Download Population Genetics - Drift

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Population Genetics - Drift
Mohammad Keramatipour MD, PhD
[email protected]
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Welcome To Medical Genetics
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Today’s Lecture
„ Overview of basic concepts
„ Allele frequency
„ Genotype frequency
„ The
Th H
Hardy
Hardyd -Weinberg
W i b
L
Law
„ Medical applications
„ Factors that change allele frequencies in population
„ Genetic drift
¾ Definition
¾ Effects
¾ Factors affecting drift
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Population Genetics: History
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Basic Definitions
„ Genes, Alleles, Genotype, and Phenotype !!
„ Emerged in the 1920s
1920s and 1930
1930ss
„ Main
M i contributors:
t ib t
Si
Sir R
Ronald
ld Fi
Fisher,
h S
Sewallll W
Wright,
i ht JJ. B
B.
„ Population Genetics:
Genetics: is the study of:
¾ Genetic variation in population and the factors that change or
maintain such variation (over many generation)
¾ Distribution of genes/alleles and inherited traits
S. Haldane
„ Direct extension of Mendelian genetics, molecular
genetics, and the idea of Darwin
„ Population
Population:: is a group of interbreeding individuals who
„ Focus changes from individual to population
share a gene pool
„ The central issue: genetic variation
„ Gene
G
pooll: consists
pool:
i t off allll genes ((or alleles)
ll l ) iin a population
l ti
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Human Population
Human Population
„ Establishment of genetic diversity & development of ethnic
„ Genetic diversity in human population
¾ Human chromosome and their loci are identical among us
¾ Alleles & their frequencies vary among population groups
groups::
groups
¾ Mutation
¾ Natural selection
¾ Reproductive isolation
8 Disease causing
g alleles
8 Neutral DNA polymorphism
„ DNA polymorphism
¾ Definition
„ Main racial divisions in human population:
¾ Caucasian (European)
¾ Blacks (African)
¾ Asian
8 Polymorphic genes
8 Monomorphic genes
¾
Different frequencies
q
of alleles
and genotypes
Average heterozygosity in individual
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Allele & Genotype Frequencies
„ Driving genotype frequencies from allele frequency
¾ Assume
A
a population
l ti
8 Gene pool
8 Assume a gene with two alleles
8 Allele A = 70%
70%
8 Allele a = 30%
30%
„ Driving
g allele frequency
y from g
genotype
y frequency:
y
¾ Example: assume a population with following genotype at locus
X with two alleles, B & b
- BB:
BB 350
- Bb: 400
- bb: 250
- Calculate the allele and genotype frequencies?
¾ Calculate the genotype frequencies
8 AA, Aa,
Aa, & aa
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HardyHardy
-Weinberg Law
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HardyHardy
-Weinberg Law
„ Driving genotype frequencies from allele frequencies?
„ 1908:
1908: Harold Hardy & Wilhelm Weinberg
¾ Introduction of a mathematical expression that:
8 Relate the allele and genotype frequencies in populations
8 Predicts g
genetic stability
y over the course of many
y
generations:
„ Hardy
Hardyy-Weinberg
g law: ((for a locus with two alleles A and a with
frequencies p and q respectively)
¾ The frequency of the three genotypes AA,
AA Aa
Aa,, and aa are given by the terms
of the binomial expansion of (p+q
p+q))2 = p2 + 2pq + q2
ÁStability of allele and genotype frequencies
ÁRefer to as “equilibrium”
equilibrium
ÁUnder a given set of conditions
¾ Whatever allele frequencies happen to be present in the population will result
in genotype frequencies of p2:2pq:q2, and these relative genotype frequencies
will remain constant from generation to generation as long as the allele
q
(p and q)
(p
q) remain constant
frequencies
„ Later development:
¾ Understanding changes in gene/allele frequencies within a
population when such equilibrium is violated
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Allele & Genotype Frequencies
„ Fundamental characteristics of a population:
¾ Allele frequency
¾ Genotype frequency
8 How can we drive such p
parameters in a p
population??
p
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¾ In general, the genotype frequencies for any known number of alleles with
allele frequencies p1, p2, ….,p
….,pn can be derived from expansion of (p1 + p2 +
….pn)2
….p
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Assumptions of HardyHardy-Weinberg Law
HardyHardy
-Weinberg Equilibrium
„ A population in HardyHardy-Weinberg Equilibrium
Equilibrium?
?
„ Hardy
Hardy--Weinberg law is based upon following
„ A population in disequilibrium
disequilibrium?
?
assumptions:
¾ Large
L
population
l ti size
i
„ No population satisfy HardyHardy-Weinberg equilibrium
¾ Random mating
completely
„ Because of large size of human population we consider
our population in HardyHardy-Weinberg equilibrium
„ This
Thi law
l
is
i used
d to d
determine
i the
h ffrequencies
i off di
disease
genes which is critical in genetic counseling specially for
autosomal recessive disorders
¾ Constant allele frequencies
8 No mutation
8 No selection
8 No migration
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Population in Equilibrium??
