Genetic variation in radiation-induced expression phenotypes

Abstract

Studies have demonstrated that natural variation in the expression level of genes at baseline is extensive, and the determinants of this variation can be mapped by a genetic-linkage approach. In this study, we used lymphoblastoid cells to explore the variation in radiation-induced transcriptional changes. We found that, among normal individuals, there is extensive variation in transcriptional response to radiation exposure. By studying monozygotic twins, we demonstrated that there is evidence of a heritable component to this variation. The postradiation variation in the expression level of several genes, including the ferredoxin reductase gene (FDXR) and the cyclin-dependent kinase inhibitor 1A gene (CDKN1A), is significantly greater (P<.001) among twin pairs than within twin pairs. The induction of FDXR by radiation showed a bimodal distribution. Our findings have important implications for understanding the genetic basis of radiation response, which has remained largely unknown due to the lack of family material needed for genetic studies. Our approach, which uses expression phenotypes in cell lines, allows us to expose cells from family members to radiation. Similar study design can be applied to dissect the genetic basis of other complex human traits.

Figure 1

Transcriptional response of FDXR to IR. The graphs show negative ddCT (a proxy for fold change, which equals 2^−ddCT) for FDXR versus time for 10 twin pairs and for 10 unrelated individuals. The members of each twin pair are shown with matching color lines.

Figure 2

Bimodal distribution of transcriptional response of FDXR to IR. Transcriptional response (calculated by AUC) of 10 sets of MZ twins (black bars) and 10 unrelated individuals (gray bars).

Figure 3

Prediction of radioresponse by use of baseline transcript abundance. Baseline transcript abundance of GADD45A (r=-0.71) (A) and CDKN1A (r=-0.72) (B) are negatively correlated with radioresponse (calculated by AUC) (n=20). Correlation coefficients between radioresponse and baseline transcript abundance for each gene are shown.

Figure 4

Correlation of IR-responsive genes. The similarity of expression phenotypes of nine IR-responsive genes was assessed by Pearson’s correlation coefficient (absolute value). The dendrogram represents hierarchical clustering of the genes by use of the average-linkage method. Expression levels of genes with branches connected to the right of the dotted line are correlated at P<.001.