RADIATION-INDUCED TOTAL-DELETION MUTATIONS IN THE HUMAN HPRT GENE - ABIOPHYSICAL MODEL-BASED ON RANDOM-WALK INTERPHASE CHROMATIN GEOMETRY

Purpose: To develop a biophysical model that explains the sizes of rad iation-induced hprt deletions. Methods: Key assumptions: (1) Deletions are produced by two DSB that are closer than an interaction distance at the time of DSB induction; (2) Interphase chromatin is modelled by a biphasic random walk distribution; and (3) Misrejoining of DSB from two separate tracks dominates at low-LET and misrejoining of DSB from a single track dominates at high-LET. Results: The size spectra for ra diation-induced total deletions of the hprt gene are calculated. Compa ring with the results of Yamada and coworkers for gamma-irradiated hum an fibroblasts the study finds that an interaction distance of 0.75 mu m will fit both the absolute frequency and the size spectrum of the t otal deletions. It is also shown that high-LET radiations produce, rel atively, more total deletions of sizes below 0.5 Mb. The model predict s an essential gene to be located between 2 and 3 Mb from the hprt loc us towards the centromere. Using the same assumptions and parameters a s for evaluating mutation frequencies, a frequency of intra-arm chromo some deletions is calculated that is in agreement with experimental da ta. Conclusions: Radiation-induced total-deletion mutations of the hum an hprt gene and intrachange chromosome aberrations share a common mec hanism for their induction.