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Global patterns of cis variation in human cells revealed by high-density allelic expression analysis


Cis-acting variants altering gene expression are a source of phenotypic differences. The cis-acting components of expression variation can be identified through the mapping of differences in allelic expression (AE), which is the measure of relative expression between two allelic transcripts. We generated a map of AE associated SNPs using quantitative measurements of AE on Illumina Human1M BeadChips. In 53 lymphoblastoid cell lines derived from donors of European descent, we identified common cis variants affecting 30% (2935/9751) of the measured RefSeq transcripts at 0.001 permutation significance. The pervasive influence of cis-regulatory variants, which explain 50% of population variation in AE, extend to full-length transcripts and their isoforms as well as to unannotated transcripts. These strong effects facilitate fine mapping of cis-regulatory SNPs, as demonstrated by dissection of heritable control of transcripts in the systemic lupus erythematosus–associated C8orf13-BLK region in chromosome 8. The dense collection of associations will facilitate large-scale isolation of cis-regulatory SNPs.

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Figure 1: Genome-wide map of AE associated SNPs.
Figure 2: Allelic expression associations in individual transcripts.
Figure 3: AE in transcripts or their isoforms and global AE associations patterns.
Figure 4: Fine mapping of C8orf13-BLK AE in two populations.


  1. 1

    Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

    CAS  Article  Google Scholar 

  2. 2

    Stranger, B.E. et al. Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007).

    CAS  Article  Google Scholar 

  3. 3

    Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

    CAS  Article  Google Scholar 

  4. 4

    Göring, H.H. et al. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat. Genet. 39, 1208–1216 (2007).

    Article  Google Scholar 

  5. 5

    Kwan, T. et al. Genome-wide analysis of transcript isoform variation in humans. Nat. Genet. 40, 225–231 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Cheung, V.G. et al. Mapping determinants of human gene expression by regional and genome-wide association. Nature 437, 1365–1369 (2005).

    CAS  Article  Google Scholar 

  7. 7

    Yan, H., Yuan, W., Velculescu, V.E., Vogelstein, B. & Kinzler, K.W. Allelic variation in human gene expression. Science 297, 1143 (2002).

    CAS  Article  Google Scholar 

  8. 8

    Pastinen, T. et al. A survey of genetic and epigenetic variation affecting human gene expression. Physiol. Genomics 16, 184–193 (2004).

    CAS  Article  Google Scholar 

  9. 9

    Pastinen, T. et al. Mapping common regulatory variants to human haplotypes. Hum. Mol. Genet. 14, 3963–3971 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Wang, H.Y. et al. Complex genetic interactions underlying expression differences between Drosophila races: analysis of chromosome substitutions. Proc. Natl. Acad. Sci. USA 105, 6362–6367 (2008).

    CAS  Article  Google Scholar 

  11. 11

    Gimelbrant, A., Hutchinson, J.N., Thompson, B.R. & Chess, A. Widespread monoallelic expression on human autosomes. Science 318, 1136–1140 (2007).

    CAS  Article  Google Scholar 

  12. 12

    Milani, L. et al. Allele-specific gene expression patterns in primary leukemic cells reveal regulation of gene expression by CpG site methylation. Genome Res. 19, 1–11 (2009).

    CAS  Article  Google Scholar 

  13. 13

    Pant, P.V. et al. Analysis of allelic differential expression in human white blood cells. Genome Res. 16, 331–339 (2006).

    CAS  Article  Google Scholar 

  14. 14

    Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).

    CAS  Article  Google Scholar 

  15. 15

    Verlaan, D.J. et al. Targeted screening of cis-regulatory variation in human haplotypes. Genome Res. 19, 118–127 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Dimas, A.S. et al. Common regulatory variation impacts gene expression in a cell type–dependent manner. Science 325, 1246–1250 (2009).

    CAS  Article  Google Scholar 

  17. 17

    Fraser, H. & Xie, X. Common polymorphic transcript variation in human disease. Genome Res. 19, 567–575 (2009).

