Ionizing radiation and genetic risks. XVII. Formation mechanisms underlying naturally occurring DNA deletions in the human genome and their potential relevance for bridging the gap between induced DNA double-strand breaks and deletions in irradiated germ

Our analysis permits the inference that, between them, these five mechanisms can explain nearly all naturally occurring deletions of different sizes identified in the human genome, NAHR and MMBIR being potentially more versatile in this regard. With respect to radiation-induced deletions, the basic studies suggest that those arising as a result of the operation of NHEJ/MMEJ processes, as currently formulated, are expected to be relatively small. However, data on induced mutations in mouse spermatogonial stem cells (irradiation in G0/G1 phase of the cell cycle and DSB repair presumed to be via NHEJ predominantly) show that most are associated with deletions of different sizes, some in the megabase range. There is thus a 'discrepancy' between what the basic studies suggest and the empirical observations in mutagenesis studies. This discrepancy, however, is only an apparent but not a real one. It can be resolved by considering the issue of deletions in the broader context of and in conjunction with the organization of chromatin in chromosomes and nuclear architecture, the conceptual framework for which already exists in studies carried out during the past fifteen years or so. In this paper, we specifically hypothesize that repair of DSBs induced in chromatin loops may offer a basis to explain the induction of deletions of different sizes and suggest an approach to test the hypothesis. We emphasize that the bridging of the gap between induced DSB and resulting deletions of different sizes is critical for current efforts in computational modeling of genetic risks.