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Following the first wave of SARS-CoV-2 infections in spring 2020, Europe experienced a resurgence of the virus starting late summer that was deadlier and more difficult to contain. Relaxed intervention measures and summer travel have been implicated as drivers of the second wave. Here, we build a phylogeographic model to evaluate how newly introduced lineages, as opposed to the rekindling of persistent lineages, contributed to the COVID-19 resurgence in Europe. We inform this model using genomic, mobility and epidemiological data from 10 West European countries and estimate that in many countries more than 50% of the lineages circulating in late summer resulted from new introductions since June 15th. The success in onwards transmission of these lineages is predicted by SARS-CoV-2 incidence during this period. Relatively early introductions from Spain into the United Kingdom contributed to the successful spread of the 20A.EU1/B.1.177 variant. The pervasive spread of variants that have not been associated with an advantage in transmissibility highlights the threat of novel variants of concern that emerged more recently and have been disseminated by holiday travel. Our findings indicate that more effective and coordinated measures are required to contain spread through cross-border travel. The research leading to these results has received funding from the European Research Council under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 725422-ReservoirDOCS) and from the European Union's Horizon 2020 project MOOD (grant agreement no. 874850), and the Bill & Melinda Gates Foundation (OPP1094793 and INV-024911). The Artie Network receives funding from the Wellcome Trust through project 206298/Z/17/Z. PL acknowledges support by the Research Foundation - Flanders ('Fonds voor Wetenschappelijk Onderzoek - Vlaanderen', G066215N, G0D5117N and G0B9317N). GB acknowledges support from the 'lnterne Fondsen KU Leuven'/Internal Funds KU Leuven under grant agreement C14/18/094, and the Research Foundation - Flanders ('Fonds voor Wetenschappelijk Onderzoek - Vlaanderen', G0E1420N). MAS acknowledges support from National Institutes of Health grant U19 Al135995 and R01 Al153044. SD is supported by the Fonds National de la Recherche Scienti(lque (FNRS, Belgium). We also gratefully acknowledge support from NVIDIA Corporation with the donation of parallel computing resources used for this research. Submitted version Preprint version

The human helminth parasite Schistosoma spp. lives in the blood vessels of over 200 million people in Africa, Asia and South-America. The most serious infections are found in children and adolescents who eventually become physically and intellectually compromised, while people who have been infected chronically may develop liver damage, kidney failure or bladder cancer. Despite the availability of a cheap and effective drug, the disease has been largely neglected compared to other more deadly diseases such as HIV/AIDS and malaria, both in terms of disease control and in terms of scientific research. Remedial action is therefore needed to gain insight into the distribution of these parasites at both a local (among humans and villages) and a global geographic scale (across regions or continents). It is essential to understand the factors and dynamics that shape transmission and the impact of selective pressures such as drug treatment. This will provide a theoretical framework that could represent a starting point for better disease control.In this thesis we performed a population genetic study to reveal the distribution of Schistosoma mansoni parasites in the basin of the Senegal River (West Africa). Molecular markers such as microsatellites or single nucleotide polymorphisms serve as ideal tools to track the transmission of parasites and infer their ancestry. However, parasite worms cannot be used as a source for DNA as they are inaccessible within the human blood vessels. A protocol was therefore optimized that allowed the sampling, DNA-extraction and molecular analysis based on low quantities of DNA obtained from individual larval parasites (chapter 2). This optimization was an important first step that enabled us to perform multiple analyses on the same individual parasite with low genotyping error rates.The case study in Northwest Senegal represents one of the most intense epidemic foci of S. mansoni. The parasite invaded this area in 1986 after the construction of two dams on the Senegal River. Parasites were obtained at four time points over a period of 14 years (1993-2007) and from several regions (Northwest Senegal, Southeast Senegal and Mali) to study the nature of the S. mansoni epidemic (chapter 3). Typing of nuclear and mitochondrial markers revealed that parasites from Northwest Senegal have a West-African origin, that they harbor moderate to high levels of genetic diversity, that they increase in population size and that some parasites are genetically different from others (chapter 3). These