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Population in Equilibrium??
„ It is very important to show if a population is in HardyHardy-Weinberg
„ Example: assume a human population of 200
equilibrium or not, in regard to an allele (specially disease casing
alleles)
„ How do you show this?
¾ Chi
Chi-square
square (χ2) test answers
this question
¾ In general chi square test
can be used to test the validity
of a hypothesis by comparing
the observed data with
expected data based on
th hypothesis
the
h
th i
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„ MN blood group frequency in this population:
¾ MM: 168
¾ MN: 30
¾ NN: 2
„ Is this population in equilibrium?
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Counting Disease Causing Alleles - 1
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Counting Disease Causing Alleles - 2
„ Using disease incidence to calculate frequency of mutant allele
„ Autosomal dominant conditions:
¾ Assume D is mutant allele with frequency of p and d is the normal
allele with frequency of q,
q (p is very small and p + q = 1 then we
can assume q ≅ 1)
„ Autosomal recessive conditions:
¾ D is the normal allele with p frequency and d is the mutant allele
with q frequency
¾ The incidence of the disease (genotype dd) is simply the allele
frequency squared (q2)
¾ Homozygous for autosomal dominant conditions are very rare in
comparison to heterozygous (p2 << 2pq), so we can ignore p2. In
other word,, we can assume all the cases are heterozygote
yg
¾ Conversely the allele frequency (q) can be calculated as the
square root of the disease incidence (q2)
¾ Frequency of heterozygotes is 2pq and q ≅ 1, so the frequency of
heterozygotes which is the observed incidence of the disease is
roughly 2p
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¾ The frequency of heterozygote carrier (i.e., the genotype Dd) is
2
2pq
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Counting Disease Causing Alleles - 3
Trying Some Examples
„ X-linked conditions:
„ Incidence of FH in a population is 1 in 500
500.. Find the
¾ The frequency of mutant allele (q) for an X-linked
X linked recessive is
frequency of mutant allele in this population?
equal to the frequency of the disease among males
„ Incidence of Tay
Tay-Sachs
Sachs disease is 1 in 3600 in
¾ The frequency of mutant allele (q) for an X-linked dominant
Ashkenazi Jewish births. Calculate the carrier frequency
in this population?
condition is half of the disease frequency among females
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Exceptions to Hardy
Hardy-Weinberg Assumptions
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Exceptions to HardyHardy-Weinberg Assumptions
„ Exceptions to random mating:
„ Assume that a mutant allele and its associated g
genotype
yp
¾ Stratification
is not in Hardy
Hardy--Weinberg equilibrium in a given
population, what this may tell you?
¾ Assortative
Assortative,, & disassortative mating
¾ Consanguinity (inbreeding)
(inbreeding), & outbreeding
¾ Maybe underlying assumptions are being violated
¾ The net effect of these exceptions:
8 Excess of homozygotes
8 Deficiency
y of heterozygotes
yg
¾ Mutation rate, and time
¾ The effect of the mutation (or disease) on survival and
reproduction
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Exceptions to Hardy
Hardy-Weinberg ..
„ Exceptions to constant allele frequency
¾ Mutation (the source of new allele)
¾ Neutral forces
Genetic drift
8 Migration (gene flow)
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¾ Adaptive forces
Natural selection
8 Heterozygous superiority or advantage: causes a
balanced polymorphism
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Genetic Drift
Effect of Genetic Drift
„ Drift & drifting:
¾ Random sampling error
„ The net effect of genetic drift:
¾ Random
R d
fifixation
ti or loss
l
off an allele
ll l
„ Genetic Drift:
¾ Random sampling error in allele frequency ??
¾ The fluctuation in allele frequency in gene pool by chance
¾ Chance / random ??
8 Survival
8 Reproduction
R
d ti
¾ Elimination of genetic variation within populations
8 Reducing heterozygosity
8 Increasing homozygosity
¾ Increasing variation between populations
¾ The effect of population size on random sampling error ???
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Genetic Drift and Population Size
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Probability of Fixation or Loss
„ The effect of genetic drift is less in large population
„ Population size = N, Mutation rate = r
„ Expected number of new mutation = 2Nr
„ Allele Frequency of the new mutation = 1/2N
„ Probability of fixation is the same as the allele frequency
in the population (consistent with random effect of genetic
drift) so = 1/2N
„ Probability of loss (elimination) = 1- Probability of fixation
= 1 - 1/2N
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Effect of Population Size on Fixation
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How Long Does Fixation Take?
