Download Genetic Drift - Carol Lee Lab

Carol Eunmi Lee
9/20/16
Hardy-Weinberg Principle
Hardy-WeinbergTheorem
• Mathematical description of Mendelian
inheritance
Godfrey Hardy
(1877-1947)
Inanon-evolvingpopulation,
frequencyofallelesand
genotypesremainconstant over
generations
You should be able to
predict the genotype
frequencies, given the
allele frequencies
Wilhem Weinberg
(1862 – 1937)
Evolutionary Mechanisms
(will put population out of HW Equilibrium):
DEVIATION
•
•
•
•
from
Hardy-Weinberg Equilibrium
Indicates that
*Epigenetic modifications change expression of alleles but not the
EVOLUTION
frequency of alleles themselves, so they won’t affect the actual
inheritance of alleles
However, if you count the phenotype frequencies, and not the
genotype frequencies , you might see phenotypic frequencies out
of HW Equilibrium due to epigenetic silencing of alleles.
(epigenetic modifications can change phenotype, not genotype)
Is happening
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Requirements of HW
Large population size
Violation
Evolution
à Epigenetic modification could affect which alleles are
exposed to natural selection (no effect of Genetic Drift)
Inbreeding & other
No Mutations
Mutations
No Natural Selection
Natural Selection
No Migration
Migration
An evolving population is one that
violates Hardy-Weinberg Assumptions
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ExamplesofDeviationfrom
Hardy-WeinbergEquilibrium
Genetic drift
Random Mating
Title goes here
Genetic Drift
Natural Selection
Mutation
Migration
Generation1
Generation2
Generation3
Generation4
AA
0.64
0.63
0.64
0.65
Aa
0.32
0.33
0.315
0.31
aa
0.04
0.04
0.045
0.04
IsthispopulationinHWequilibrium?
Ifnot,howdoesitdeviate?
Whatcouldbethereason?
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Carol Eunmi Lee
9/20/16
Sources of Genetic Variation
Evolutionary Mechanisms
Mutation generates
genetic variation
Genetic Drift (and Inbreeding)
Natural Selection
Natural Selection acts on
genetic or epigenetic
variation in a population
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Without genetic or
epigenetic variation,
Natural Selection cannot
occur
Without genetic or
epigenetic variation,
Natural Selection cannot
occur
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(1)Migration
Mutation generates
genetic variation
Natural Selection acts on
genetic or epigenetic
variation in a population
Genetic Drift causes
fluctuations in allele
frequencies and can
reduce genetic variation
Today’s OUTLINE:
Sources of Genetic Variation
Natural Selection
Epigenetic modification
changes expression of
genes
(2)GeneticDrift
Epigenetic modification
changes expression of
genes
(3)EffectivePopulationSize
(4)ModelofGeneticDrift
Genetic Drift causes
fluctuations in allele
frequencies and can
reduce genetic variation
(5)Heterozygosity
(6)AConsequenceofGeneticDrift:Inbreeding
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Migration (fairly obvious)
§
Impact of Migration
Can act as a Homogenizing force
(If two populations are different, migration between
them can reduce the differences)
§
A population could go out of HW equilibrium
with a lot of migration
■
■
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Title goes here
Immigration: could introduce
genetic variation into a population
Emigration: could reduce genetic
variation in a population
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Carol Eunmi Lee
9/20/16
Sewall Wright
(1889-1988)
• Sewall Wright worked on agricultural
stocks (e.g. cows), and was
consequently interested in small,
inbred populations
Random Genetic Drift
• Thus, he regarded Inbreeding and
Genetic Drift as particularly
important genetic mechanisms
• Genetic Drift and Inbreeding could
generate new gene interactions
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• These new gene interactions
(epistasis caused by new
recombinations) are the main
substrate for selection
“Null Model”
