TY - JOUR
T1 - Random breakage and reunion chromosome aberration formation model; an interaction - Distance version based on chromatin geometry
AU - Sachs, R. K.
AU - Levy, D.
AU - Chen, A. M.
AU - Simpson, P. J.
AU - Cornforth, M. N.
AU - Ingerman, E. A.
AU - Hahnfeldt, P.
AU - Hlatky, L. R.
N1 - Funding Information:
The authors are grateful to A. Edwards, D. Goodhead,C.GriÝ nandJ.R.K.Savageforuseful comments and discussions. Research was supported by NIH grants CA8836(2R.K.S.), CA7468(9P.H.), and GM5752(A.M4.C.andD.L.), by NSF grants 9892 40(L.R.4H.)andDMS-919917(D.L6.),by DOE grant DE-FG03-00R6E992(0R.K..S) andby EU Contracts PL0004 a9nd F51PC04T95001 (P.S.).
PY - 2000
Y1 - 2000
N2 - Purpose: Using published FISH data for chromosome aberration production in human fibroblasts by hard X-rays to test a breakage-and-reunion model. Methods: The model assumed pairwise misrejoining, random apart from proximity effects, of DNA double-strand break (DSB) free ends. CAS (chromosome aberration simulator) Monte Carlo computer software implementing the model was modified to use a distance algorithm for misrejoining instead of using DSB interaction sites. The modification (called CAS2) allowed a somewhat more realistic approach to large-scale chromatin geometry, chromosome territories and proximity effects. It required adding a third adjustable parameter, the chromosome territory intersection factor, quantifying the amount of intertwining among different chromosomes. Results: CAS2 gave somewhat better results than CAS. A reasonable fit with a few discrepancies was obtained for the frequencies at three different radiation doses of many different aberration types and of aberrations involving various specific chromosomes in a large data set using one-paint FISH scoring. The optimal average chromosome territory intersection factor was ~ 1.1, indicating that, for an arbitrarily chosen location in the nucleus, on average slightly more than two chromosomes have very nearby loci. Without changing the three parameter values, a fit was also obtained for a corresponding, smaller, two-paint data set. Conclusions: A random breakage-and-reunion model incorporating proximity effects by using a distance algorithm gave acceptable approximations for many details of hard X-ray aberration patterns. However, enough discrepancies were found that the possibility of an additional or alternate formation mechanism remains.
AB - Purpose: Using published FISH data for chromosome aberration production in human fibroblasts by hard X-rays to test a breakage-and-reunion model. Methods: The model assumed pairwise misrejoining, random apart from proximity effects, of DNA double-strand break (DSB) free ends. CAS (chromosome aberration simulator) Monte Carlo computer software implementing the model was modified to use a distance algorithm for misrejoining instead of using DSB interaction sites. The modification (called CAS2) allowed a somewhat more realistic approach to large-scale chromatin geometry, chromosome territories and proximity effects. It required adding a third adjustable parameter, the chromosome territory intersection factor, quantifying the amount of intertwining among different chromosomes. Results: CAS2 gave somewhat better results than CAS. A reasonable fit with a few discrepancies was obtained for the frequencies at three different radiation doses of many different aberration types and of aberrations involving various specific chromosomes in a large data set using one-paint FISH scoring. The optimal average chromosome territory intersection factor was ~ 1.1, indicating that, for an arbitrarily chosen location in the nucleus, on average slightly more than two chromosomes have very nearby loci. Without changing the three parameter values, a fit was also obtained for a corresponding, smaller, two-paint data set. Conclusions: A random breakage-and-reunion model incorporating proximity effects by using a distance algorithm gave acceptable approximations for many details of hard X-ray aberration patterns. However, enough discrepancies were found that the possibility of an additional or alternate formation mechanism remains.
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U2 - 10.1080/09553000050201064
DO - 10.1080/09553000050201064
M3 - Article
C2 - 11133039
AN - SCOPUS:0033635874
SN - 0955-3002
VL - 76
SP - 1579
EP - 1588
JO - International Journal of Radiation Biology
JF - International Journal of Radiation Biology
IS - 12
ER -