Lecture: Genetic Basis of Complex Phenotypes Advanced Topics in Computa8onal Genomics
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1 Lecture: Genetic Basis of Complex Phenotypes Advanced Topics in Computa8onal Genomics
2 Genome Polymorphisms
3 A Human Genealogy TCGAGGTATTAAC The ancestral chromosome
4 From SNPS TCGAGGTATTAAC TCTAGGTATTAAC TCGAGGCATTAAC TCTAGGTGTTAAC TCGAGGTATTAGC TCTAGGTATCAAC * ** * *
5 To Haplotypes A disease muta8on
6 Population-Based Association Study Case/control data are collected from unrelated individuals All individuals are related if we go back far enough in the ancestry Balding, Nature Reviews Gene8cs, 2006
7 Type of Polymorphisms Each variant is called an allele " Almost always bi-allelic" Account for most of the genetic diversi ty among different (normal) individual, e.g. drug response, disease susceptib ility
8 Advantages of SNPs in Genetic Analysis of Complex Traits Abundance: high frequency on the genome Posi8on: throughout the genome coding region, intron region, promoter site Ease of genotyping Less mutable than other forms of polymorphisms SNPs account for around 90% of human genomic varia8on About 10 million SNPs exist in human popula8ons Most SNPs are outside of the protein coding regions 1 SNP every 600 base pairs More than 5 million common SNPs each with frequency 10-50% account for the bulk of human DNA sequence difference It is es8mated that ~60,000 SNPs occur within exons; 85% of exons are within 5 kb of the nearest SNP
9 Causal Mutations and Genetic Markers Causal Muta8on X X X SNP Marker Linkage Disequilibrium SNP marker serves only as a marker for the causal muta8on In order to find the causal muta8on, fine mapping (sequencing the SNP region) is required
10 Linkage Analysis vs. Association Analysis Strachan & Read, Human Molecular Gene8cs, 2001
11 Overview Single SNP associa8on test Discrete- valued phenotype: case/control study Con8nuous- valued phenotype: quan8ta8ve traits Correc8ng for mul8ple tes8ng Leveraging linkage disequilibrium Mul8marker associa8on test Genotype imputa8on method
12 Single SNP Association Analysis: Case/Control Study For each marker locus, find the 3x2 con8ngency table containing the counts of three genotypes Genotype Case Control AA Ncase,AA Ncontrol,AA Aa Ncase,Aa Ncontrol,Aa aa Ncase,aa Ncontrol,aa 2 χ Total Ncase Ncontrol test with 2 df, or Fisher s exact test under the null hypothesis of no associa8on Genotype score = the number of minor alleles
13 Single SNP Association Analysis: Case/Control Study Alterna8vely, assume an addi8ve model, where the heterozygote risk is approximately between the two homozygotes Form a 2x2 con8ngency table. Each individual contributes twice from each of the two chromosomes. Genotype Case Control A Gcase,A Gcontrol,A a Gcase,a Gcontrol,a Total 2xNcase 2xNcontrol 2 χ test with 1df
14 Single SNP Association Analysis: Continuous-valued Traits Con8nuous- valued traits Also called quan8ta8ve traits Cholesterol level, blood pressure etc. For each locus, fit a linear regression using the number of minor alleles at the given locus of the individual as covariate
15 Genetic Model for Association Addi8ve effect Major allele homozygote: 0 Heterozygote: a + a x k Minor allele homozygote: 2a k=1: dominant effect of the minor allele k=0: no dominance k=- 1: dominant effect of the minor allele
16 Penetrance Propor8ons of individuals carrying a par8cular allele that possess an associated trait Alleles with high penetrance are easier to detect in associa8on analysis
17 Correcting for Multiple Testing What happens when we scan the genome of 1 million markers for associa8on with α = 0.05? 50,000 (=1 millionx0.05) SNPs are expected to be found significant just by chance We need to be more conserva8ve when we decide a given marker is significantly associated with the trait. Correc8on methods Bonferroni correc8on Permuta8on test
18 Bonferroni Correction If N markers are tested, we correct the significance level as α = α/n Assumes the N tests are independent, although this is not true because of the linkage disequilibrium. Overly conserva8ve for 8ghtly linked markers
19 Permutation Procedure Step 1: Compute the test sta8s8c T using the original dataset Step 2: Set Nsig = 0 Step 3: Repeat 1:Nperm Step 3a: Randomly permute the individuals in the phenotype data to generate datasets with no associa8on (retain the original genotype) Step 3b: Find the test sta8s8cs Tperm of SNPs using the permuted dataset Step 3c: if T> Tperm, Nsig = Nsig+1 Step 4: Compute p- value as (1- Nsig/Nperm) This approach is computa8onally demanding because onen a large N perm is required.