“Null Model”
■
■
No Evolution: Null Model to test if no evolution
is happening should simply be a population in
Hardy-Weinberg Equilibrium
■
No Selection: Null Model to test whether
Natural Selection is occurring should have no
selection, but should include Genetic Drift
◆
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This is because Genetic Drift is operating even
when there is no Natural Selection
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Evenafterthesynthesistherelativeimportanceof
NaturalSelectionandGeneticDriftweredebated
• DuringtheEvolutionarySynthesis,SewallWrightfocused
moreonimportanceofGeneticDrift,whereasFisherfocused
onNaturalSelection
No Selection: A model that tests for the
presence of Natural Selection should include
Genetic Drift
◆
This is because Genetic Drift is operating even
when there is no Natural Selection
◆
So the null model that tests for natural selection
should include demography, population growth
and decline, as population size directly affects the
level of genetic drift acting on a population
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Motoo Kimura (1924-1994)
The Neutral Theory of
Molecular Evolution
• ShortlyaftertheEvolutionarySynthesismanyfocusedon
selectiontothepointofassumingthatmostphenotypeswere
theresultofNaturalSelection
• EmphasisonGeneticDriftresurgedinthe1970s,80swith
Kimura’s“NeutralTheory”
Classic Paper: Kimura, Motoo. 1968.
Evolutionary rate at the molecular level. Nature.
217: 624–626.
• Theninthe2000sand2010sinterestinSelectionincreased
withtheabilitytodetectsignaturesofNaturalSelectionin
genomesequencedata
Classic Book: Kimura, Motoo (1983). The
neutral theory of molecular evolution.
Cambridge University Press.
Title goes here
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Carol Eunmi Lee
9/20/16
Molecular Clock
Observationsofaminoacidchangesthatoccurredduringthedivergence
betweenspecies,showthatmolecularevolution(mutations)takesplaceat
aroughlyconstantrate.
The Neutral Theory of
Molecular Evolution
• TheNeutraltheorypositsthatthevastmajority
ofevolutionarychangeatthemolecularlevelis
causedbyrandomgeneticdriftratherthan
naturalselection.
Thissuggeststhatmolecularevolutionisconstantenoughtoprovidea
“molecularclock”ofevolution,andthattheamountofmolecularchange
betweentwospeciesmeasureshowlongagotheysharedacommon
ancestor.
• NeutraltheoryisnotincompatiblewithDarwin'stheoryof
evolutionbynaturalselection:adaptivechangesare
acknowledgedaspresentandimportant,buthypothesizedtobea
smallminority ofevolutionarychange.
Fromthis,Kimuraconcludedthatnot
muchselectionisgoingon(because
thepatternofregularmutationsisnot
obscuredbyselection),andthatmost
evolutionisinfluencedbyGeneticDrift.
Figure:therateofevolutionofhemoglobin.
Eachpointonthegraphisforapairof
species,orgroupsofspecies.FromKimura
(1983).
• Recenttestsofselectionhavefoundthatinmanycasesevolution
isnotneutral,eveninnon-codingregionsofthegenome.
• Nevertheless,theneutraltheoryisusefulas thenullhypothesis,
fortestingwhethernaturalselection isoccurring.
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Definition: Changes in allele frequency from
one generation to the next simply due to chance
(sampling error).
■
This is a NON ADAPTATIVE evolutionary
force.
■
■
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Genetic Drift
I. Random Genetic Drift
■
Motoo Kimura
Darwin did not consider genetic drift as an
evolutionary force, only natural selection.
■
Genetic Drift happens when populations are
limited in size, violating HW assumption of
infinite population size
When population is large, chance events cancel
each other out
When population is small, random differences in
reproductive success begin to matter much more
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Effective Population Size
Effective Population Size
■
The concept of effective population size
Ne was introduced by Sewall Wright, who
wrote two landmark papers on it (Wright
1931, 1938).
