population genetics and multifactorial inheritance 2002 consanguinity genetic drift founder effect...
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Population Geneticsand
Multifactorial Inheritance 2002
• 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 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
Coefficient of relationship
• Parent-child First ½
• Siblings First ½
• Uncle-niece Second ¼• 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 first degree.
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
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
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 new mutant alleles by mutation and removal by negative selection
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
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 10-15– NIDDM 4
• λ1
– Schizophrenia 10– Autism ~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
• Tuberculosis (USA)• Leprosy (India)• Poliomyelitis (USA)• Hepatitis B (Taiwan)
• 62% 18%• 52% 22%• 36% 6%• 35% 4%
MZ DZ
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