Although chromosomes are the largest and most important of all biomolecules, comparatively little is known about their large-scale geometric configurations and motions during cell cycle interphase. Radiation-produced chromosome aberrations, especially the rich variety of aberrations that can no be scored using fluorescent in situ hybridization techniques, are informative about chromosome structure during G0/G1, because the relative frequency of different aberration types is influenced by chromosome geometry and motion. Aberrations are also robustly implicated in all the medical aspects of radiobiology, including carcinogenesis, killing of cells in tumors or surrounding normal tissues, and retrospective biodosimetry. In particular, exchange-type, intrachromosomal, chromosome aberrations (chromosome interchanges, i.e., inversions and ring/deletion events) are important for all these reason, but are as yet less well understood, experimentally and theoretically, than are other aberration types. Intrachanges are important especially because they are formed much more frequently than randomness estimates based on genomic content would predict. The high frequency stems fro proximity effects, which enhance the probability of pairwise DSB illegitimate recombination if the two DSBs are initially formed close together, as they typically are if both DSBs are on the same chromosome. For example, inversions play a role in carcinogenesis similar to that of translocations, and they may be almost as frequent as translocations because there are so many small inversions; similarly, small deletions can be carcinogenic. The grant will undertake theoretical and computer calculations, relating proximity effects fo intrachanges at low or high LET to large-scale interphase chromatin geometry. Recent polymer models of large-scale chromatin conformation during G0/G1 will be extended to incorporate chromatin tethering and chromatin motion. The polymer models lead to predictions on the intrachange size spectrum; for example estimates on the frequency of intrachanges too small to be observed microscopically can be derived from the observed ratio of intra-arm to inter-arm intrachanges. Mechanistic computer and biophysical modeling is proposed as a comparatively inexpensive way to maximize information obtainable on chromatin geometry from the rapidly increasing database on aberrations, and to help guide experiments.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Radiation Study Section (RAD)
Program Officer
Pelroy, Richard
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Berkeley
Biostatistics & Other Math Sci
Schools of Arts and Sciences
United States
Zip Code
Sachs, Rainer K; Arsuaga, Javier; Vazquez, Mariel et al. (2002) Using graph theory to describe and model chromosome aberrations. Radiat Res 158:556-67
Vazquez, M; Greulich-Bode, K M; Arsuaga, J et al. (2002) Computer analysis of mFISH chromosome aberration data uncovers an excess of very complicated metaphases. Int J Radiat Biol 78:1103-15
Ponomarev, A L; Cucinotta, F A; Sachs, R K et al. (2001) Monte Carlo predictions of DNA fragment-size distributions for large sizes after HZE particle irradiation. Phys Med 17 Suppl 1:153-6
Ponomarev, A L; Sachs, R K (2001) Radiation breakage of DNA: a model based on random-walk chromatin structure. J Math Biol 43:356-76
Radivoyevitch, T; Kozubek, S; Sachs, R K (2001) Biologically based risk estimation for radiation-induced CML. Inferences from BCR and ABL geometric distributions. Radiat Environ Biophys 40:1-9
Radivoyevitch, T; Sachs, R K; Nikiforov, Y E et al. (2001) On target cell numbers in radiation-induced H4-RET mediated papillary thyroid cancer. Radiat Environ Biophys 40:191-7
Costes, S; Sachs, R; Hlatky, L et al. (2001) Large-mutation spectra induced at hemizygous loci by low-LET radiation: evidence for intrachromosomal proximity effects. Radiat Res 156:545-57
Ponomarev, A L; Brenner, D; Hlatky, L R et al. (2000) A polymer, random walk model for the size-distribution of large DNA fragments after high linear energy transfer radiation. Radiat Environ Biophys 39:111-20
Sachs, R K; Rogoff, A; Chen, A M et al. (2000) Underprediction of visibly complex chromosome aberrations by a recombinational-repair ('one-hit') model. Int J Radiat Biol 76:129-48
Sachs, R K; Levy, D; Chen, A M et al. (2000) Random breakage and reunion chromosome aberration formation model; an interaction-distance version based on chromatin geometry. Int J Radiat Biol 76:1579-88

Showing the most recent 10 out of 15 publications