In Evolution, when we talk about
population size, we mean
effective population size
■
■
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Title goes here
Sewall Wright defined it as "the number of breeding
individuals in an idealized population that would show the
same amount of dispersion of allele frequencies under
random genetic drift or the same amount of inbreeding as the
population under consideration”
OK, easier definition: Effective population size is the
number of individuals in a population that actually
contribute offspring to the next generation.
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Carol Eunmi Lee
9/20/16
Effective Population Size
■
Why do we care about effective population
size Ne?
The effective population size is always either equal to
or less than the census population size (N).
The effective population size is usually smaller than the real
census population size because not everyone breeds and
leaves offspring.
■
Unequal sex ratio, variation in number of offspring,
overlapping generations, fluctuations in population size,
nonrandom mating could lead to an effective population size
that is smaller than the census size.
■
■
Ne =
■
4Nm Nf
(Nm + Nf )
where Nm = number of males, Nf = number of females
from this equation, you can see that unequal sex ratio would lead 25
to lower N e
Because Ne is the actual unit of evolution,
rather than the census size N
Why? Because only the alleles that actually
get passed onto the next generation count in
terms of evolution… the individuals that do
not mate or have offspring are evolutionary
dead ends…
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Example of sampling error
Chance Events (no Selection)
Green fur:
Blue fur:
There is always an element of chance, in:
■
■
G (dominant)
b (recessive)
IfGb x Gb mate,thenextgenerationisexpectedtohave:3:1
Ratioof Green to blue (GG, Gb, bG, bb)
Who leaves Offspring
Butthismightnothappen
■
■
# of Offspring
Onefamilycouldgetthisunusualfrequencyjustduetochance:
Youmightget:bb, bb, bb, bb
And,soyoumightaccidentallylosetheGallelenotforany
reason,butjustduetochance
Which Offspring survive
(which gametes, which alleles)
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Thelargerthepopulation,themoretheseeffectsaverageout,
andfrequenciesapproachHWequilibrium
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Consequences of Genetic Drift
Why is this not Selection?
Random fluctuations in allele frequency
Selection happens when some survive for
a reason: better adapted.
If population size is reduced:
Genetic Drift is just a numbers game.
Which gamete gets fertilized, which allele
gets passed on is RANDOM
1. At the Allelic level: Random fixation of Alleles
(loss of alleles)
2. At the Genotypic level: Loss of Heterozygosity
(because of fewer alleles)
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Title goes here
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Carol Eunmi Lee
9/20/16
Random Shift in Allele Frequencies across Generations
Probability of loss of alleles is greater in
smaller populations
■
■
■
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For example, if there are 50 different alleles
in population
…and a new population is founded by only
10 individuals
Then the new population will be unable to
capture all 50 alleles, and many of the alleles
will be lost
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Bottleneck Effect
Random fixation of alleles
FIXATION: When an allele frequency becomes 100%
The other alleles are lost by chance
Fluctuations are much larger in smaller populations
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Probability of fixation
of an allele
■
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Probability of fixation
of an allele
Probability of fixation of an allele =
the allele’s starting frequency
(Sewall Wright 1931)
That is, if the frequency of an allele
is 0.10 (10% in the population),
then its probability (chances) of
fixation (going to 100% in the
population) is 0.10, or 10%
Title goes here
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■
■
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Probability of fixation of an allele =
the allele’s starting frequency
(Sewall Wright 1931)
That is, if the frequency of an allele
is 0.10 (10% in the population),
then its probability (chances) of
fixation (going to 100% in the
population) is 10%
WHY?
