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Generation and Comparative Genomics of Synthetic Dengue Viruses

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Comparative Genomics (RECOMB-CG 2017)

Part of the book series: Lecture Notes in Computer Science ((LNBI,volume 10562))

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Abstract

Synthetic virology is an important multidisciplinary scientific field, with emerging applications in biotechnology and medicine, aiming at developing methods to generate and engineer synthetic viruses. Here we demonstrate a full multidisciplinary pipeline for generation and analysis of synthetic RNA viruses and specifically apply it to Dengue virus type 2 (DENV-2). The major steps of the pipeline include comparative genomics of endogenous and synthetic viral strains. In particular, we show that although the synthetic DENV-2 viruses were found to have lower nucleotide variability, their phenotype, as reflected in the study of the AG129 mouse model morbidity, RNA levels, and neutralization antibodies, is similar or even more pathogenic in comparison to the wildtype master strain. These results may suggest that synthetic DENV-2 may enhance virulence if the correct sequence is selected. The approach reported here can be used for understanding the functionality and the fitness effects of any set of mutations in viral RNA. It can be also used for editing RNA viruses for various target applications.

E. Goz and Y. Tsalenchuck—Equal contribution.

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Acknowledgment

E.G. is supported, in part, by a fellowship from the Edmond J. Safra Center for Bioinformatics at Tel-Aviv University. T.T. is partially supported by the Minerva ARCHES award.

Author information

Authors and Affiliations

  1. Department of Biomedical Engineering, Tel-Aviv University, Ramat Aviv, Israel

    Eli Goz, Shimshi Atar & Tamir Tuller

  2. SynVaccine Ltd., Ramat Hachayal, Tel Aviv, Israel

    Eli Goz, Yael Tsalenchuck, Rony Oren Benaroya, Tahel Altman & Tamir Tuller

  3. Institute for Antiviral Research, Utah State University, Logan, UT, USA

    Justin Julander

  4. Sagol School of Neuroscience, Tel-Aviv University, Ramat Aviv, Israel

    Tamir Tuller

Authors
  1. Eli Goz
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  2. Yael Tsalenchuck
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  4. Shimshi Atar
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  7. Tamir Tuller
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Correspondence to Tamir Tuller .

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Editors and Affiliations

  1. University of Campinas, Campinas, São Paulo, Brazil

    Joao Meidanis

  2. Rice University, Houston, Texas, USA

    Luay Nakhleh

Appendix: Supplementary Material

Appendix: Supplementary Material

  1. 1.

    No difference in various genomic features in 100 codon regions around SNV compared to regions that do not contains SNVs

    figure a
  2. 2.

    Multiple alignment of 618 DENV-2 genomes analyzed in this study - conservation scores

Multiple alignment conservation score was defined by us as an average sum-of-pair score (SP). For the i-th column in the alignment we define P ijk  = 1 for every pair A ij and A ik of elements (either nucleotides of amino acids, depending on the type of the aligned sequences) which are equal to each other and P ijk  = 0 otherwise. The score Si for the ith column is

$$ S_{i} = \frac{1}{{N\left( {N - 1} \right)/2}}\mathop \sum \limits_{j = 1}^{N} \mathop \sum \limits_{k = j + 1}^{N} P_{ijk} $$

and the SP for the alignment is:

$$ SP = \frac{1}{M}\mathop \sum \limits_{i = 1}^{M} S_{i} $$

The following values summarize the SP scores for the multiple alignment of 618 DENV-2 coding sequences analyzed in this study: SP(amino acids) = 0.97, SP(nucleotides) = 0.94

  1. 3.

    List of regions selected for strong/weak folding energy used in this study

Coordinates of regions predicted to be selected for strong/weak folding energy can be found in the following tables (see details in reference [16] in main text):

Each row in a file corresponds to one region (number of rows = number of regions) and contains 3 comma separated values x, y, z in the following order:

Region start coordinate, region end coordinate, maximum folding selection conservation index (FSCI) in the cluster.

The coordinates are given with respect to the start of the polyprotein coding sequence in the reference genome NC_001474.2. E.g., coordinates x, y for some region correspond to the nucleotides at x-th and y-th positions in the coding sequence of NC_001474.2

figure bfigure b

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Goz, E. et al. (2017). Generation and Comparative Genomics of Synthetic Dengue Viruses. In: Meidanis, J., Nakhleh, L. (eds) Comparative Genomics. RECOMB-CG 2017. Lecture Notes in Computer Science(), vol 10562. Springer, Cham. https://doi.org/10.1007/978-3-319-67979-2_3

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  • DOI: https://doi.org/10.1007/978-3-319-67979-2_3

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