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    slides of ASHG talk slides of ASHG talk Presentation Transcript

    • Gene expression levels in African Americans vary with both cis and trans genetic ancestry Alkes L. Price Harvard School of Public Health November 15, 2008
    • Outline 1. Population differences in human gene expression 2. Impact of cis vs. trans regulation on expression levels
    • Outline 1. Population differences in human gene expression 2. Impact of cis vs. trans regulation on expression levels
    • Many studies have reported population differences
    • Population differences could have non-genetic basis • Differences due to environment? (Idaghdour et al. 2008) • Differences in cell line preparation? (Stranger et al. 2007) • Differences due to batch effects? (Akey et al. 2007) (Reviewed in Gilad et al. 2008)
    • Admixed population enable strong validation • Different individuals inherit different ancestry proportions • Uniformity of environmental and experimental variables • African Americans (African + European ancestry) have been used to study population differences in other phenotypes
    • Ancestry proportions vary in African Americans Coriell HD100AA (Affymetrix 6.0) AA CEU CHB+JPT YRI
    • Ancestry proportions vary in African Americans Coriell HD100AA (Affymetrix 6.0) AA: 21% ± 14% European ancestry YRI CHB+JPT CEU
    • Gene expression experiment Does gene expression in 60 CEU + 60 YRI vary with ancestry? 60 CEU + 60 YRI from HapMap , 89 AA from Coriell HD100AA Gene expression measurements at 4,197 genes obtained using Affymetrix Focus array
    • Gene expression experiment Does gene expression in 60 CEU + 60 YRI vary with ancestry? Does gene expression in 89 AA vary with % European ancestry? 60 CEU + 60 YRI from HapMap, 89 AA from Coriell HD100AA Gene expression measurements at 4,197 genes obtained using Affymetrix Focus array
    • Gene expression experiment Does gene expression in 60 CEU + 60 YRI vary with ancestry? Does gene expression in 89 AA vary with % European ancestry? 60 CEU + 60 YRI from HapMap, 89 AA from Coriell HD100AA Gene expression measurements at 4,197 genes obtained using Affymetrix Focus array c
    • Gene expression differences in African Americans validate CEU-YRI differences c = 0.43 (± 0.02) ( P -value < 10 -25 )
    • c = 0.43 (± 0.02) ( P -value < 10 -25 ) Validation in African Americans is independent of size of CEU-YRI differences
    • Outline 1. Population differences in human gene expression 2. Impact of cis vs. trans regulation on expression levels
    • Efforts to map specific regulatory variants • Linkage mapping (Morley et al. 2004, Goring et al. 2007, Emilsson et al. 2008) • Genome-wide association studies (Cheung et al. 2005, Stranger et al. 2007, Emilsson et al. 2008, Schadt et al. 2008) Morley et al. 2004 identified more trans than cis linkage signals. More recent studies identified more cis than trans associations BUT there may be greater power to detect cis effects (Reviewed in Gilad et al. 2008).
    • Efforts to map specific regulatory variants • Linkage mapping (Morley et al. 2004, Goring et al. 2007, Emilsson et al. 2008) • Genome-wide association studies (Cheung et al. 2005, Stranger et al. 2007, Emilsson et al. 2008, Schadt et al. 2008) Morley et al. 2004 identified more trans than cis linkage signals. More recent studies identified more cis than trans associations BUT there may be greater power to detect cis effects (Reviewed in Gilad et al. 2008). Admixture enables an unbiased approach.
