– 3-year PhD funded by CNRS for genomics and transcriptomics data analysis of the Plasmodium falciparum malaria parasite.
– In a young dynamic team based in Montpellier, South of France, with many worldwide collaborators
– Keywords: population genetics & genomics, single-cell RNA-seq, molecular epidemiology, antigenic variation.
Most malaria deaths are caused by Plasmodium falciparum, a unicellular eukaryote parasite transmitted by Anopheles mosquitoes. Despite the heavy burden of the disease, most human infections are asymptomatic (afebrile) and can last for months/years. In regions where malaria is seasonal, such as in The Gambia, West Africa, these asymptomatic infections probably act as a reservoir during the dry season when there is no or little transmission. Long-lasting infections could be turned to our advantage if we study them as a new host-pathogen interaction model, by regular sampling of an asymptomatic volunteer, investigating the parasite biology in its natural environment. More details on our research can be found on this on this post.
From 2014 to 2017, we collected fingerprick blood samples every 3 months in a population of ~1000 inhabitants in a Gambian village. At the start of the 2017 dry season, we also recruited a cohort of 50 volunteers who were all asymptomatic carriers for P. falciparum. Monthly blood samples were taken for 6 months over the entire dry season. A total of 435 blood samples were collected, including this time series of monthly samples from the same volunteers over a 6-month period. This dataset represents a unique opportunity to address novel questions about the parasite biology. More specifically, we are interested in discovering how the parasite establishes a chronic infection, through changes at the transcriptomic levels.
Projects here under are only a suggestion, the exact project will be defined based on the student’s abilities and expertise. Your work will be entirely computer-based, but you will be part of a team mixing ‘dry’ and ‘wet’ lab research.
Project 1: P. falciparum population genetics and genomics
As outlined above, we collected blood samples all year round from a village over two and a half year. P. falciparum DNA was extracted and genotyped and/or whole genome sequenced in collaboration with MalariaGEN at the Sanger Institute. A dataset of about 400 parasite DNA barcodes and 100 parasite genomes is now available. Here we want to describe the first parasite genomes sequenced from asymptomatic infections, and investigate the impact of the dry season selective pressure on the parasite population. This longitudinal approach also allows us to tackle the question of the duration of a P. falciparum chronic infection. Preliminary analysis revealed, for example, that a child was infected asymptomatically with the same P. falciparum strain for over 2.5 years. This overturns the dogma on duration of a P. falciparum infection.
Your task is to fully characterise the parasite population genetic diversity, using genotyping, genomic and epidemiologic data. The analysis will include PCA, Fst, chromosome painting, EHH, iHS, etc.
Project 2: Can P. falciparum sense its environment and adapt to it via transcriptional regulation?
In areas where rains are seasonal, two distinct patterns of malaria fluctuate, from high prevalence with a wide range of clinical outcome in the wet season, to low prevalence mainly asymptomatic in the dry season. The mechanisms allowing the parasite to survive in chronic infections during the dry season, and restart transmission as vector population increases with the ensuing wet season, remain to be investigated. We hypothesize that P. falciparum is able to sense its environment and dampens its virulence with seasonality.
In collaboration with colleagues at the London School of Hygiene & Trop Med, we are currently optimizing a single-cell RNA-seq approach to P. falciparum.
Your task, using ‘bulk’ and single-cell parasite transcriptomes, is to identify differentially regulated genes in the dry vs wet season, in symptomatic vs asymptomatic infections, and identify putative candidates involved in cell growth. The analysis will include normalization, PCA for clustering and tSNE for representation, correlating bulk and single cell data with Pearson correlation, drawing gene co-expression networks within each identified cluster (subpopulation), etc.
The transcriptome dataset, which will be linked with in vitro growth assays, will be crucial in understanding how the parasite successfully establishes a chronic infection over the dry season, yet triggers a new epidemic over the following transmission season. It also has the potential of identifying dormant parasites, a discovery that would guide malaria elimination strategies.
– Population genomics with over 100 P. falciparum genomes collected from severe malaria or uncomplicated cases in Benin. In collaboration with Gwladys Bertin (Paris), Joe Zhu and Jacob Garcia (Oxford, UK).
– Identification of the micro-indels and structural variant mutation rates in P. falciparum in vitro using data from “clone trees” (Hamilton 2016 NAR and unpublished data).
