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elston - Human Genetics Genetic Epidemiology 1 Family trees...

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1 Human Genetics Human Genetics Genetic Epidemiology Genetic Epidemiology
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2 Family trees can have a lot of nuts
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3 Genetic Epidemiology - Aims Genetic Epidemiology - Aims 1. Gene detection 2. Gene characterization mode of inheritance allele frequencies prevalence, attributable risk
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4 Genetic Epidemiology - Methods Genetic Epidemiology - Methods Aggregation Segregation Co-segregation Association
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5 Segregation Segregation Can the dichotomy or trichotomy be explained by Mendelian segregation? affected and unaffected or two distributions: determined by a dominant or recessive allele Also possible: three distributions:
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6 Likelihood (parameter(s); data) Probability (data | parameter(s)) founders nonfounders observed ( ) ( | , ) ( | ) l l l j j i j f m i j P G P G G G P Y G ϕ ϕ ϕ The joint probability of the genotypes and phenotypes of all the members of a pedigree can be written as nonfounders 1 2 founders observed ( ; ) ( ) ( | , ) ( | ). l l l L j j n i j f m G G G i j L Y P G P G G G P Y G ϕ ϕ ϕ ϕ �� ��
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7 Transmission Probabilities Transmission Probabilities P(AA transmits A) = τ AA A P(Aa transmits A) = τ Aa A P(aa transmits A) = τ aa A Value if there is Mendelian segregation 1 ½ 0
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8 We examine segregating sibships The proportion of sibs affected is larger than expected on the basis of Mendelian inheritance The likelihood must be conditional on the mode of ascertainment We need to know the proband sampling frame Ascertainment Ascertainment
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9 Cosegregation Cosegregation Chromosome segments are transmitted Cosegregation is caused by linked loci ultimate statistical proof of genetic etiology
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10 Methods of Linkage Analysis Methods of Linkage Analysis Trait model-based – assume a genetic model underlying the trait Trait model-free - no assumptions about the genetic model underlying the trait (parametric) (non-parametric) Ascertainment is often not an issue for locus detection by linkage analysis
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11 Model-based Linkage Analysis Model-based Linkage Analysis If founder marker genotypes are unknown, we can 1) estimate them 2) use a database If founder marker genotypes are known or can be inferred exactly, no increase in Type 1 error smallest Type 2 error when the model is correct All parameters other than the recombination fraction are assumed known
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12 1 2 founders nonfounders observed ( ; ) ( ) ( | , ) ( | ). j j n i j f m G G G i j P G P G G G P Y G ϕ ϕ ϕ ϕ �� �� l l l L L Y ( | , ) is expressed as a function of 2-locus transmission probabilities j j j f m P G G G ϕ (1 ) 2 2 AB AB AB ab ab ab AB AB Ab aB ab ab and θ θ τ τ τ τ - = = = =
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13 Model-free Linkage Analysis Model-free Linkage Analysis Identity-in-state versus Identity-by-descent Identity-in-state versus Identity-by-descent Two alleles are identical by descent if they are copies of the same parental allele A A 1 A A 1 A A 1 A A 2 A A 1 A A 2 A A 1 A A 2 IBD IBD
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14 Sib pairs share Sib pairs share 0, 1 or 2 alleles identical by descent at a marker locus 0, 1 or 2 alleles identical by
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