L16 Population Genetics-2

8/10/2019 L16 Population Genetics-2

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Population genetics


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Types of polymorphism

Restriction fragment length polymorphism (RFLP)

Single nucleotide polymorphism (SNP) 10 millions

Minisatellites/variable number tandem repeats (VNTR)

Microsatellites or short tandem repeats (STR)

Frequencies of polymorphic alleles may varysignificantly in different populations

Currently a new type of the genomic variation named CNV(copy number variation) is extensively studied.

CNV range from Kb to MbMost CNV are rare variants

Some CNV can be associated with the diseases.

Just to remind


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Your class of 100 people has been typed for a two-allele polymorphism (alleles labeled A and a), and the

following 3 genotype counts were obtained:Genotype Number of individuals

A,A 30A,a 50

a,a 20Total number of allele = 100 x 2 = 200

Number of allele A = (30 x 2)+ 50 = 110

Number of allele a= 50 + (20 x 2) = 90

Frequency of allele A = 110/200 = 0.55

Frequency of allele a = 90/200 = 0.45

Allele frequency ?


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Neutral polymorphism : SNP rs213934 A/G(HapMap project)

Japanese 0.434Caucasians 0.292African ancestry in SW USA 0.035Nigerian 0

Frequencies of polymorphic alleles mayvary significantly in different populations

Polymorphism associated with disease:

sickle cell mutation

African Americans 0.05Caucasians 0


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Hardy-Weinberg equilibrium/law:I. Genotypes distribution

Frequency of allele A = pFrequency of allele a = q

p+q = 1

1= p2

+ 2pq + q2

p2= frequency of homozygote AA

2pq = frequency of heterozygote Aa

q2 = frequency of homozygote aa


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Hardy-Weinberg Equilibrium:Single Nucleotide Polymorphism

SNP A/C

1 = p2

+ 2pq + q2

p2= frequency of homozygote AA= 0.72= 0.492pq = frequency of heterozygote AC = 2x0.7x0.3= 0.42

q2 = frequency of homozygote CC = 0.32= 0.09

p = 0.7 (frequency of allele A)q = 0.3 (frequency of allele C)

Expected distribution of genotypes in 100 individualsAA= 0.49 x 100 = 49 individualsAC = 0.42 x 100 = 42 individualsCC = 0.09 x 100 = 9 individuals


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Single nucleotide polymorphism SNP17361 G/T:

the frequency of a minor allele T is 0.4. What is

the frequency of heterozygotes G/T?

A. 18%

B. 28%

C. 38%

D. 48%

E. 58%

Q


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Single nucleotide polymorphism SNP17361 G/T:

the frequency of a minor allele T is 0.4. What isthe frequency of heterozygotes G/T?

A. 18%

B. 28%C. 38%

D. 48%

E. 58%

q = 0.4p=1 - 0.4 = 0.6

2pq = 2 x 0.6 x 0.4 = 0.48 (48%)

A


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Hardy-Weinberg equilibrium inMendelian diseases

1 = p2

+ 2pq + q2

p2= frequency of normal homozygote NN

2pq = frequency of heterozygote NM

q

2

= frequency of mutant homozygote MM

Frequency of normal allele N = pFrequency of mutant allele M = q


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Hardy-Weinberg equilibriumAutosomal dominant disease

1 = p2+ 2pq + q2p2= frequency ofhealthy (normal homozygote NN)

2pq = frequency of affected(heterozygote NM)

q2 = frequency of affected(mutant homozygote MM)



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Hardy-Weinberg equilibriumAutosomal recessive disease


1 = p2+ 2pq + q2

p2= frequency ofhealthy (normal homozygote NN)

2pq = frequency of healthy(heterozygote NM)



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Hardy-Weinberg equilibriumX-linked recessive disease


Males:p = frequency of healthy(normal hemizygote N)

q = frequency of affected (mutant hemizygote M)

Females:1 = p2+ 2pq + q2

p2

= frequency ofhealthy (normal homozygote NN)




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Most typical exam questions

q is given

Find carrier frequency

Find disease frequency

Disease frequency (incidence) is given

Find disease allele frequency

Find carrier frequency

Carrier frequency is givenFind disease allele frequency

Find disease frequency


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Estimation of carrier frequency forautosomal recessive disease

It is difficult and often impossible to identifycarrier frequency directly

Hardy-Weinberg equilibrium allows for estimationof carrier frequency from disease incidence

Incidence of phenylketonuria (PKU) in Caucasians :

1 in 10,000Mutant allele frequency?

Carrier frequency ?


