diff genotypes remain exactly same from 1 gen to next
How long does it take to achieve H-W eq for an autosomal gene?
- 1 gen
How is H-W eq reached for multiple alleles?
- same way, assign letters p, q, r etc.
- sum total of results of cross will = 1
How is H-W eq reached for sex-linked genes?
- genotype freqs in XX females follow H-W
- XY males hemizygous for sex-linked genes, so genotype freqs reflect allele freqs
- allele freqs in males and females same at H-W eq, but don’t reach eq in 1 gen
- in males in any 1 gen, freq same as females of previous gen
- in females in any 1 gen, freq is mean of male and female freqs in prev gen
- X chromosomes being exchanged
- final freq of allele in both sexes is weighted mean of original freqs (females double weighted as 2 X chromosomes)
For sex-linked genes, what proportion of rare alleles are in homozygotes/heterozygotes?
- few homozygotes for rare alleles, mainly carried in heterozygotes
- DIAG*
What is Darwinian fitness (W)?
- relative reproductive ability of genotype
- W=1 for genotype prod most offspring
What is the selection coefficient (s)?
- intensity of selection against genotype
In incomplete dominance, what is the value of t?
- 0
What diff genotypes can be selected against in directional selection?
- recessive homozygote (aa)
- dominant allele (AA, Aa)
- 1 allele, no dominance (Aa, aa)
What is directional selection?
- 1 allele favoured so increase in freq in pop over time –> can go towards fixation or deletion
What is purifying selection?
- directional selection can also remove new deleterious alleles
What is an eg. of directional selection?
- peppered moth
- dark carbonaria phenotype initially rare phenotype
- increased to over 90% in industrial revolution, over 50 years
- classic series of studies by Kettlewell provided evidence that carbonaria form less visible to bird predators than typica form on soot-polluted tree trunks in industrial areas
- after clean air legislation and de-industrialisation, freq of typical form increased again
How does rate of increase in dominant allele, A, change during directional selection?
- slow when few copies of A
- faster as more copies of A
- slow when a mostly in heterozygotes
What is balancing selection and an example?
- selection operates to maintain balanced polymorphism in pop
- so heterozygotes show higher fitness than either homozygote (not necessarily same but both less than 1) = heterozygote adv
- eg. maintenance of sickle-cell allele Hb-S through resistance of heterozygotes to malarial parasite
What is disruptive selection, and what can it lead to?
- against heterozygote, both homozygotes equally fit
- can lead to speciation through reproductive isolation
What is freq dep selection, and 2 examples?
- fitness of phenotype varies with frequency
- eg. birds have search image for prey –> rare snail shell morph may have high fitness as not recognised, as freq increase, fitness decreases, as birds start to recognise
- eg. butterfly that protects itself by being distasteful to birds –> for strategy to work must be commonest form so birds learn to avoid, so fitness decreases as freq decreases
How does H-W assume an infinite pop size?
- assuming other H-W assumptions true, if p1 and p2 represent freq of allele A in 2 successive gens:
- -> for infinite pop p1 = p2
- -> for finite pop p1 ≈ p2
What are Monte Carlo simulations, and what do they show?
- computer simulations of small polymorphic pops, demonstrate random genetic drift can lead to fixation
- for allele w/ initial freq of 0.5, equally likely to be lost or fixed
- for allele w/ initial freq of >0.5 likely to be lost
- initial freq of new allele will be low, so likeliest fate is to be lost, even if pot gives high fitness
What is a pop bottleneck?
- temp reduction in pop size
What can affect pop bottlenecks?
- strong genetic drift
Why can effective pop size (Ne) be less than actual pop?
- in ideal pop all individuals have same chance of prod offspring and pop size constant
- if this not true then Ne less than actual pop
What is the Ne for a fluctuating pop?
- harmonic mean
What is the founder effect?
- when new pop arises from few founders
- allele freqs in founders differ from parent pop due to random sampling, may not be representative of original pop
- genetic drift in small pop
- any rare allele inc in founding pop will have freq of at least 1/2N
What is an example of the founder effects?
- Afrikaner pop of South Africa mainly descended from 1 shipload Dutch immigrants
- 40% current pop share surnames of original 20 settlers
- modern pop inc 30,000 carriers of dominant gene for porphyria variegata –> much higher freq than modern Dutch pop, defective protoporphyrinogen oxidase gives severe reaction to barbiturates
Why is mating not always random?
- assortative mating
- inbreeding
What is +ve assortative mating, and some examples?
- choose mates phenotypically similar to themselves
- eg. early and late flowering plants, human height, IQ, no. rooms in parents house
- increased homozygosity of pop for genes affecting trait used for mate selection
What is -ve assortative mating, and some examples?
- choose mates phenotypically different to themselves
- eg. MHC (major histocompatibility complex) in humans, being heterozygous beneficial, identified by smell
- decreased homozygosity of pop for genes affecting trait used for mate selection
What is inbreeding, how does it affect pops and what are some examples?