results suggest that the epidemic of schistosomiasis in Northwest Senegal was probably not elicited by a few S. mansoni parasites, but that the colonization history is much more complex. It is most likely that a multitude of parasites successfully colonized the local human population. Furthermore, most of the parasite genetic variation observed in the region was found within individual human hosts (chapter 4), suggesting that they accumulate a wide range of parasites during their lifetime. However, children appeared to be much more infected by related parasites than adult hosts, who tended to be infected by more genetically diverse parasites. The age-dependent recruitment of genetically diverse parasite infections may be explained by (1) genotype-dependent concomitant immunity that leads to selective recruitment of genetically unrelated worms with host age, and/or (2) the genetic mixing bowl hypothesis, where older hosts have been exposed to a wider variety of parasites than children.Currently the cheap and effective drug praziquantel is used to treat schistosomiasis. However, this could lead to serious bottlenecks in S. mansoni populations, possibly leading to increased inbreeding, low levels of genetic diversity and the random fixation of (possibly deleterious) alleles. The effect of treatment on the genetic composition of S. mansoni populations was therefore studied using data obtained from simulations of an island model at equilibrium (chapter 5) and from naturally collected parasites before and after treatment (chapter 6). Both studies showed that treatment has only a limited effect on the genetic diversity of schistosome populations. Complementary simulations revealed that only a sustained treatment policy could decrease schistosome population sizes and therefore drive the success of a control program.This thesis has shed new light on the factors that shape the distribution of S. mansoni parasites. The main conclusion is that S. mansoni populations harbor substantial levels of genetic diversity, and hence are able to cope with strong selection pressures such as chemotherapeutic treatment. This large evolutionary potential will hamper attempts either to control or to eliminate these parasites, as well as complicate the development of new drugs or vaccines. ACKNOWLEDGEMENTS I SUMMARY III SAMENVATTING V LIST OF ABBREVIATIONS AND LIST OF SYMBOLS VII TABLE OF CONTENTS IX CHAPTER 1 1 GENERAL INTRODUCTION CHAPTER 2 17 OPTIMAL SAMPLE STORAGE AND EXTRACTION PROTOCOLS FOR RELIABLE MULTILOCUS GENOTYPING OF THE HUMAN PARASITE SCHISTOSOMA MANSONI CHAPTER 3 31 INVASION GENETICS OF SCHISTOSOMA MANSONI IN NORTHWEST SENEGAL REVEALS SIGANTURES OF POPULATION EXPANSION CHAPTER 4 51 INBREEDING WITHIN HUMAN SCHISTOSOMA MANSONI: DO HOST-SPECIFIC FACTORS SHAPE THE GENETIC COMPOSITION OF PARASITE INFRAPOPULATIONS? CHAPTER 5 75 FIGHTING A LOSING BATTLE? A SIMULATION-BASED APPROACH TO THE IMPACT OF COMMUNITY-BASED DRUG TREATMENT ON THE GENETIC DIVERSITY OF SCHISTOSOME POPULATIONS CHAPTER 6 89 REGULAR TREATMENTS OF PRAZIQUANTEL DO NOT IMPACT ON THE GENETIC MAKE-UP OF SCHISTOSOMA MANSONI IN NORTHWEST SENEGAL CHAPTER 7 101 GENERAL DISCUSSION GLOSSARY 119 REFERENCES 123 LIST OF PUBLICATIONS 137 status: published

Quantifying the contribution of the various processes that influence population genetic structure is important, but difficult. One of the reasons is that no single measure appropriately quantifies all aspects of genetic structure. An increasing number of studies is analysing population structure using the statistic D, which measures genetic differentiation, next to GST, which quantifies the standardized variance in allele frequencies among populations. Few studies have evaluated which statistic is most appropriate in particular situations. In this study, we evaluated which index is more suitable in quantifying postglacial divergence between three-spined stickleback (Gasterosteus aculeatus) populations from Western Europe. Population structure on this short timescale (10 000 generations) is probably shaped by colonization history, followed by migration and drift. Using microsatellite markers and anticipating that D and GST might have different capacities to reveal these processes, we evaluated population structure at two levels: (i) between lowland and upland populations, aiming to infer historical processes; and (ii) among upland populations, aiming to quantify contemporary processes. In the first case, only D revealed clear clusters of populations, putatively indicative of population ancestry. In the second case, only GST was indicative for the balance between migration and drift. Simulations of colonization and subsequent divergence in a hierarchical stepping stone model confirmed this discrepancy, which becomes particularly strong for markers with moderate to high mutation rates. We conclude that on short timescales, and across strong clines in population size and connectivity, D is useful to infer colonization history, whereas GST is sensitive to more recent demographic events.