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Frequency of MM = q2 = 1/10,000q= square root of 1/10000= 1/10000 = 1/100p= 1 1/100 = 0. 99 1 (approximation can beused because the disease/mutation is rare)

Carrier frequency = 2pq = 2 x1 x 1/100 = 1/50

p2+ 2pq + q2p2= frequency of homozygote NN

2pq = frequency of heterozygote NM

q2 = frequency of homozygote MM

Incidence of phenylketonuria (PKU) in Caucasians :1 in 10,000

Mutant allele frequency

Carrier frequency ?p= frequency of normal alleleq = frequency of mutant allele


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PKU incidence in China : 1 in 100,000

Carrier frequency ?

optional

i l


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PKU incidence in China : 1 in 100,000

Frequency of MM = q2 = 1/100,000q=1/100000 = 1/316p= 1 1/316 = 0. 999 1Carrier frequency = 2pq = 2 x1 x 1/316 = 1/158

p2+ 2pq + q2

p2= frequency of homozygote NN2pq = frequency of heterozygote NM

q2 = frequency of homozygote MM

p= frequency of normal alleleq = frequency of mutant allele

Mutant allele frequency?Carrier frequency ?

optional


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Frequencies of mutant PKU allele andPKU carriers are different in Caucasians

and Chinese

PKU incidence in Caucasians : 1 in 10,000q= 1/100

Carrier frequency = 1/50

PKU incidence in China : 1 in 100,000q= 1/316

Carrier frequency = 1/158


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From carrier frequency to

disease and allelefrequency

A biochemical or enzymatic carriertesting is available just for a limited

number of genetic disorders, particularlyfor Tay-Sachs disease


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Tay-Sachs disease is an autosomal recessive

disorder for which the carrier frequency inindividuals of Ashkenazi Jewish descent is

about 1 in 30.

How frequent is Tay-Sachs disease in this

population?

1 = p2+ 2pq + q2



q2

= frequency of affected(mutant homozygote MM)


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Tay-Sachs disease is an autosomal recessivedisorder for which the carrier frequency inindividuals of Ashkenazi Jewish descent is about

1 in 30.How frequent is Tay-Sachs disease in this

population?

2pq = 1/30In case of rare genetic disease the frequency ofmutant allele (q) is small, thus p 12pq 2q = 1/30

q = 1/60The frequency of disease = q2 =( 1/60)2 = 1/3600

Answer: 1 in 3600


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Hardy-Weinberg equilibriumX-linked diseases


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Because males have only a single X chromosome, each

affected male has one copy of the disease-causing

recessive mutation. Thus, the incidence of an X-linked

disease in males is a direct estimate of the gene

frequency in the population.

X-linked diseases

Disease frequency in males = q


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X-linked recessive:

Males:q affectedp - unaffected

Females:q2affected2pq - carrierp2- unaffected

X-linked dominant:

Males:q affectedp - unaffected

Females:

q2affected2pq - affectedp2 - unaffected


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Color blindness

8% Caucasian males have color blindnessq= ?

p = ?Females

Normal non-carrier = ?

Normal carrier = ?

Color-blindness = ?

X-linked recessive


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X-linked recessive

Color blindness

Males

q= 0.08p = 0.92

8% Caucasian males have color blindness

Females

Normal non-carrier = p2= 0.922=0.846

Normal carrier = 2pq = 2 x 0.92 x 0.08 = 0.1472

Color-blindness = q

2

= 0.08

2

=0.0064


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G6PD deficiency in 70 of 1080 males (70/1080= 0.065)q =p=

FemalesNormal non-carrier =Carrier =

G6PD deficiency

Blood Cells Mol Dis, 2003, 31 (2) , 201-205

optional


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G6PD deficiency in 70 of 1080 males (70/1080= 0.065)q = 0.065

p= 1- 0.065= 0.935

FemalesNormal non-carrier = p2=0.9352 =0.874 (87.4%)Carrier = 2pq = 2 x 0.935 x 0.065 = 0.121 (12,1%)G6PD deficiency = q2= 0.0652= 0.0042 (0.4%)

Blood Cells Mol Dis, 2003, 31 (2) , 201-205

optional


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Hardy-Weinberg equilibrium

Autosomal dominant disease

1 = p2+ 2pq + q2


2pq = frequency of affected(heterozygote NM)