„ Chance of fixation for a new mutation: how many
„ In large population (N is very large), new mutations are
generation is it likely to take?
more likely to occur
„ But each new mutation has a lower chance of being
„ Again it depends on the number of individuals in the
fixed and higher chance of being lost
population and it is equal to:
t = 4N
(t is the average number of generations to achieve
fixation))
„ In small population (N is small), the probability of new
mutation is small
„ But the likelihood of fixation is relatively large
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„ Allele fixation will take much longer in large population
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Factors Slowing The Effects of Drift
Points to Remember !!!
„ Genetic drift ultimately operates in a directional manner
„ Large
g p
population
p
size
with regard to allele frequency (fixation or elimination)
„ Migration between subpopulations
„ Mutation
„ Over time genetic drift will cause fixation of one allele for
any gene so heterozygosity and polymorphism go to zero
((if g
genetic drift is the only
y force operating
p
g within a
population)
„ Natural selection (heterozygote advantage ??)
„ The impact of genetic drift is more significant in smaller
population
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Medical Implication
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Common Form of Genetic Drift
„ Founder effect
¾ Definition
¾ Different allele frequencies than the original population
¾ Less genetic variation than the original population
¾ Examples
8 Huntington disease in the region of Lake Maracaibo,
Venezuela
„ Ethnic differences in the frequency of various genetic
diseases
¾ Differences in allele frequencies in different populations, why?
¾ Why some deleterious alleles are relatively common in certain
populations?
„ Two main factors:
¾ Genetic drift
8 Founder effect
8 The bottleneck effect
¾ Heterozygote
H
advantage
d
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8 Type I tyrosinemia in Lac Saint Jean region of Quebec (a
French--Canadian subpopulation)
French
ÁFrequency 1/685
685,, versus 1/100 000 in other part of Quebec
ÁAll due to same mutation in fumarylacetoacetase enzyme (a splice
donor site mutation in intron 12
12))
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Founder Effect: Finland
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Finland Population: An Example
„ Finish population:
¾ Develop from 400000 to 5 million during the last 300 years
¾ Distinctive pattern of singlesingle-gene disorders
¾ High
g frequencies of at least 20 singlesingle
g -g
gene disorders
8 Choroideremia
Choroideremia:: X
X--linked degenerative eye disease
X-linked choroideremia
Hyperornithinemia
Á400 reports all over the world
Á1/3 from
f
a smallll population
l ti iin Fi
Finland
l d
ÁA family descendent from a couple born in the 1640
1640ss
8 Hyperornithinemia
yp
with gy
gyrate atrophy
p y of the choroid and
retina
ÁAR disease with deficiency of ornithine aminotransferase
ÁSpecific mutation
mutation, not seen in other part of the world
8 PKU is very rare in Finland
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AR Diseases in Different Population
Founder Effect
„ More example:
¾ Ellis
Ellis--van Creveld Syndrome (recessive form of dwarfism) in Old
Order Amish of Lancaster County, Pennsylvania
¾ Tay-Sachs
Tay Sachs disease in Ashkenazi Jewish
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Common Forms of Genetic Drift
„ The bottleneck effect
¾ Same effect as founder effect
8 Reduced population size
8 Reduced
R d
d gene pooll
8 Different allele frequencies
¾ Example:
¾ Probably modern human !!!
¾ The African cheetah population
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∆CCR
CCR5
5 Allele Frequencies
Drift vs. Heterozygote Advantage
„ Heterozygote advantage
¾ Balanced polymorphism
¾ Example:
8 Malaria & hemoglobinopathies
g
„ Drift versus heterozygote advantage
¾ Which one is responsible for increased frequency of some
deleterious alleles?
¾ Difficult
Diffi lt tto fifind
d out!!,
t!! example:
l
¾ CCR
CCR5
5: a cell surface cytokine receptor, entry point for some
strains of HIV
8 ∆CCR
CCR5
5 allele frequency??
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Conceptual Questions
Conceptual Questions
„ Regarding genetic drift, specify the True or False
„ In genetic drift, what is drifting? Why is this an
statements:
¾ Over the long run, genetic drift will lead to allele
fixation or loss.
¾ When a new mutation occurs within a population,
genetic drift is more likely
g
y to cause the loss of the new
allele rather than the fixation of the new allele.
¾ Genetic drift promotes genetic diversity between
populations.
¾ Genetic drift promotes genetic diversity in large
populations.
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appropriate term to describe this phenomenon?
„ Why is genetic drift more significant in small populations?
Why does it take longer for genetic drift to cause allele
fixation in large population than in small ones?
„ Describe what happens to allele frequencies during the
bottleneck effect
effect. Discuss the relevance of this effect with
regard to species that are approaching extinction.
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Practical Examples
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Thank you for listening, any comments?
„ A group of four birds flies to a new location and initiated
the formation of a new colony. Three of them are
homozygous DD
DD,, and one bird is heterozygous Dd (for a
particular locus).
¾ What is the probability that the d allele will become
fixed in the population?
¾ If fixation occurs, how long will it take?
¾ How will the growth of the population, from generation
to generation, affect the answers to parts a and b?
Briefly explain please.
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