- mating between relatives
- more likely in small pops
- increased homozygosity of pop for all genes
- eg. 1st cousin matings in humans –> tends to approx double risk of inheriting serious recessive condition
- selfing in plants –> doesn’t take long for whole genome to become homozygous
- leads to inbreeding depression
What is the inbreeding coefficient?
- F = (He - Ho) / He
- where Ho = observed heterozygosity from H-W
- where He = expected heterozygosity from H-W
How can we measure extent of inbreeding?
- look at extent heterozygosity decreased compared to H-W
- look at extent homozygosity increased compared to H-W
What is identity by descent (IBD) for 1st cousin matings?
- chance of inheriting A1/A1 from grandparents = 1/64
- F (increase in homozygosity) = 1/64 x 4 (for 4 diff alleles) = 1/16
How will the av coefficient of inbreeding and its rate change in a finite pop?
- increase every gen
- rate increase faster in smaller pops
How can pop structure, ie. subpops affect H-W?
- H-W assumes all individual scan pot mate w/ each other
- but many local subpops may exist, w/in which mating may be truly random
- random genetic drift may result in fixation in diff subpops (could be in either direction)
- -> pop as whole will show higher homozygosity than predicted by H-W
- -> special eg. of inbreeding
- more conventional inbreeding may also be promoted if subpops small
When can subpops fixed for 1 gene, become fixed for others?
- new mutation must be assoc w/ particular allele at each closely linked locus
Why does recombination decrease linkage diseq?
- allows other alleles to occur w/ mutation
What is hitch-hiking?
- new beneficial mutation selected for
- for closely linked neutral gene, allele that happens to be assoc w/ new mutation also favoured
- may occur simultaneously for no. genes in vicinity of new adv allele, resulting in selective sweep (decreases genetic variation in vicinity of new adv allele as it goes through fixation)
- DIAG*
What decreases the effect of hitch-hiking?
- recombination, breaks assoc of beneficial mutation and neutral allele
What is finding a selective sweep area an indicator of?
- recent +ve selection event
How can linkage diseq be maintained, instead of decaying over time?
- selection for haplotypes in which tightly linked alleles show beneficial epistatic interactions
- eg. genes for mimicry in butterflies
What are the phenotypes of Papilio memnon butterflies?
- only females show mimicry
- all males bright blue, as makes more successful at mating, even if damaging to own survival
How is Batesian mimicry shown in Papilio memnon?
- palatable species mimics distasteful one
- at least 3 tightly linked loci in supergene postulated to account for mimicry patterns
- putative recombinants poor mimics, so selected against
- if freq palatable increases too much and gets more common, then system not effective
- so often see wide variety of morphs that mimic diff distasteful species
What is Mullerian mimicry?
- distasteful species resemble one another
- more effective at deterring predators if high freq
- expect only 1 morph in 1 geographical location, but may be diff morphs in diff geographical locations
What is a supergene, and their characteristics?
- group of closely linked polymorphic genes in linkage diseq w/ one another
- diff haplotypes, where each corresponds to diff phenotype
- complex epistatic interactions
- > 1 haplotype assoc w/ high W
How are supergenes maintained?
- if recombination (not common) then would gen haplotypes w/ low W
- so selected against
- therefore maintain supergene through selection against recombination
When are supergenes found and why?
- when diff morphs in same geographical location (Batesian)
- if geographically separate (Mullerian) then no chance of recombination, so have no. diff genes
How is Mullerian mimicry shown in Heliconius numata, and what studies were carried out?
- (unusually) many morphs in same location
- aurora dominant to silvana
- no recombination in P locus, but is to either side
- did assoc study between series of SNPs alleles and aurora/silvana wing morphs –> found high assoc in P locus and low outside
- looked directly for linkage diseq between SNPs using heat map (uses r^2)
- polymorphism for inversion locked in haplotypes, so can’t undergo COs
- aurora assoc w/ 1 arrangement caused by inversion and silvana by another
What is a heat map?
- looks at pairwise combos of particular SNPs
- to look at degree of linkage diseq between them
How is sex-limited Batesian mimicry shown in Papilio polytes?
- males don’t show mimicry and only some females do
- single polymorphic locus that decide if females show mimicry and if they do, what morph
- supergene locus co-localised region already known to play role in sex determination
- in butterflies, sex determination by autosomal doublesex gene, the transcript of which shows differential splicing, gender dep on way splices
- assoc study showed v strong assoc between morphs and doublesex gene –> suggesting supergene is only 1 gene (w/in gene polymorphism for at least 1 inversion, has tight control of COs w/in gene)
- -> haplotypes are just alleles of this gene
- -> each haplotype corresponds to series of specific mutations at diff points w/in gene, so to maintain allele, need inversion to suppress COs
Why does a single crossover within an inversion loop have different effects, depending on whether the inversion is pericentric or paracentric?
- paracentric inversion = centromere outside inversion
- pericentric inversions inc centromere
- diff effects arise from special properties of centromere
- -> no centromere means chromosome cannot be processed on spindle and lost
- -> 2 centromeres means chromosome will form bridge at anaphase 1 and may break
How is change in allele freqs due to inbreeding calc?
- AA = +pqF
- Aa = -2pqF
- aa = +pqF