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Carol Eunmi Lee
9/20/16
Probability of fixation
of an allele
■
■
Ifapopulationhas2N alleles
Theprobabilityofeachallelebeing
fixed= 1
2N
■
IfthereareX #copiesofthatallelein
€
thepopulation,thentheprobabilityof
fixationforthatalleleis
■
X
2N
Thisistheproportion(%)ofallelesin
thepopulation €
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Genetic Drift: Random Fixation
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Genetic Drift:
Random Fixation
Genetic Drift: Random Fixation
As populations get
smaller, the probability
of fixation goes up
After 7
generations, all
allelic diversity
was lost… the
population
became fixed for
allele #1 just due
to chance
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Heterozygosity
■
■
■
■
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Title goes here
Heterozygosity: frequency of heterozygotes in
a population (% of heterozygotes)
Often used as an estimate of genetic variation
in a population
HW expected frequency of heterozygotes in a
population = 2p(1-p)
As genetic drift drives alleles toward fixation or
loss, the reduction in number of alleles causes
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the frequency of heterozygotes to go down
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Carol Eunmi Lee
9/20/16
Heterozygosity
Grey line = theoretical
expected
heterozygosity:
TheExpectedHeterozygosity followingapopulation
bottleneck
(frequencyofHeterozygotesinthenextgeneration
=Hg+1):
g+1
g+1
g
e
g
e
Note in this equation that as population
size 2Ne gets small, heterozygosity in the
next generation Hg+1, goes down
Blue line = observed
heterozygosity (%
heterozygotes in population)
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Loss of Variation
Allele frequencies
Heterozygosity
declines faster in
smaller
populations
0.36
0.16
Lots of Alleles:
0.20
0.24
0.04
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Lots of alleles --> Lots of genotypes:
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Loss of Allelic Variation
Possible genotype combinations
Allele frequencies
■
Due to Genetic Drift
0.53
0.067
0.20
0.20
0
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Title goes here
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Carol Eunmi Lee
9/20/16
No Genetic Variation = No Natural Selection
Loss of Allelic Variation due to
Genetic Drift results in
Increased Homozygosity
Fewer possible genotype combinations
Increase in homozygosity
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No Genetic Variation = No Natural Selection
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Genetic Drift and Natural Selection
■
■
Because of the randomness introduced by
Genetic Drift, Natural Selection is less
efficient when there is genetic drift
Thus, Natural Selection is more efficient in
larger populations, and less effective in
smaller populations
Selection has nothing to act on
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How do you detect Genetic Drift?
Allele A1 Demo
■
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• Impact of Effective Population Size
• Impact of starting allele frequency
■
• Interaction between Natural Selection
and Genetic Drift
■
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Title goes here
Randomfluctuationsinallelefrequencies
Fluctuationsinnon-codingandnon-functional
regionsofthegenome
Thesamepatternoffluctuationsacrossthese
regionsofthegenome(samedemographicfactors
wouldactacrossthegenome)- butmtDNAnot
same
Fluctuationsinallelefrequenciescorrespondto
demographyofthepopulation(populationsize)
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Carol Eunmi Lee
9/20/16
Dilemma for Conservationists
Consequences of Genetic Drift
---> Random fluctutations in allele frequency
If population size is reduced and Drift acts more
intensely, we get:
• It is easier to remove genetic diversity
than create it… especially variation that
is potentially adaptive
1. At the Allelic level: Random fixation of Alleles
(loss of alleles)
Census size: Roughly
2000-3000 cheetahs
live in Namibia today
2. At the Genotypic level: Inbreeding, Reduction
in Heterozygosity (because of fewer alleles)
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The effective
population size is
much lower
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2. Genetic Drift often
leads to Inbreeding
With small population size,
heterozygosity goes down,
homozygosity goes up
■
■
Inbreeding is a consequence of Genetic drift
in small populations, resulting from loss of
alleles
Due to loss of alleles, there is an increase in
homozygosity
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Calculationsliketheseareusedingeneticcounseling
andanimalbreedingto calculateF,thecoefficientof
inbreeding(developedbySewallWright)
Inbreeding
Mating among genetic relatives, often
because of small population size
Alleles at a locus will more likely become
homozygous
A consequence of loss of alleles due to genetic
drift (reduction in population size)
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Title goes here
F=fixationindex,ameasureofhomozygosity;theprobability
thattwogenesatanylocusinanindividualareidenticalby
descentfromthecommonancestor(s)ofthetwoparents
(homozygous,ratherthanheterozygous).