    CAS  Article  Google Scholar 

  18. 18

    Cooper, J.D. et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat. Genet. 40, 1399–1401 (2008).

    CAS  Article  Google Scholar 

  19. 19

    Barrett, J.C. et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat. Genet. 40, 955–962 (2008).

    CAS  Article  Google Scholar 

  20. 20

    Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).

    CAS  Article  Google Scholar 

  21. 21

    Babak, T. et al. Global survey of genomic imprinting by transcriptome sequencing. Curr. Biol. 18, 1735–1741 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Serre, D. et al. Global differential allelic expression in the human genome: a robust approach to identify genetic and epigenetic cis-acting mechanisms regulating gene expression. PLoS Genet. 4, e1000006 (2008).

    Article  Google Scholar 

  23. 23

    Campino, S. et al. Validating discovered cis-acting regulatory genetic variants: application of an allele specific expression approach to HapMap populations. PLoS One 3, e4105 (2008).

    Article  Google Scholar 

  24. 24

    Cheung, V.G. et al. Monozygotic twins reveal germline contribution to allelic expression differences. Am. J. Hum. Genet. 82, 1357–1360 (2008).

    CAS  Article  Google Scholar 

  25. 25

    Choy, E. et al. Genetic analysis of human traits in vitro: drug response and gene expression in lymphoblastoid cell lines. PLoS Genet. 4, e1000287 (2008).

    Article  Google Scholar 

  26. 26

    Tao, H., Berno, A.J., Cox, D.R. & Frazer, K.A. In vitro human keratinocyte migration rates are associated with SNPs in the KRT1 interval. PLoS One 2, e697 (2007).

    Article  Google Scholar 

  27. 27

    Kerkel, K. et al. Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat. Genet. 40, 904–908 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Maynard, N.D., Chen, J., Stuart, R.K., Fan, J.B. & Ren, B. Genome-wide mapping of allele-specific protein-DNA interactions in human cells. Nat. Methods 5, 307–309 (2008).

    CAS  Article  Google Scholar 

  29. 29

    Hoberman, R. et al. A probabilistic approach for SNP discovery in high-throughput human resequencing data. Genome Res. 19, 1542–1552 (2009).

    CAS  Article  Google Scholar 

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This work was supported by Genome Canada, Genome Québec and Illumina, Inc. T.P. holds a Canada Research Chair. H.H.H.G. carried out work in facilities constructed with support from Research Facilities Improvement Program Grant Number C06 RR017515 from the National Center for Research Resources, National Institutes of Health and a gift from the SBC Foundation.

Author information




T.P. and K.L.G. conceived the research. B.G., D.K.P., T.K., E.G., D.J.V., J.L., K.L.G., D.S. and T.P. designed the experiments. D.K.P., E.G., D.J.V., V.K., K.C.L.L., V.G., J.D. and M.-M.J. conducted the experiments. B.G., D.K.P., H.H.H.G., R. Hoberman, P.B., R. Hamon, A.G., M.B. and T.P. designed the computational and analytical methods. B.G., T.K., L.M., D.J.V., R. Hoberman, A.K.N., K.L.G. and T.P. analyzed the data. E.J.H. contributed primary osteoblast cell lines. T.P. drafted the manuscript and all authors contributed to the final manuscript writing and its revisions.

Corresponding author

Correspondence to Tomi Pastinen.

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Competing interests

The authors KL Gunderson, DK Pokholok and J Le are employed by Illumina Inc and KL Gunderson owns stock in the company.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–13, Supplementary Tables 2–5, 7–9 and Supplementary Note (PDF 1526 kb)

Supplementary Table 1

Details of 7785 AE associations detected at permutation significance 0.005 (XLS 1132 kb)

Supplementary Table 6

High confidence full transcript AE associations (XLS 158 kb)

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Ge, B., Pokholok, D., Kwan, T. et al. Global patterns of cis variation in human cells revealed by high-density allelic expression analysis. Nat Genet 41, 1216–1222 (2009).

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