Office of Biological and Environmental Research

DOE Low Dose Radiation Program Workshop IV

Abstract

Title: Chromosome Spatial Clustering Uncovered Through Radiogenic Aberrations

Authors: R Sachs, J Arsuaga, K Greulich-Bode, M Vazquez, P Hahnfeldt, D Brenner, L Hlatky

Chromosome-chromosome spatial associations have been implicated in some cases of forming extra specific chromosome aberrations associated with cancers. We analyzed chromosome aberrations induced by low-linear transfer (LET) radiation in order to compare relative participation of the human chromosomes in interchanges and to characterize systematic spatial clustering of chromosomes. A new mFISH data set, specifying color junctions in metaphases of human peripheral blood lymphocytes after in vitro exposure to low-LET, was analyzed, separately and also in combination with previously published results. The table shows results for the combined data set, concentrating on the 22 autosomes, for which the most extensive data are available. Each entry gives the number of cells that contain at least one color junction between the indicated chromosomes. Monte Carlo (MC) computer simulations and mathematical modeling guided the data analysis.

Systematic statistical tests on the data of the table confirmed two clusters of chromosomes, {1,16,19,21, 22} and {13,14,15,21,22}, as having their members on average closer to each other than randomness would predict. The first set has been reported previously to be near the center of the interphase nucleus and to be formed mainly by gene-rich chromosomes, while the second set comprises the nucleolus chromosomes. These results suggest a possible interplay between chromosome positioning and transcription. Considerable randomness of chromosome-chromosome juxtapositions was also found as indicated qualitatively by the fact that almost all the entries in the table are non-zero. Nine other chromosome clusters suggested in the literature did not reach statistical significance. If these other associations are present, they are too weak, too variable in time, too variable from cell to cell, or involving only too small parts of chromosomes to show up in these whole chromosome studies.

In addition we found, consistent with previous results, that chromosome participation in interchanges is approximately proportional to the two-thirds power of the DNA content (Figure). The data points are obtained as sums over row + column in the table. The theoretical lines are obtained from MC simulations.

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