Unravelling genotypic and phenotypic variation in helminth populations

Helminth infections affect over 1.5 billion people and countless animals globally, causing significant disease burdens such as pain, disability, developmental delays, and, in severe cases, death. Consequently, human helminth infections are the target of global mass drug delivery campaigns, and in veterinary settings, hundreds of millions of animals are persistently treated with anthelmintic drugs to prevent and cure infections. Helminths' incredible ability to survive and adapt lies in their capacity to generate and maintain significant genetic variation upon which selection can act, which in turn determines their adaptive potential. The genetic basis for this adaptive potential is, however, poorly understood. This major knowledge gap, largely due to the high genetic diversity and experimental intractability of most helminth species, limits our ability to understand these processes. Overcoming this challenge is crucial for successfully treating disease and predicting the outcomes of long-term control programmes. In the first phase of my Future Leaders Fellowship, I used the sheep gastrointestinal parasite Haemonchus contortus as a genetically tractable, natural host-parasite system to understand the genetic mechanisms underpinning parasite adaption. In the next phase of my FLF, I will extend this work to focus on more complex, natural helminth populations that infect humans and animals around the world. This work seeks to better characterise genetic diversity in natural helminth populations, understand how parasites adapt to host and environmental change, and define drug treatment responses of parasites in the context of their natural, complex environment. To address the new knowledge gaps posed above, I have three key aims: To understand the strengths and weaknesses of using single genomes versus multi-genome assemblies to understand global variation in parasites. To measure the species diversity of helminth populations and their response to drug treatment and association with disease To determine the genetics of drug treatment responses by helminths, accounting for host-parasite interactions. The first aim addresses both technical and biological challenges using reference genomes to understand genetic variation. Reference genomes are a fundamental cornerstone of genomics, yet they can strongly bias the interpretation of data depending on the quality, contiguity, and completeness of the genome assembly. This work will define the strengths and limitations of a single reference genome versus multiple genome references for understanding global genetic variation and will set a precedent for future studies using large-scale genomics to address genetically diverse organisms such as helminths. Addressing the second aim is fundamentally important in understanding what defines a population of parasites and how that population changes over time. This work has the potential to revolutionise the use of high-throughput, information-rich tools to diagnose and monitor helminth populations infecting billions of people worldwide. The third aim addresses the relationship between genetic and phenotypic change in parasite populations. Increasing use of drugs to control parasites worldwide represents a significant selection pressure that may lead to drug resistance; however, it is currently unknown to what degree the host impacts exposure or response to treatment. Moreover, gastrointestinal helminths live in a complex environment surrounded by the host microbiome, and it is unknown to what degree the microbiome protects or increases susceptibility to helminth infection. Understanding these relationships could lead to alternative approaches to support treatment or recovery from helminth infections, which is critically important in low-resource settings where these infections disproportionally and severely impact childhood development and nutrition.