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Autosomal dominant diseases

1= p2+ 2pq + q2

Most dominant diseases are rare, it means q is smalland an approximation p 1 can be usedMost patients with AD disease are heterozygotesDisease frequency = 2pq + q2 2pq 2q

q= disease frequency/2

Familial hypercholesterolemia in USA : 1/500 or 0.002

Therefore q= 0.001Frequency of homozygotes = q2= (0.001)2= 0.000 0011 in a million

optional


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Hardy-Weinberg Law:II. The population genotype frequencies from

generation to generation will remain constant, if

allele frequency remain constantIf you want to know why it is true see the

following table

optional


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Large population

Random mating

No migration

Assumptions underlying the

Hardy-Weinberg law


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Factors that disturb Hardy-Weinberg equilibrium

Non-random matingStratificationAssortative mating

Consanguinity/inbreedingGenetic drift in small population

Founder effect

Mutation selection

Migration and gene flow


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Non-random mating

Assortative mating

Consanguinity/inbreeding

Stratification


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Non-random mating: Assortative marriage

The choice of the mate who possesses

some particular trait

Congenital deafness

Congenital blindness

Achondroplasia


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Non-random mating: Consanguinity

Marriage between relatives

Non-random mating: Inbreeding

In genetic isolates the chance of mating withanother carrier may be as high as in consanguineous

marriages

Geographically isolated populations

Religious groups (Old Order Amish, Mennonites etc)

Slide 1


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Non-random mating: Stratification

US population: many groups(strata)WhitesAfrican AmericansNative AmericansAsian AmericansHispanics

African Americas 10% of US populationFrequency of SC mutation in African Americans qAA=0.05Frequency of SC mutation in other group is practically 0Frequency of SC mutation in US population qtotal= 0.05/10 =0.005

(optional)

Sickle cell (SC) mutation in the USA

Stratification Slid 2


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Stratification

Frequency of the SC disease expected from Hardy-Weinberg equilibrium in US population:

qtotal2= 0.0052= 0.000025

However the mating is not random - most marriages areinside the group (stratum) and the real estimate of SCdisease in African Americans is

qAA2= 0.052 = 0.0025

Because African Americans are 10% of the US population,

then the real frequency of the disease in the USpopulation is0.0025/10= 0.00025

This is 10 times more than expected from Hardy-Weinberg equilibrium

African Americas(AA) 10% of US populationFrequency of sickle cell (SC) mutation in AA = qAA=0.05Frequency of SC mutation in US population qtotal= 0.05/10 = 0.005

Slide 2(optional)


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Factors that disturb Hardy-Weinberg equilibrium

Non-random matingStratificationAssortative mating

Consanguinity/inbreedingGenetic drift in small population

Founder effect

Mutation selection


Just to remindyou where weare


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Increased fertility or survival of mutationcarriers for reason

unrelated to carrying the mutation

leads to a

change in allele frequency

Genetic drift in small populations -chance event

In small populations allele frequencies canfluctuate form generation to generation by

chance (genetic drift)


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The founder effect is the loss of genetic

variation that occurs when a new population is

established by a very small number of individuals

from a larger population

Founder effect


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Mutation selection

Positive selection ( increased fertilityor survival because of mutation)

Negative selection ( decreased fertilityor survival because of mutation)

Eff t f t ti l ti i diff t i


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PKU incidence in Caucasians : q2= 1/10,000

Carrier frequency = 2pq = 2 x1 x 1/100 = 1/50

Dominant disease:all mutant alleles are under negative selective

pressure

Autosomal recessive diseases:selection has less effect

because most mutant alleles are in heterozygotesand therefore escape negative selection

Number of mutant PKU alleles in carriers 1/50----------------------------= ---------- = 100Number of mutant PKU alleles in affected 2/10,000

Effect of mutation selection is different indominant and recessive diseases


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Positive selection for heterozygotes(Heterozygote advantage)

Resistance to malariaSickle cell anemia/Thalassemia/G6PD deficiency

Resistance to effect of chloride-secreting diarrhea

Cystic fibrosis

Resistance to some infectionsTay-Sachs disease

fl


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Migration can change allele frequency by gene flow slow diffusion of genes across a barriers

Map of Ancient human migration


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Ethnic differences in the frequency of geneticdiseases may be due to

Genetic drift

Founder effect

Positive selection for heterozygotes(Heterozygote advantage)


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Tay-Sachs disease is common in

Ashkenazi Jews because of:

Founder effect

Inbreeding

Heterozygote advantage

Ashkenazi Jews (those originating from theWestern and Eastern Europe diaspora), who make upmore than 80 percent of world Jews and are

believed to be descended from about 1,500 Jewishfamilies dating back to the 14th century


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L16 Population Genetics-2

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