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Carol Eunmi Lee
9/20/16
Probability of getting two triangles
Probability of getting two squares
Probability of getting the same allele from the grandmother
Mate between half-siblings
Mate between full-siblings
Slightly different from
textbook 7.36, where 2 nd
generation mates
between full siblings
The probability for identity by descent
for both alleles
Probability of getting grandma’s allele
Probability for identity by descent for
both alleles
Textbook 7.36
Probability of getting grandpa’s allele
Mate between full-siblings
small population size à genetic drift
à loss of alleles à decrease in
heterozygosity à increase in
homozygosity à
à increase of exposure of deleterious
alleles
Textbook 7.36
The probability of getting grandma or
grandpa’s allele
Consequences of Inbreeding
ConsequencesofInbreeding
• Deleteriousrecessiveallelesareexposedas
homozygotes
(andlessmaskedintheheterozygousstate)
§ Increase in Homozygosity:
Exposure of recessive alleles
(that could be subjected to selection)
Inbreeding Depression
• Thesedeleteriousrecessiveallelesgetremovedoutof
aninbredpopulationmorerapidly,becausetheyare
exposedtonaturalselection
(reduction in survival and fitness)
§ Lower genotypic diversity (poor response to
natural selection)
--->thisprocessisaidedbySex,discussedinNext
Lecture(onVariation)
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Title goes here
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Carol Eunmi Lee
9/20/16
Mechanism:
■
■
■
■
Increasing genetic distance
Fitness
Most deleterious alleles are
recessive
On average each of us carries 35 lethal recessive alleles
These deleterious alleles are
expressed in inbred individuals
In Heterozygotes, these
deleterious recessives are
masked, and not exposed to
selection
Alleles
Locus1
A
a
Locus2
B
b
Locus3
C
c
Inbreeding
Depression
Hybrid Vigor
Outbreeding
Depression
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Examples of Inbreeding
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Inbreeding and Conservation
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Inbreeding and Agriculture:
Vexing Problem:
§ How do we prevent extinctions?
Because we have focused excessively on a few
breeds, effective population sizes of many crops
are incredibly small
§ How do we maximize genetic variance in a population?
§ What should we preserve?
(species, populations, habitats, ecosystems???)
600 breeds of livestock have disappeared
~78 breeds lost each year
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Title goes here
1000-1500 breeds of livestock are
considered at risk of extinction
(30% of current breeds)
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Carol Eunmi Lee
9/20/16
Recent efforts have focused on outcrossing to
increase fitness in agricultural stocks
8 million Holstein cows are
descendents of 37 individuals!!!
Neurological disorders
Autoimmune diseases
Fertility problems
Duvick, D. N. 2002. Biotechnology in the 1930s: the development of hybrid
maize. Nature Reviews Genetics. 2: 69-74.
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Bruce, W. B., G. O. Edmeades, and T. C. Barkre. 2002. Review Article:
Molecular and physiological approaches to maize improvement for drought
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tolerance. Journal of Experimental Botany. 53: 13-25.
