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Genetic Analysis of Genome-wide Variation in Human Gene Expression Morley M. et al. Nature 2004,430: 743-747. Yen-Yi Ho Outline • • • • • • Introduction Data Method: Linkage analysis Results Discussion Comments Introduction Goal : Identify loci associated with variation in expression levels Nucleus regulators Genomic DNA mRNA Target mRNA Cis and Trans regulation Trans-regulator Cis-regulator Target gene expression phenotype Data Centre d'Etude du Polymorphisme Humain (CEPH) families are Utah residents with ancestry from northern and western Europe. • 14 families with genotype and expression data available for all parents and a mean of eight offspring (range 7-9) • 2,756 autosomal SNP genetic loci (100kb within cluster, 3 Mb between cluster). • Gene expression phenotypes ~8,500 gene expression phenotypes in immortalized B cells using Affymetrix Genome Focus Array. Expression intensity was scaled to 500 and transformed by log2. • 3,554 most variable expression phenotypes are selected (between > within variation). • Using CEPH unrelated individuals (94 grandparents), two array replicates per individual was performed. The within individual variation was indicated by the mean of variance of array replicates. Method: Linkage analysis A1 A2 A3A4 A1 A3 A1 A3 IBD=2 IBD: identical-by-descent A1 A2 A3 A4 A1 A3 IBD=1 A1 A4 A1 A2 A3 A4 A1 A3 A2 A4 IBD=0 (Yi1 Yi 2 ) 2 (Yi1 Yi 2 ) 2 E (DIS) 0 1 I(IBD=2) + 2 I(IBD=1) H 0 : 1 2 0 F RSS0 RSS1 ~ F2,n 1 RSS1 DIS: (Yi1 Yi 2 ) 2 , the distance of gene expression between sib 1 and 2. n: the total number of sibpairs For a particular target gene expression 15 t-statistics 10 5 SNP1 2 3 4 5 Genetic Locus Results Criteria 1 : t > 5 (P-value < 4.3 10 7, LOD > 5.3) : 142 expression phenotypes have at least one significant regulator. Criteria 2 : t > 4 (P-value < 3.7 10 5 , LOD > 3.4): 984 expression phenotypes have at least one significant regulator. Cis and trans- regulation Under criteria 1, • 27/142 (19%) expression phenotype have only a single cis-regulator. • 110/142 (77.5%) expression phenotype have only a single trans-regulator. • 2 /142 have a cis and a trans-acting regulator • 3 /142 gene expression have two trans-acting regulator Under criteria 2, 164 / 984 (16%) has multiple regulators T-statistic 1 2 Gene expression 3 . “Target” . . 4 7 …1 Criteria 2 1 3 3554 t > 3.4 0 0 ... ... 8 6 1 1 SNP 1 2 3 …0 1 1 …..2756 SNP 1 2 3 …..2756 Genetic Locus “regulator” 5 Mb window (total 491 windows) Master regulator 31 25 14q32 20q13 Divide the autosomal genome into 491 windows of 5 Mb, and count the number of regulators in the regions under criteria 2 (total 984 phenotypes with significant linkages). Co-regulation • Use the gene expression levels of 94 CEPH grandparents • Hierarchical clustering was performed and group genes by the correlation of the 31 target gene expression levels • Permutation test was used to determine the significant level of pair-wise correlation. 14 / 31 Population-based association analysis for cis-regulators (SNP regulator) Discussion • The study applied genome-wide mapping method to identify the chromosomal regions regulate to the gene expression phenotypes. • This type of study has the potential to uncover complicated transcriptional control. • Cis-, trans-acting and master regulators were discovered. • The linkage results are reliable as verified by association study and qRT-PCR. Comments • In this study, gene expression measured in immortalized B cells may be very different from the expression of human B cells in the blood. • Co-regulated genes and the pathways that connect genes are identified. • We would be even more interested in utilizing the data to improve our understanding of human disease. Genotype Gene expression Phenotype • Candidate regions have cis-effects. • Different phenotype / expression signatures associated with different “regulators”. Statistical design and analysis issues Design: • Choice of relative type or pedigree in humans. • Choice of tissue and timing of mRNA sampling. Analysis: • Multiple testing: linkage location, transcripts. • Regulatory hotspots: methods to find master regulatory loci. • Regulatory networks: searching for small sets of Co-regulated transcripts. Reference 1. 2. 3. 4. 5. Genetic analysis of genome-wide variation in human gene expression. Moley M., Molony C.M, Teresa M. Weber T.M. et al. Nature 430:743-747 (2004). Genetics of gene expression surveyed in maize, mouse, and man. Schadt E.E., Monks S.A., Drake T.A. et al. Nature 422: 297-302 (2003). Mapping expression in randomized rodent genomes. Broman K.W. Nature Genetics 37: 209-210 (2005). Natural variation in human gene expression assessed in lymphoblastoid cells. Cheung V.G., Conlin L.K., Weber T.M. et al. Nature Genetics 33: 422-425 (2003). Mapping determinants of human gene expression by regional and genome-wide association. Cheung V.G., Spielman R.S., Ewens K.G. et al. Nature 437: 1365-1369 (2005). Question?