20 Multi-marker Association Test Idea: a haplotype of mul8ple SNPs is a beoer proxy for a true causal SNP than a single SNP Exploit the linkage disequilibrium structure in genome Form a new allele by combining mul8ple SNPs for a haplotype SNP A SNP B Auxiliary Markers for Haplotypes Test the haplotype allele for associa8on
21 Multi-marker Association Test Mul8- marker approach can capture dependencies across mul8ple markers SNPs in LD form a haplotype that can be tested as a single allele Can achieve the same power with data collected for fewer samples Challenge as the size of haplotype increases Haplotype of K SNPs results in 2 K different haplotypes, but the number of samples corresponding to each haplotype decreases quickly as we increase K Large K requires a large sample size
22 Integrating large-scale functional genomic data to dissect the complexity of yeast regulatory networks Nature Gene8cs, (J. Zhu et al.)
23 Yeast Genomic Datasets (Zhu et al.) Yeast genomic datasets - Genotypes from 112 segregants from a yeast cross between BY and RM strains - Microarray gene- expression data - Transcrip8on factor binding site data - Protein- protein interac8on data
24 Analysis Procedure (Zhu et al.) Gene expression data analysis to infer gene coexpression network eqtl (expression quan8ta8ve trait locus) analysis Gene expression data as phenotype data Can we iden8fy the gene8c locus that controls the expression of genes? Learning a predic8ve model for yeast gene network Integrate mul8ple genomic data to infer gene network gene expression/eqtl/tfbs/ppi data
25 Gene Coexpression Network Hierarchical clustering of genes Iden8fied gene modules How to validate the gene modules? GO enrichment analysis as a proxy
26 Gene Set Enrichment Analysis Given a subset of genes, we would like to test whether these genes share a common func8on. KEGG pathway and gene ontology (GO) database provide informa8on on known gene func8on
27 Gene Set Enrichment Test for Computational Validation of Gene Clusters Suppose we have generated k clusters (sets of gene profiles) C 1,,C k. How do we assess the significance of their rela8on to m known (poten8ally overlapping) categories G 1,,G m (e.g., GO categories)? Let's start by comparing a single cluster C i with a single category G j. The p- value for such a match is based on the hyper- geometric distribu8on. This is the probability that a randomly chosen C i elements out of N would have m elements in common with G j. P(l) = G i N G i m C i m N C i m: the total number of genes in C i that overlap with G j
28 Overlap: m genes P(l) = G i N G i m C i m N C i N genes Genes in cluster C j Genes in G j in the given GO category
29 Network Modules, GO Enrichment, eqtl Hotspots
30 eqtl Hotspots eqtl hotspots: pleiotropic control of mul8ple genes by a common genomic locus cis eqtl: affected genes are physically located in cis to the genomic locus trans eqtl: affected genes are located distantly from the eqtl
31 Network Modules, GO Enrichment, eqtl Hotspots
32 eqtl Hotspots No ground truth for eqtls. How to validate the results? Use results from knockout experiments, TFBS experiments as a proxy Again, gene set enrichment analysis
33 TFBS Target Enrichment, Knock-Out Signature Enrichment
34 Learning Bayesian Networks: Integrating Different Genomic Data Incorpora8ng more genomic data into network learning can increase the predic8ve power for regulators Bayesian network I (BN raw ) Derived from gene expression data Bayesian network II (BN qtl ) Derived from gene expression, eqtl data Bayesian network III (BN full ) Derived from gene expression, eqtl, TFBS (ChIP- chip experiments), PPI data
35 Incorporating eqtls in Network Learning A two step analysis: First perform eqtl analysis Incorporate the iden8fied eqtls in the network learning process For a given eqtl, genes with cis eqtls can be parents of genes with trans eqtls For a given eqtl, genes with trans eqtls are not allowed to be parents of genes with cis eqtls.
36 Computationally Identified Causal Regulators
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