Full-color painting reveals an excess of radiation-induced dicentrics involving homologous chromosomes

Abstract

Purpose: To determine the ratio of homologous to heterologous dicentric chromosomes induced in human cells by ionizing radiation. This ratio is influenced by, and thus potentially informative about, underlying DNA damage/repair/misrepair processes and also the geometry of individual chromosome domains within the interphase nucleus.

Materials and methods: 24-color mFISH (multiplex fluorescent in situ hybridization) was used to determine the ratio of 1-color (homologous) to 2-color (heterologous) dicentrics produced in human lymphocytes or fibroblasts by γ-rays, alpha particles, or iron ions at various doses. Assuming that randomness independent of homology holds, the expected homologue:heterologue ratio for diploid human male cells is ∼0.024, as shown by deriving a formula applicable to simple interchanges and then extending the result, via Monte Carlo simulation, to the general situation where complex aberrations are also considered.

Results and conclusions: There was a substantial excess of homologous dicentrics, with probability of occurrence by chance less than 0.02 for each of the three radiations and only about 10⁻⁸ for all the data combined. Overall, approximately 18 homologous dicentrics were expected but 47 were found, including 11 involving chromosome 1. Observed excesses were similar for both sparsely and densely ionizing radiations. Geometric proximity of homologues is a possible explanation for the overabundance; in that case more extensive statistics should eventually uncover a linear energy transfer (LET) dependence. An alternative possibility, not ruled out by the present data, is homology-dependent misrepair.

Keywords:

• DNA repair
• dicentric chromosome aberrations
• proximity dependent DNA misrepair
• homologous repair