Random breakage and reunion chromosome aberration formation model; an interaction-distance version based on chromatin geometry.
OBJECTIVE
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 approximately 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.
Sachs
R K
RK
Department of Mathematics, University of California, Berkeley 94720, USA. sachs@math.berkeley.edu
Levy
D
D
Chen
A M
AM
Simpson
P J
PJ
Cornforth
M N
MN
Ingerman
E A
EA
Hahnfeldt
P
P
Hlatky
L R
LR
D000465:Algorithms; D002843:Chromatin / Q000737:chemistry* / Q000528:radiation effects*; D002869:Chromosome Aberrations; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000528:radiation effects / Q000648:ultrastructure; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008954:Models, Biological; D009010:Monte Carlo Method; D012984:Software; D014965:X-Rays
D002843:Chromatin; D004247:DNA