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bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.05.611453
preprint
3
Article
Human and bats genome robustness under COSMIC mutational signatures
Song Joon-Hyun http://orcid.org/0000-0002-0085-4888

Zeng Ying
Davalos Liliana M http://orcid.org/0000-0002-4327-7697

MacCarthy Thomas
Larijani Mani
Damaghi Mehdi http://orcid.org/0000-0002-7744-6161

13 9 2024
2024.09.05.611453https://creativecommons.org/licenses/by-nc/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.05.611453
nihpp-2024.09.05.611453.pdf
Carcinogenesis is an evolutionary process, and mutations can fix the selected phenotypes in selective microenvironments. Both normal and neoplastic cells are robust to the mutational stressors in the microenvironment to the extent that secure their fitness. To test the robustness of genes under a range of mutagens, we developed a sequential mutation simulator, Sinabro, to simulate single base substitution under a given mutational process. Then, we developed a pipeline to measure the robustness of genes and cells under those mutagenesis processes. We discovered significant human genome robustness to the APOBEC mutational signature SBS2, which is associated with viral defense mechanisms and is implicated in cancer. Robustness evaluations across over 70,000 sequences against 41 signatures showed higher resilience under signatures predominantly causing C-to-T (G-to-A) mutations. Principal component analysis indicates the GC content at the codon's wobble position significantly influences robustness, with increased resilience noted under transition mutations compared to transversions. Then, we tested our results in bats at extremes of the lifespan-to-mass relationship and found the long-lived bat is more robust to APOBEC than the short-lived one. By revealing APOBEC as the prime driver of robustness in the human (and other mammalian) genome, this work bolsters the key potential role of APOBECs in carcinogenesis, as well as evolved countermeasures to this innate mutagenic process. It also provides the baseline of the human and bat genome robustness under mutational processes associated with cancer.
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pmc
