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.
Subscribe to Journal
Get full journal access for 1 year
only $17.42 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Emilsson, V. et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).
Stranger, B.E. et al. Population genomics of human gene expression. Nat. Genet. 39, 1217–1224 (2007).
Dixon, A.L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).
Göring, H.H. et al. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat. Genet. 39, 1208–1216 (2007).
Kwan, T. et al. Genome-wide analysis of transcript isoform variation in humans. Nat. Genet. 40, 225–231 (2008).
Cheung, V.G. et al. Mapping determinants of human gene expression by regional and genome-wide association. Nature 437, 1365–1369 (2005).
Yan, H., Yuan, W., Velculescu, V.E., Vogelstein, B. & Kinzler, K.W. Allelic variation in human gene expression. Science 297, 1143 (2002).
Pastinen, T. et al. A survey of genetic and epigenetic variation affecting human gene expression. Physiol. Genomics 16, 184–193 (2004).
Pastinen, T. et al. Mapping common regulatory variants to human haplotypes. Hum. Mol. Genet. 14, 3963–3971 (2005).
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).
Gimelbrant, A., Hutchinson, J.N., Thompson, B.R. & Chess, A. Widespread monoallelic expression on human autosomes. Science 318, 1136–1140 (2007).
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).
Pant, P.V. et al. Analysis of allelic differential expression in human white blood cells. Genome Res. 16, 331–339 (2006).
Frazer, K.A. et al. A second generation human haplotype map of over 3.1 million SNPs. Nature 449, 851–861 (2007).
Verlaan, D.J. et al. Targeted screening of cis-regulatory variation in human haplotypes. Genome Res. 19, 118–127 (2009).
Dimas, A.S. et al. Common regulatory variation impacts gene expression in a cell type–dependent manner. Science 325, 1246–1250 (2009).
Fraser, H. & Xie, X. Common polymorphic transcript variation in human disease. Genome Res. 19, 567–575 (2009).
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).
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).
Hom, G. et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N. Engl. J. Med. 358, 900–909 (2008).
Babak, T. et al. Global survey of genomic imprinting by transcriptome sequencing. Curr. Biol. 18, 1735–1741 (2008).
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).
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).
Cheung, V.G. et al. Monozygotic twins reveal germline contribution to allelic expression differences. Am. J. Hum. Genet. 82, 1357–1360 (2008).
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).
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).
Kerkel, K. et al. Genomic surveys by methylation-sensitive SNP analysis identify sequence-dependent allele-specific DNA methylation. Nat. Genet. 40, 904–908 (2008).
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).
Hoberman, R. et al. A probabilistic approach for SNP discovery in high-throughput human resequencing data. Genome Res. 19, 1542–1552 (2009).
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.
The authors KL Gunderson, DK Pokholok and J Le are employed by Illumina Inc and KL Gunderson owns stock in the company.
Supplementary Figures 1–13, Supplementary Tables 2–5, 7–9 and Supplementary Note (PDF 1526 kb)
Details of 7785 AE associations detected at permutation significance 0.005 (XLS 1132 kb)
High confidence full transcript AE associations (XLS 158 kb)
About this article
Cite this article
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). https://doi.org/10.1038/ng.473
Miniature inverted repeat transposable elements cis-regulate circular RNA expression and promote ethylene biosynthesis, reducing heat tolerance in Populus tomentosa
Journal of Experimental Botany (2021)
Scientific Reports (2021)
Genetic components of root architecture and anatomy adjustments to water‐deficit stress in spring barley
Plant, Cell & Environment (2020)
International Journal of Gynecology & Obstetrics (2020)
Genome-wide analysis of spatiotemporal allele-specific expression in F1 hybrids of meat- and egg-type chickens