Hi-C implementation of genome structure for in silico models of radiation-induced DNA damage

Developments in the genome organisation field has resulted in the recent methodology to infer spatial conformations of the genome directly from experimentally measured genome contacts (Hi-C data). This provides a detailed description of both intra- and inter-chromosomal arrangements. Chromosomal intermingling is an important driver for radiation-induced DNA mis-repair. Which is a key biological endpoint of relevance to the fields of cancer therapy (radiotherapy), public health (biodosimetry) and space travel. For the first time, we leverage these methods of inferring genome organisation and couple them to nano-dosimetric radiation track structure modelling to predict quantities and distribution of DNA damage within cell-type specific geometries. These nano-dosimetric simulations are highly dependent on geometry and are benefited from the inclusion of experimentally driven chromosome conformations. We show how the changes in Hi-C contract maps impact the inferred geometries resulting in significant differences in chromosomal intermingling. We demonstrate how these differences propagate through to significant changes in the distribution of DNA damage throughout the cell nucleus, suggesting implications for DNA repair fidelity and subsequent cell fate. We suggest that differences in the geometric clustering for the chromosomes between the cell-types are a plausible factor leading to changes in cellular radiosensitivity. Furthermore, we investigate changes in cell shape, such as flattening, and show that this greatly impacts the distribution of DNA damage. This should be considered when comparing in vitro results to in vivo systems. The effect may be especially important when attempting to translate radiosensitivity measurements at the experimental in vitro level to the patient or human level.Author summary: We have used a technique which allows us to understand how parts of our DNA are organised within a cell nucleus. This technique has previously shown differences in the organisation between different cell-types. In this study, we show that these differences produce significant change in the way our DNA is damaged when exposed to radiation. This is important to understand as one of the primary ways we treat cancer is using radiotherapy. However, whilst we attempt to target the cancer with radiation, some healthy tissue also receives radiation. It is the radiation delivered to the healthy tissue which limits how much radiation we can safely give to the cancer without causing significant side effects in patients. To know how much radiation we can give, over time, we have learnt generally safe amounts of radiation that can be given to healthy tissue. Even so, sometimes patients will still have worse side effects than what we would have predicted. If we want to further improve our treatments and patient safety, we need to better understand how this safe limit varies between each patient. The first step in to fully understanding this process comes from a better understanding of how different cell-types are affected by radiation, which is partly driven by DNA organisation, shown in this work.