Poster Presentation 50 Years Shine-Dalgarno Symposium 2023

Incorporating RNA Secondary-Structure to Improve Viral Phylogenetics and Drug-Target Design (#106)

Rosa E Prahl 1 , Denis Bauer 1 2 3 , Laurence Wilson 1 2
  1. The Australian e-Health Research Centre, Transformational Bioinformatics Group, CSIRO, Black Mountain/ Acton, ACT, Australia
  2. Applied Biosciences, Faculty of Science and Engineering/ Macquarie University, Sydney, New South Wales, Australia
  3. Department of Biomedical Sciences, Macquarie University, Sydney, New South Wales, Australia

Understanding the evolutionary history of viruses, particularly RNA viruses such as SARS-CoV-2, is critical to understanding them and developing effective treatments such as vaccinations. Most evolutionary methods rely on phylogenetic analyses based on the RNA sequences. Previous studies, however, have shown that incorporating the RNA secondary structures (S2s) can improve the resolution power of phylogenetic trees (Patiño-Galindo et al. 2018). In this research work, we aimed to develop a method which combined phylogenetic analysis with S2s to better understand how a virus is evolving. As a proof-of-concept, we analysed the SARS-CoV-2, Human Immunodeficiency Virus (HIV) and Hepatitis C Virus (HCV) phylogenies. The RNA structures from HIV and HCV were previously obtained experimentally from Siegfried et al. 2014 and Mauger et al. 2015, respectively. The RNA structures for SARS-CoV-2 were revealed by high-throughput studies from Huston et al. (2020) and Lan et al. (2020) (Reviewed in Manfredonia and Incarnato 2020). Incorporation of S2s allows us to identify regions of the genome under increased selection pressure to maintain both the encoded information and potentially functional secondary structures. These regions could potentially be ideal targets for intervention strategies such as vaccines, as the increased selection pressure on them makes it harder for the virus to develop an escape mutation. This approach based on RNA models and S2s will be fundamental for developing a new method for reconstructing phylogenetic studies of human viruses where molecular clock models and diversification rates are also implemented.

  1. Huston NC, Wan H, de CA Tavares R, Wilen C, and Pyle AM (2020) Comprehensive in-vivo secondary structure of the SARS-CoV-2 genome reveals novel regulatory motifs and mechanisms. Biorxiv. Doi: 10.1101/2020.07.10.197079.
  2. Kirtipal N, Bharadwaj S, and Kang SG (2020) From SARS to SARS-CoV-2, insights on structure, pathogenicity and immunity aspects of pandemic human coronaviruses. Infect Genet Evol. 85:104502. Doi: 10.1016/j.meegid.2020.104502.
  3. Lan TCT, Allan MF, Malsick LE, Khandwala S, Nyeo SSY, Bathe M, Griffiths A, and Rouskin S (2020) Structure of the full SARS-CoV-2 RNA genome in infected cells. Biorxiv. Doi: 10.1101/2020.06.29.178343.
  4. Mauger DM, Golden M, Yamane D, Williford S, Lemon SM, Martin DP, and Weeks KM (2015) Functionally conserved architecture of hepatitis C virus RNA genomes. Proc Natl Acad Sci U S A. 112:3692–2697. Doi: 10.1073/pnas.1416266112.
  5. Patiño-Galindo JÁ, González-Candelas F, and Pybus OG (2018) The Effect of RNA Substitution Models on Viroid and RNA Virus Phylogenies. Genome Biol Evol. 10:657–666. Doi: 10.1093/gbe/evx273. Doi: 10.1093/gbe/evx273.
  6. Siegfried NA, Busan S, Rice GM, Nelson JAE, and Weeks KM (2014) RNA motif discovery by SHAPE and mutational profiling (SHAPE-MaP). Nat Methods 11:959–965. Doi: 10.1038/nmeth.3029.