Genetic Diseases due to Inbreeding have
afflicted many Royal Families
Inbreeding
depression in
humans
George III
Insane due to
Porphyria
Examples:
Porphyria: accumulation of porphyrin
precursors, causes insanity;
Dominant, but more intense in the
homozygous form
Mary, Queen of Scots
George III, loss of American colony
Acromegaly: Overproduction of GH
by the pituitary gland; recessive
Charles II, King of Spain (1665-1700)
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Porphyria in the Royal Families of Europe
Charles II
Hemophilia: “Victoria’s Secret”
“Hapsburg Jaw”
X-linked, shows up in males
Cognitively disabled
Daughters spread it among the royals,
impotent
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downfall of Russian monarchy
Royal Pedigree of the
“Hapsburg Jaw”
George III
In small populations,
individuals tend to mate
with relatives
Dominant, but more intense in the homozygous form
Title goes here
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= expression of the disorder
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Carol Eunmi Lee
9/20/16
Inbreeding within Royal
Families has been reduced
in recent years
Royal Pedigree of
Hapsburg Jaw
= expression of the disorder
= m arriage with close relative
Diana was a 7 th cousin of Charles,
rather than a first or second
cousin (which was the normal
practice previously)
Inbreeding within the Royal
Families of Europe was
genetically “disasterous”
Kate Middleton is neither an aristocrat nor
a royal, but the marriage was approved
given the modern recognition of the perils
of inbreeding… this marriage is an
example of genetic immigration (Migration)
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into an enclosed population
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Amish in Lancaster County, PA
Articles on British Royalty and Inbreeding:
Descendents of ~200 Swiss who emigrated mid-1700s.
News Article:
http://www.telegraph.co.uk/news/worldnews/e
urope/spain/5158513/Inbreeding-causeddemise-of-the-Spanish-Habsburg-dynastynew-study-reveals.html
Closed genetic
population for 12+
generations.
Original Scientific Article:
http://www.plosone.org/article/info:doi/10.1371/jou
rnal.pone.0005174
Host to 50+ identified
inherited disorders
(many more
uncharacterized)
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Examples of Diseases that Afflict Amish Populations
High levels of infant mortality
High Incidence of brain damage
Large number of metabolic disorders, such as PKU
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There is nothing special about the Amish,
genetically speaking (or Royal Families).
• There are about ~200 of you here, similar to the size of the
Ellis-van Creveld (dwarfism) syndrome
1/14 in Amish
founding Amish population in Lancaster county, Pennsylvania.
Glutaric aciduria type I
1/200 in Amish
descendents would be related and mating with one another.
• If all of you were stranded on a desert island, eventually your
• Each of us carries 3-5 lethal recessive alleles.
High incidence of bipolar
disorder
Polydactyly (6 fingers)
Title goes here
• If 200 people each had 3-5 different recessive lethals and
started forming a closed population, eventually, hundreds of
genetic disorders would emerge.
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Carol Eunmi Lee
9/20/16
Summary
Dating Service
FIND Your Genetically
Most Distant Mate!!!!
(For example, Scientificmatch.com
matches people that differ in their
MHC loci; people that differ at
these loci tend to be more attracted
to one another)
(1) Genetic Drift occurs when a population is small,
and leads to random loss of alleles due to
sampling error
(2) Inbreeding, an extreme consequence of Genetic
Drift, results in increases in homozygosity at many
loci, including recessive lethals
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CONCEPTS
Genetic Drift
Effective population size
Fixation
Heterozygosity
Inbreeding
Inbreeding Depression
Heterozygote advantage
1. When is Genetic Drift LEAST likely to operate?
(A) When there are migrants between populations
(B) When populations are fragmented and isolated
(C) When population size is small
(D) When population size is very very large
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2. Which of the following is FALSE regarding
inbreeding?
3. Which of the following is FALSE regarding
Genetic Drift?
(A) Inbreeding could result as a consequence after
genetic drift has acted on a population
(B) Populations with lower allelic diversity tend to have
lower genotypic diversity (more homozygous)
(C) Selection acts more slowly in inbred populations to
remove deleterious recessive alleles
(D) One way to reduce inbreeding in a population is to
bring in migrants from another population
Title goes here
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(A) Genetic Drift occurs more rapidly in
smaller populations
(B) In populations of finite size, random
changes in allele frequency occur at each
generation
(C) Genetic Drift could lead to inbreeding due
to loss of alleles
(D) Genetic Drift occasionally leads to the
generation of favorable alleles
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Carol Eunmi Lee
9/20/16
■
■
■
■
Answers to sample exam
questions:
1D
2C
3D
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Title goes here
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