    • Admixed populations enable distinction between local ( cis ) versus genome-wide ( trans ) ancestry Population 1 Population 2 1 generation later
    • Admixed populations enable distinction between local ( cis ) versus genome-wide ( trans ) ancestry Population 1 Population 2 2 generations later
    • Admixed populations enable distinction between local ( cis ) versus genome-wide ( trans ) ancestry Population 1 Population 2 several generations later
    • Admixed populations enable distinction between local ( cis ) versus genome-wide ( trans ) ancestry Population 1 Population 2 several generations later Local ancestry = 0, 1 or 2 copies from population 1
    • What do cis ancestry and trans ancestry mean? Local ancestry = 0, 1 or 2 copies from population 1 at gene expression gene g cis ancestry trans ancestry Genome-wide ancestry (e.g. 20% European)
    • HAPMIX program estimates ancestry at each location in the genome with high accuracy • Haplotype-based inference of local ancestry in admixed populations (S. Myers and colleagues, submitted)
    • Both cis and trans ancestry contribute to validation of CEU-YRI differences in African Americans Gene expression in 60 CEU + 60 YRI varies with ancestry Gene expression in 89 AA varies with genome-wide ancestry c = 0.43
    • Both cis and trans ancestry contribute to validation of CEU-YRI differences in African Americans Gene expression in 60 CEU + 60 YRI varies with ancestry Gene expression in 89 AA Gene expression in 89 AA varies with cis ancestry varies with trans ancestry c cis c trans
    • Both cis and trans ancestry contribute to validation of CEU-YRI differences in African Americans Gene expression in 60 CEU + 60 YRI varies with ancestry Gene expression in 89 AA Gene expression in 89 AA varies with cis ancestry varies with trans ancestry c cis = 0.05 c trans = 0.38 (P-value = 6×10 -6 ) (P-value < 10 -25 )
    • Impact of cis vs. trans ancestry on gene expression π cis = (Impact of cis ancestry) / (Impact of cis + trans ancestry) = 0.05 / 0.43 = 12%
    • Impact of cis vs. trans ancestry on gene expression π cis = (Impact of cis ancestry) / (Impact of cis + trans ancestry) = 0.05 / 0.43 = 12% ± 3%
    • Impact of cis vs. trans variants on gene expression π cis = 12% ± 3% applies to all regulatory variants if Impact of cis ancestry Impact of cis variants Impact of trans ancestry Impact of trans variants =
    • Impact of cis vs. trans variants on gene expression π cis = 12% ± 3% applies to all regulatory variants if Impact of cis ancestry Impact of trans ancestry Impact of cis variants Impact of trans variants =
    • Impact of cis vs. trans variants on gene expression π cis = 12% ± 3% applies to all regulatory variants if Impact of cis ancestry Impact of trans ancestry Impact of cis variants Impact of trans variants We analyzed ~3,000 cis eQTL SNPs and ~700 trans eQTL SNPs from a recent study of gene expression in liver (Schadt et al. 2008) and obtained similar F ST values (matching genome-wide averages). This supports π cis = 12% ± 3% for all regulatory variants. =
    • Conclusions • Admixed populations enable a strong validation of heritable population differences in gene expression. This validation is robust to non-genetic factors. • Only a small fraction of heritable variation in gene expression is due to cis regulation. Most gene regulation is in trans .
    • Acknowledgements Price AL, Patterson N, Hancks DC, Myers S, Reich D, Cheung VG & Spielman RS. Effects of cis and trans genetic ancestry on gene expression in African Americans. PLoS Genet , in press. Richard Spielman David Reich Vivian Cheung Simon Myers Nick Patterson Dustin Hancks Alkes Price Oxford HMS/Broad UPenn HSPH
    • Other species: cis vs. trans in Drosophila “ The median percentage of regulatory divergence within species explained by cis -regulatory differences was 35%” (Wittkopp et al. 2008) “ For 14% of genes with an expression difference, cis regulation plays a role, usually in conjunction with trans regulation” (Wang et al. 2008)
    • Magnitude of population differences in gene expression CEU vs. YRI differences observed in CEU+YRI samples: 20% of CEU+YRI gene expression variation. CEU vs. YRI differences validated in African Americans: 20% × 0.43 = 9% of CEU+YRI gene expression variation. Q ST (CEU,YRI) = 0.09 / (2 – 0.09) = 0.05. (analogue of F ST ; reviewed in Merila & Crnokrak 2001) This is lower than F ST (CEU,YRI) = 0.16 using SNP data.