hardy-weinberg equilibrium · hardy-weinberg equilibrium • explains why, in a large population...
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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