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Genetic analysis of radiation-induced changes in human gene expression

Abstract

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.

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Figure 1: Individual variation in gene expression response to ionizing radiation.
Figure 2: Genome scans for four expression phenotypes.
Figure 3: Results of knockdown of five regulators of radiation-expression phenotypes.

Accession codes

Primary accessions

Gene Expression Omnibus

Data deposits

The microarray data are deposited in the GEO database under accession number GSE12626.

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Acknowledgements

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.).

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Correspondence to Vivian G. Cheung.

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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

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