Poster #68 - Ian Deosaran

Using the substitution-mutation rate ratio test (c/µ) and the Near Neutral Balanced Selectionist Theory (NNBST) to Analyze the Mutational Spectrum of Monkeypox Virus

Deosaran, I., & Wu, C. Department of Chemistry and Biochemistry & Department of Biological & Biomedical Sciences, Rowan University, Glassboro, NJ 08028, USA

Monkeypox virus (MPXV) is a zoonotic orthopoxvirus closely related to the variola virus, which causes smallpox. Monkeypox has emerged as a significant public health concern in recent years, particularly in Central and East Africa. Understanding the molecular evolution of MPXV is integral for the development of antivirals to combat the virus. To accomplish this we applied our substitution-mutation rate ratio test (c/μ), where μ is meticulously approximated and independent of genetic codon tables and Markov mutation models, to explicate the molecular evolution of MPXV using empirical sequence data. c/μ is powerful to quantify the fractions of different mutation types at each nucleotide site in a genome, which we have previously demonstrated using SARS-COV-2 genomic sequence data. c/μ analysis revealed the MPXV genome, Translated Region and Inverted Terminal Repeats exhibited an L-shaped c/μ Distribution of Fitness Effects, substitution timelines exhibiting molecular clock and low percentage of strictly neutral mutations. These findings are inconsistent with conventional Neo-Darwinism Selectionist Theory, Kimura's Neutral Theory and Ohta's Nearly-Neutral Theory of molecular evolution but are consistent with Nearly-Neutral Balanced Selectionist Theory (NNBST), which suggests the balancing of nearly neutral mutations produce the molecular clock instead of strictly neutral mutations, challenging the core tenants of natural selection and genetic drifting mechanisms of evolution. The top mutations identified through c/μ > 1 are mostly consistent with their literature-reported adaptive and deleterious mutation effects. Molecular modeling of top mutation effects identified through c/μ illustrated interest in targeting the B6R surface glycoprotein, as increased binding affinity to monoclonal antibodies was discovered in-vitro, providing both insights into MPXV drug development and additional support to the c/μ test in probing viral evolution.