Detection of germline variants in human population chronically exposed to high level natural background radiation in Kerala coast

BACKGROUND: Genetic effects due to long term exposure to low doses of ionizing radiation (LDIR) in humans are not well understood. Human population living in high level natural radiation areas (HLNRAs) of Kerala coast in India are continuously exposed to chronic LDIR emanating from monazite containing beach sand for many generations. The background radiation level in this area varies from < 1.0 to 45mGy/year. The people residing in HLNRAs sometimes receives background radiation dose which is approximately 10-40 times higher than the people living in adjacent normal level natural radiation areas (NLNRAs). This population provides a unique opportunity to identify, if present, a mutational signature due to chronic low-dose radiation exposure in humans. We have employed whole exome sequencing approach to determine germline mutational changes in the lymphocytes of healthy individuals from HLNRAs (mean background dose: 31.8 ± 5.4 mGy/year, mean age: 43.0 ± 5.9 years) and compared them with healthy individuals from NLNRAs (mean background dose: 0.9 ± 0.2 mGy/year, mean age: 43.0 ± 11.3 years). RESULTS: Our results revealed that the overall number of single nucleotide variants (SNVs) and insertions/deletions (indels) were not significantly different in HLNRA (7744 SNVs, 880 indels) and NLNRA (7951 SNVs, 856 indels) groups. A similar number of protein affecting mutations (PAMs) were observed in HLNRA (1925) and NLNRA (2082) individuals. Interestingly, several unique SNVs were identified in both the groups. In HLNRA, unique SNVs were overrepresented in genes involved in important biological pathways such as DNA repair (EXO1, PARP2, DDB1, POLQ, LIG1), epigenetic modification (KDM5D, SETDB2, KMT2B, BRD8, SIRT1), cell cycle progression (CDK14, CCND1) etc. Furthermore, significant predominance of C > T transitions which were unique to HLNRA group was observed preferentially at CpG dinucleotide regions. Analysis with REVEL and AloFT tools did not show any increase in potentially pathogenic mutations including those involved in carcinogenesis in HLNRA individuals exposed to chronic radiation. CONCLUSION: This study did not show any significant changes in genetic variants due to long term exposure to LDIR in human population living in HLNRAs of Kerala coast. However, presence of unique SNVs and C > T transitions in CpG islands of HLNRA individuals indicate the possible role of epigenetic mechanisms i.e. DNA methylation in response to chronic LDIR in this population. This study significantly enhances the current understanding of radiation induced genetic changes and associated cancer risk in human population.