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 individuals 1 and contribute to individual differences in response to radiation 2 . Here we identify regulators that influence expression levels of radiation-responsive genes. We treated radiation-induced changes in gene expression as quantitative phenotypes 3,4 , 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 transacting 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.In the past 20 years there has been a large increase in the use of radiation in medical diagnostic procedures and treatment protocols. Radiation is genotoxic and induces DNA damage in human cells. To ensure genomic integrity, cells mount complex responses that depend on changes in gene expression. It has long been known that individuals vary in their sensitivity to radiation. This individual variability is also observed at the gene expression level 1 . We and others have used genetic studies to identify chromosomal regions and genetic variants that influence expression levels of many genes in human cells at the baseline 5-9 .Here we extend our analysis by genetic mapping of regulatory elements that influence radiation-induced changes in gene expression.We used microarrays to measure the expression levels of genes in irradiated immortalized B cells from members of 15 Centre d'Étude du Polymorphisme Humain (CEPH) UtahCorrespondence and requests for materials should be addressed to V.G.C. (vcheung@mail.med.upenn.edu). Full Methods and any associated references are available in the online version of the paper at www.nature.com/nature.Supplementary Information is linked to the online version of the paper at www.nature.com/nature. Author InformationThe microarray data are deposited in the GEO database under accession number GSE12626. Reprints and permissions information is available at www.nature.com/reprints. 10 . Data were collected for cells at baseline and at 2 and 6 h after exposure to 10 Gy of ionizing radiation. Of the 10,174 genes on the microarrays that are expressed in immortalized B cells, we focused on 3,280 'ionizing-radiation-responsive' genes that showed at least a 1.5-fold change in gene expression levels at 2 h and/or 6 h after irradiation relative to the baseline. For each of these 3,280 genes we calculated the ratio of expression level at 2 h after irradiation relative to the expression level at the bas...

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