Transcript Incomplete penetrance

Population Genetics
and
Multifactorial Inheritance 2002
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Consanguinity
Genetic drift
Founder effect
Selection
Mutation rate
Polymorphism
Balanced
polymorphism
• Hardy-Weinberg
Equilibrium
Hardy-Weinberg Equilibrium
• Explains why, In a large population with
random mating:
• 1. Allele frequencies do not change from
generation to generation
• 2. Genotype frequencies are determined by
allele frequencies at that locus
Note error in “AA offspring” footer !
Allele frequencies in X-linked
disorders
• Males are hemizygous for the X-chromosome:
therefore frequency of affected males = frequency
of the mutant allele, q
• For rare XLR disorders, frequency of
heterozygous carrier females is twice the
frequency of affected males, or 2q
• Frequency of homozygous females is very low, q²
Applications of HWE
• Determination of allele frequency and
heterozygote carrier frequency in a
population for which the frequency of the
trait is known
Hemophilia A and Parahemophilia
• 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
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Small populations/ Non-random mating
Selection
Mutation
Migration and gene flow
Coefficient of relationship
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Parent-child
Siblings
Uncle-niece
First cousins
First
First
Second
Third
½
½
¼
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 first
degree.
Genetic Drift/ Founder Effect
Single (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
Factors that alter gene frequency
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Small populations/ Non-random mating
Selection
Mutation
Migration and gene flow
Selection
• Biological fitness (f)
• Positive and negative selection
• Selection on AD, AR, XLR
Factors that alter gene frequency
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Small populations/ Non-random mating
Selection
Mutation
Migration and gene flow
Mutation
• Effect of gene size
• Effect of paternal age
• Balance between introduction of new
mutant alleles by mutation and removal by
negative selection
Factors that alter gene frequency
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Small populations/ Non-random mating
Selection
Mutation
Migration and gene flow
Migration and gene flow
• Tracking human migrations
• Cohanim
• Lemba
Polymorphism
• The occurrence of two or more genetically
determined alternative phenotypes in a population
at such a frequency that the rarest could not be
maintained by recurrent mutation alone
• Practically---a genetic locus is considered
polymorphic if one or more of the rare alleles
has(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
Multifactorial Inheritance
Complex Common Diseases
Evidence for Genetic Factors in
Common Complex Diseases
• Familial aggregation
• Twin studies
• Mendelian forms of disease
Familial Aggregation
Increased risk to relatives: λR
• λS
– IDDM
– NIDDM
10-15
4
• λ1
– Schizophrenia
– Autism
10
~100
MD (and MD2B): A chronic condition with
significant 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 degree
relative
• D No affected 1st or 2nd degree
relatives
Evidence for Genetic Factors in
Common Complex Diseases
• Familial aggregation
• Twin studies
• Mendelian forms of disease
Twin Studies
Twin studies in infectious disease
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Tuberculosis (USA)
Leprosy (India)
Poliomyelitis (USA)
Hepatitis B (Taiwan)
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MZ
DZ
62%
52%
36%
35%
18%
22%
6%
4%
Evidence for Genetic Factors in
Common Complex Diseases
• Familial aggregation
• Twin studies
• Mendelian forms of disease
Diabetes Mellitus
Maturity onset diabetes of the young
(MODY)
Association and Linkage
• ASSOCIATION of a specific allele at a
genetic locus with disease in a population
– Candidate gene
• LINKAGE. Co-segregation in families of a
marker locus, regardless of specific allele,
with disease.
Implications
• Identification of genetic markers of liability
to common complex disease.
• Environmental triggers have greatest impact
on genetically predisposed.
• Identification of susceptible individuals aids
identification of environmental triggers.
• Medical intervention can be focused on
those at greatest risk.
Threshold Model
Predictions from Threshold
Model
• Recurrence risks are average
• Risk increases with # of affected relatives
• Risk increases with severity of
malformation
• Differential risk increases as frequency
decreases
• Sex differences
Affected Sib Pair