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Population Geneticsand

Multifactorial Inheritance 2002

• Consanguinity

• Genetic drift

• Founder effect

• Selection

• Mutation rate

• Polymorphism

• Balancedpolymorphism

• Hardy-WeinbergEquilibrium

Hardy-Weinberg Equilibrium

• Explains why, In a large population withrandom mating:

• 1. Allele frequencies do not change fromgeneration to generation

• 2. Genotype frequencies are determined byallele frequencies at that locus

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Note error in “AA offspring” footer !

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Allele frequencies in X-linkeddisorders

• Males are hemizygous for the X-chromosome:therefore frequency of affected males = frequencyof the mutant allele, q

• For rare XLR disorders, frequency ofheterozygous carrier females is twice thefrequency of affected males, or 2q

• Frequency of homozygous females is very low, q_

Applications of HWE

• Determination of allele frequency andheterozygote carrier frequency in apopulation for which the frequency of thetrait is known

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Hemophilia A and Para-hemophilia

• Hemophilia A:– XLR

– Frequency 1/5000

– Female carriers 1/2500

• Parahemophilia– Rare AR

– Frequency 1/1,000,000

– Heterozygote carrier frequency 1/500

Factors that alter gene frequency

• Small populations/ Non-random mating

• Selection

• Mutation

• Migration and gene flow

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Coefficient of relationship

• Parent-child First _

• Siblings First _

• Uncle-niece Second _

• First cousins Third 1/8

Selected Michigan Marriage Laws(Amended 1956)

SEC 3. No man shall marry his mother,grandmother, daughter, granddaughter,stepmother, grandfather’s wife, son’s wife,grandson’s wife…..or cousin of the firstdegree.

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Genetic Drift/ Founder EffectSingle (few) founder mutations

• Finns (“located on the edge of the populated world”)

– Indo-European immigration 2000 years ago– Population of 50,000 in 12th century, 5 million today

• Ashkenazim– Migration to Rhineland in 9th century, to Eastern

Europe in 14th century– Population 10-20,000 in Poland in 16th century, 11M

worldwide today– Repeated “bottlenecks” (pogroms)

• Amish

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Factors that alter gene frequency

• Small populations/ Non-random mating

• Selection

• Mutation

• Migration and gene flow

Selection

• Biological fitness (f)

• Positive and negative selection

• Selection on AD, AR, XLR

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Factors that alter gene frequency

• Small populations/ Non-random mating

• Selection

• Mutation

• Migration and gene flow

Mutation

• Effect of gene size

• Effect of paternal age

• Balance between introduction of newmutant alleles by mutation and removal bynegative selection

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Factors that alter gene frequency

• Small populations/ Non-random mating

• Selection

• Mutation

• Migration and gene flow

Migration and gene flow

• Tracking human migrations

• Cohanim

• Lemba

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Polymorphism

• The occurrence of two or more geneticallydetermined alternative phenotypes in a populationat such a frequency that the rarest could not bemaintained by recurrent mutation alone

• Practically---a genetic locus is consideredpolymorphic if one or more of the rare alleleshas(have) a frequency of at least 0.01.

• Examples: MHC, SNPs, SSRs

Balanced polymorphism• Balance of positive and negative selection

Malaria and genetic disorders of red blood cells

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Multifactorial Inheritance

Complex Common Diseases

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Evidence for Genetic Factors inCommon Complex Diseases

• Familial aggregation

• Twin studies

• Mendelian forms of disease

Familial Aggregation

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Increased risk to relatives: _R

• _S

– IDDM 10-15

– NIDDM 4

• _1

– Schizophrenia 10

– Autism ~100

MD (and MD2B): A chronic condition withsignificant physical, mental, emotional, and

financial consequences

• A a first degree relative (sib,parent)

• B a second degree relative (aunt,uncle,grandparent

• C More than one 1st and/or 2nd degreerelative

• D No affected 1st or 2nd degreerelatives

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Evidence for Genetic Factors inCommon Complex Diseases

• Familial aggregation

• Twin studies

• Mendelian forms of disease

Twin Studies

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Twin studies in infectious disease

• Tuberculosis (USA)

• Leprosy (India)

• Poliomyelitis (USA)

• Hepatitis B (Taiwan)

• 62% 18%

• 52% 22%

• 36% 6%

• 35% 4%

MZ DZ

Evidence for Genetic Factors inCommon Complex Diseases

• Familial aggregation

• Twin studies

• Mendelian forms of disease

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Diabetes Mellitus

Maturity onset diabetes of the young(MODY)

Association and Linkage

• ASSOCIATION of a specific allele at agenetic locus with disease in a population– Candidate gene

• LINKAGE. Co-segregation in families of amarker locus, regardless of specific allele,with disease.

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Implications

• Identification of genetic markers of liabilityto common complex disease.

• Environmental triggers have greatest impacton genetically predisposed.

• Identification of susceptible individuals aidsidentification of environmental triggers.

• Medical intervention can be focused onthose at greatest risk.

Threshold Model

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Predictions from ThresholdModel

• Recurrence risks are average

• Risk increases with # of affected relatives

• Risk increases with severity ofmalformation

• Differential risk increases as frequencydecreases

• Sex differences

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Affected Sib Pair