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Investigating the within-host diversity of SARS-CoV-2 and its implications for transmission dynamics - NU/LSHTM project

Title of PhD project / theme

Investigating the within-host diversity of SARS-CoV-2 and its implications for transmission dynamics

Supervisory team

LSHTM:

Damien Tully (Lead) Damien.Tully@lshtm.ac.uk

Stéphane Hué Stephane.Hue@lshtm.ac.uk

Nagasaki University:

Shingo Inoue samakirice2012@gmail.com

Nabeshima Takeshi mtmikami@tm.nagasaki-u.ac.jp

Chris Smith Christopher.Smith@lshtm.ac.uk

Brief description of project / theme

The ongoing COVID-19 pandemic has witnessed the generation of over 150,000 genomes of the causative agent, the virus SARS-CoV-2, across the globe. To date, the focus of most genomic studies has been at the population level, i.e. on genetic changes observed in the viral consensus genome which represent the dominant variation within infected individuals. Although such data has been key to understanding the spread and evolution of the virus [1], the intra-host evolutionary dynamics of SARS-CoV-2 remain poorly understood [2].

The aim of this PhD project is to utilize publicly-available raw sequencing datasets (Amplicon and RNA-Sequencing data) to understand the full underlying within-host diversity of the virus and its potential impact on transmission, pathogenesis and vaccine design. Specifically, this project will use phylogenetic methods to evaluate (1) whether SARS-CoV-2 within-host diversity can provide further resolution for identifying transmission clusters and (2) whether any inferences on the direction of transmission can be made with high statistical support, as is done for other viruses [3]. To gain further insights into how SARS-CoV-2 within-host dynamics affects which viral variants are transmitted, we will search for genomic signatures of transmission from known households [4] and outbreaks [5] and explore whether factors such as host’s age, sex, geographical location, infection status (asymptomatic, symptomatic) and clinical outcome are related to viral genetic diversity.

[1] Worobey M, Pekar J, Larsen BB, Nelson MI, Hill V, Joy JB, Rambaut A, Suchard MA, Wertheim JO, Lemey P. The emergence of SARS-CoV-2 in Europe and North America. Science. 2020 Sep 10:eabc8169. doi: 10.1126/science.abc8169.

[2] Villabona-Arenas CJ, Hanage WP, Tully DC. Phylogenetic interpretation during outbreaks requires caution. Nat Microbiol. 2020 Jul;5(7):876-877. doi: 10.1038/s41564-020-0738-5.

[3] Ratmann O, Grabowski MK, Hall M, Golubchik T, Wymant C, Abeler-Dörner L, Bonsall D, Hoppe A, Brown AL, de Oliveira T, Gall A, Kellam P, Pillay D, Kagaayi J, Kigozi G, Quinn TC, Wawer MJ, Laeyendecker O, Serwadda D, Gray RH, Fraser C; PANGEA Consortium and Rakai Health Sciences Program. Inferring HIV-1 transmission networks and sources of epidemic spread in Africa with deep-sequence phylogenetic analysis. Nat Commun. 2019 Mar 29;10(1):1411. doi: 10.1038/s41467-019-09139-4.

[4] Rockett RJ, Arnott A, Lam C, Sadsad R, Timms V, Gray KA, Eden JS, Chang S, Gall M, Draper J, Sim EM, Bachmann NL, Carter I, Basile K, Byun R, O'Sullivan MV, Chen SC, Maddocks S, Sorrell TC, Dwyer DE, Holmes EC, Kok J, Prokopenko M, Sintchenko V. Revealing COVID-19 transmission in Australia by SARS-CoV-2 genome sequencing and agent-based modeling. Nat Med. 2020 Sep;26(9):1398-1404. doi: 10.1038/s41591-020-1000-7.

[5] Sekizuka T, Itokawa K, Kageyama T, Saito S, Takayama I, Asanuma H, Nao N, Tanaka R, Hashino M, Takahashi T, Kamiya H, Yamagishi T, Kakimoto K, Suzuki M, Hasegawa H, Wakita T, Kuroda M. Haplotype networks of SARS-CoV-2 infections in the Diamond Princess cruise ship outbreak. Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):20198-20201. doi: 10.1073/pnas.2006824117.

The role of LSHTM and NU in this collaborative project

The LSHTM have extensive experience in viral genomic studies, next-generation sequencing and phylogenetic analyses. With professional supervision from researchers at NU the student will gain the expertise of epidemiological, clinical tropical medicine and virology research that will be needed to meet the objectives of the project. The PhD student will spend time in the UK and in Japan and both institutions will work together on study design, analysis and dissemination of findings. 

Particular prior educational requirements for a student undertaking this project

The ideal candidate will hold a masters or undergraduate (minimum) degree.

Prior experience with viral sequence data, bioinformatics and a knowledge of molecular evolution is preferred. Technical expertise with at least one computer coding language (ideally python or R) is also highly desirable. Verbal and written English proficiency are required.

Since this project is at the forefront of research on the use of phylogenetics for a newly emerged viral pathogen, a high degree of personal motivation is essential.

Skills we expect a student to develop/acquire whilst pursuing this project

The student is expected to develop a number of key skills including the handling and analysis of high-throughput viral genetic data, the analysis of viral molecular evolution and phylogenetic reconstruction. In addition, the student will build skills in epidemiology, programming, big data analyses, scientific communication (written and oral) and grant writing.