Humans are exposed to radiation through the environment and in medical settings. To deal with radiation-induced damage, cells mount complex responses that rely on changes in gene expression. These gene expression responses differ greatly between individuals1 and contribute to individual differences in response to radiation2. Here we identify regulators that influence expression levels of radiation-responsive genes. We treated radiation-induced changes in gene expression as quantitative phenotypes3,4, and conducted genetic linkage and association studies to map their regulators. For more than 1,200 of these phenotypes there was significant evidence of linkage to specific chromosomal regions. Nearly all of the regulators act in trans to influence the expression of their target genes; there are very few cis-acting regulators. Some of the trans-acting regulators are transcription factors, but others are genes that were not known to have a regulatory function in radiation response. These results have implications for our basic and clinical understanding of how human cells respond to radiation.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Correa, C. R. & Cheung, V. G. Genetic variation in radiation-induced expression phenotypes. Am. J. Hum. Genet. 75, 885–890 (2004)
Amundson, S. A. et al. Integrating global gene expression and radiation survival parameters across the 60 cell lines of the National Cancer Institute Anticancer Drug Screen. Cancer Res. 68, 415–424 (2008)
Cheung, V. G. et al. Natural variation in human gene expression assessed in lymphoblastoid cells. Nature Genet. 33, 422–425 (2003)
Brem, R. B., Yvert, G., Clinton, R. & Kruglyak, L. Genetic dissection of transcriptional regulation in budding yeast. Science 296, 752–755 (2002)
Morley, M. et al. Genetic analysis of genome-wide variation in human gene expression. Nature 430, 743–747 (2004)
Cheung, V. G. et al. Mapping determinants of human gene expression by regional and genome-wide association. Nature 437, 1365–1369 (2005)
Schadt, E. E. et al. Genetics of gene expression surveyed in maize, mouse and man. Nature 422, 297–302 (2003)
Dixon, A. L. et al. A genome-wide association study of global gene expression. Nature Genet. 39, 1202–1207 (2007)
Stranger, B. E. et al. Genome-wide associations of gene expression variation in humans. PLoS Genet. 1, e78 (2005)
Dausset, J. et al. Centre d’Étude du Polymorphisme Humain (CEPH): collaborative genetic mapping of the human genome. Genomics 6, 575–577 (1990)
Haseman, J. K. & Elston, R. C. The investigation of linkage between a quantitative trait and a marker locus. Behav. Genet. 2, 3–19 (1972)
Lander, E. & Kruglyak, L. Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nature Genet. 11, 241–247 (1995)
Pan, D. et al. Down-regulation of CT120A by RNA interference suppresses lung cancer cells growth and sensitizes to ultraviolet-induced apoptosis. Cancer Lett. 235, 26–33 (2006)
Vairapandi, M., Balliet, A. G., Hoffman, B. & Liebermann, D. A. GADD45b and GADD45g are cdc2/cyclinB1 kinase inhibitors with a role in S and G2/M cell cycle checkpoints induced by genotoxic stress. J. Cell. Physiol. 192, 327–338 (2002)
Selvakumaran, M. et al. The novel primary response gene MyD118 and the proto-oncogenes myb, myc, and bcl-2 modulate transforming growth factor β1-induced apoptosis of myeloid leukemia cells. Mol. Cell. Biol. 14, 2352–2360 (1994)
Price, A. L. et al. Effects of cis and trans genetic ancestry on gene expression in African Americans. PLoS Genet. 4, e1000294 (2008)
Rockman, M. V. & Kruglyak, L. Genetics of global gene expression. Nature Rev. Genet. 7, 862–872 (2006)
Abecasis, G. R., Cardon, L. R. & Cookson, W. O. A general test of association for quantitative traits in nuclear families. Am. J. Hum. Genet. 66, 279–292 (2000)
Samuels-Lev, Y. et al. ASPP proteins specifically stimulate the apoptotic function of p53. Mol. Cell 8, 781–794 (2001)
Chen, H. & Sharp, B. M. Content-rich biological network constructed by mining PubMed abstracts. BMC Bioinformatics 5, 147 (2004)
Chen, Z. et al. CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. Dev. Cell 3, 339–350 (2002)
Sato, N., Mizumoto, K., Nakamura, M. & Tanaka, M. Radiation-induced centrosome overduplication and multiple mitotic spindles in human tumor cells. Exp. Cell Res. 255, 321–326 (2000)
Pant, P. V. et al. Analysis of allelic differential expression in human white blood cells. Genome Res. 16, 331–339 (2006)
Li, Y. et al. Mapping determinants of gene expression plasticity by genetical genomics in C. elegans . PLoS Genet. 2, e222 (2006)
Smith, E. N. & Kruglyak, L. Gene-environment interaction in yeast gene expression. PLoS Biol. 6, e83 (2008)
International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005)
Burdick, J. T., Chen, W. M., Abecasis, G. R. & Cheung, V. G. In silico method for inferring genotypes in pedigrees. Nature Genet. 38, 1002–1004 (2006)
Shete, S., Jacobs, K. B. & Elston, R. C. Adding further power to the Haseman and Elston method for detecting linkage in larger sibships: weighting sums and differences. Hum. Hered. 55, 79–85 (2003)
Wigginton, J. E. & Abecasis, G. R. PEDSTATS: descriptive statistics, graphics and quality assessment for gene mapping data. Bioinformatics 21, 3445–3447 (2005)
Myers, A. J. et al. Minimizing off-target effects by using diced siRNAs for RNA interference. J RNAi Gene Silencing 2, 181–194 (2006)
We thank D. George and W. Ewens for advice and discussion, A. Bruzel, S. Solomon, T. Weber and K. Halasa for technical help, and C. McGarry for manuscript preparation. Some analyses for this paper were performed by using the program package S.A.G.E., which is supported by a grant from the National Center for Research Resources. This work is supported by grants from the National Institutes of Health (to V.G.C. and R.S.S.), by seed grants from the University of Pennsylvania Center for Excellence in Environmental Toxicology (to V.G.C.), by the W. W. Smith Endowed Chair (to V.G.C.) and the Howard Hughes Medical Institute (to V.G.C.).
About this article
Cite this article
Smirnov, D., Morley, M., Shin, E. et al. Genetic analysis of radiation-induced changes in human gene expression. Nature 459, 587–591 (2009). https://doi.org/10.1038/nature07940
Association of combined engagement in cognitive and physical activity with domain‐specific cognitive function: The Shanghai Aging Study
International Journal of Geriatric Psychiatry (2021)
Alzheimer's Research & Therapy (2021)
International Journal of Geriatric Psychiatry (2020)
Frontiers in Aging Neuroscience (2020)
TOMM40 and APOE variants synergistically increase the risk of Alzheimer’s disease in a Chinese population
Aging Clinical and Experimental Research (2020)