Ionising radiation and genetic risks. XVI. A genome-based framework for risk estimation in the light of recent...

The aim of this paper is to examine a framework for computational modelling of genetic risks of radiation using the human genome as the starting point. The convergence of insights gained from knowledge of repair of DNA double-strand breaks in mammalian somatic cells and of the architecture of the human genome makes this framework possible. We inquire whether the concepts underlying the framework remain valid in the light of advances in DNA repair studies and human genome research during the past five years.

We reviewed the advances in DNA repair studies and genome research, and in the latter, we focused on advances subsequent to the discovery of copy number variation in the genome which include an assessment of its nature, extent, mechanisms involved and its role in health and disease.

Our study shows that the concepts underlying our framework are valid. More specifically, the view that segmental duplications (which are abundant in the genome) can serve as entry points for modelling the origin of radiation-induced deletions via non-allelic homologous recombination in germ cells of human female remains robust.

We posit that progress in genetic risk estimation in the 21st century will be driven mainly by the integration of genomic knowledge with that of DNA repair mechanisms, the latter involved in the origin of spontaneously-occurring deletions (which cause genomic disorders in humans) and of radiation-induced deletions in mammalian cells and extending the insights to irradiated human germ cells.