Elston - 1 Human Genetics Human Genetics Genetic Epidemiology Genetic Epidemiology 2 Family trees can have a lot of nuts 3 Genetic Epidemiology

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Unformatted text preview: 1 Human Genetics Human Genetics Genetic Epidemiology Genetic Epidemiology 2 Family trees can have a lot of nuts 3 Genetic Epidemiology - Aims Genetic Epidemiology - Aims 1. Gene detection 2. Gene characterization mode of inheritance allele frequencies → prevalence, attributable risk 4 Genetic Epidemiology - Methods Genetic Epidemiology - Methods • Aggregation • Segregation • Co-segregation • Association 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: 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 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 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 9 Cosegregation Cosegregation • Chromosome segments are transmitted • Cosegregation is caused by linked loci ultimate statistical proof of genetic etiology 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 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 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- = = = = 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 14 Sib pairs share Sib pairs share 0, 1 or 2 alleles identical by...
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This note was uploaded on 02/13/2012 for the course BIO 126 N/A taught by Professor N/a during the Spring '10 term at University of Phoenix.

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Elston - 1 Human Genetics Human Genetics Genetic Epidemiology Genetic Epidemiology 2 Family trees can have a lot of nuts 3 Genetic Epidemiology

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