– And many, many more…
Your skills (essentials)
- A Master in biostatistics / bioinformatics / population genetics, or in molecular biology with a strong background in biostatistics and programming
- Demonstrated experience in “Omics” data analysis
- Able to work independently
- Great communication skills in English
- Stay focused on answering a specific biological question, from the initial analysis to publication
- Passionate about scientific discoveries
Your skills (desirable)
- Knowledge about malaria biology and population genetics
- Wet-lab experience is a plus, but not essential
- Willing to supervise a Master student in bioinformatics / epidemiology
- Participate actively in the lab and institute life
Who we are
Antoine Claessens (PI) is a malariologist who trained at Edinburgh University, the Sanger Institute, LSHTM and the MRC-Gambia. He recently joined Montpellier University as a “Chargé de Recherche INSERM”. He was awarded an ATIP and an ANR-JC.
Currently the team consists of one post-doc and one Master student. Two PhD students will be recruited around Sep 2019, one for lab-based research and one for data analysis (this advert). Each year, 2 Master students in bioinformatics / epidemiology will join the team for up to 6 months. We are likely to recruit another post-doc towards late 2019.
What you can expect / what we can offer
The 3-year PhD will be funded by CNRS (substantially higher salary than other sources of funding). You will be part of DIMNP and you will closely interact with experienced bioinformaticians from the bioinformatics platform and with population geneticists from MIVEGEC. Both ‘UMR’ are very international, with highly competent and friendly scientists. More generally, Montpellier is a large hub for research in Life Sciences, particularly in the field of evolutionary biology.
I will try my best to transmit my passion about P. falciparum biology; you might find yourself dreaming about var genes too. As we will be a small team, you can expect more of my time dedicated to you, but I do not want to micromanage. I expect you to work hard, yet you will have freedom on working hours etc. All our current research projects are in collaboration with international laboratories, there is an opportunity to work in the USA/UK for a short period of time. If you are planning to stay in academic research, I will help you secure a post-doc position.
If you are from abroad: Being able to speak French is not a requirement; your colleagues will speak English fluently. We will help you with the administrative task of moving to France. Many aspects of the cost of life, such as childcare, are relatively cheap. Most importantly, the quality of life in South of France is hard to beat!
Key collaborators and recent publications:
Umberto D’Alessandro (MRC-Gambia)
Teun Bousema (Radboud UMC, Netherlands)
David Conway (LSHTM, UK)
Dominic Kwiatkowski, MalariaGEN, Lia Chappell (Sanger Institute)
Franck Prugnolle and Virginie Rougeron (MIVEGEC, Montpellier)
Arthur Talman (Sanger / MIVEGEC)
Silvia Portugal (Heidelberg, Germany)
Ian Cheeseman (Texas Bio Med, USA)
|Claessens A, Adams Y, …, Bozdech Z and Rowe JA. Group A-like PfEMP1s mediate cytoadherence to human brain endothelial cells. Proc Natl Acad Sci USA 2012.
|How P. falciparum bind to blood microvessels in vitro (microarray transcriptomic approach)
|Claessens A*, Hamilton W*, …, Rayner J, Kwiatkowski D. Generation of antigenic diversity in Plasmodium falciparum by structured rearrangement of var genes during mitosis. PLOS Genetics 2014. *joint first author.
|New chimeric var gene sequences are generated during parasite growth in vitro.
|Hamilton W*, Claessens A*, Otto T, …, Rayner J, Kwiatkowski D. Extreme mutation bias and high AT content in Plasmodium falciparum. Nucleic Acid Research 2016.
|An excess of G:C to A:T transitions explains the AT-richness of P.f. genome
|Claessens A, Affara M, Assefa S, Kwiatkowski D & Conway D. Culture adaptation of malaria parasites selects for convergent loss-of-function mutants. Scientific Reports 2017.
|In vitro culture selects for loss-of-function mutations (genomic approach)
|Claessens A*, Harris LM*, Stanojcic S*, Merrick C. RecQ helicases in the malaria parasite Plasmodium falciparum affect genome stability, gene expression patterns and DNA replication dynamics. PLOS Genetics 2018.
|Helicase PfWRN maintains genome integrity
Interested in applying? Please send an email to firstname.lastname@example.org with subject “PhD #0002 – keep me updated”. Starting date: September 2019 (to be discussed).