Organisation and regulation of parasitism-associated genomic islands

It is estimated that at least 40% of animals have a parasitic lifestyle. Parasites contribute to a huge global disease burden, for example, soil-transmitted helminths such as Strongyloides parasites, infect 1.5 billion people globally. Investigating the genomic and genetic basis of parasitism is important for understanding the fundamental principles of what makes a parasite a parasite and the evolution of parasitism. Furthermore, understanding how the genes involved in parasitism are regulated and organised can inform the development of control strategies and treatments for parasite infections. We have discovered that genes important for parasitism are physically arranged in clusters or 'parasitism-associated genomic islands' (PGIs) in the genome. Organisation of these genes into PGIs is likely to be important in rapidly turning on these genes during infection. This is important for the parasite so that it can rapidly respond to, and survive in, the harsh environment of its host. In this project we will investigate PGIs in a parasitic worm which infects the gut of mammals. We aim to investigate the common features and differences of PGIs across several different species of closely related gut worm parasites (Strongyloides spp.) to identify features in PGIs that are shared or different. We will use DNA and RNA sequencing to generate data to carry out this aim. We will also carry out experiments to explore how PGIs are regulated. We will look for specific signatures associated with histone proteins, which are involved in packaging DNA sequences, to establish if PGIs are precisely regulated by histone proteins during parasitism. We will also use a technology called Hi-C to see how different parts of the genome interact with each other during parasitism and how these interactions relate to PGIs. Finally, we have discovered that RNA molecules that don't code for proteins are also located in PGIs and these molecules are known to be important for regulating genes that are in close proximity. We will use an improved method to sequence and identify these non-coding RNA molecules, and investigate if they are involved in turning the genes on or off in PGIs.

Soil-transmitted helminths (STH), such as Strongyloides, infect over 1.5 billion people globally and are estimated by the WHO to cause millions of years loss due to disability. We have discovered that genes associated with parasitism are physically clustered in the genome in 'parasitism-associated genomic islands' (PGIs) in the gastrointestinal parasitic nematode Strongyloides ratti. We postulate that the organisation of genes into PGIs is an important feature of parasitic nematode genomes and facilitates transcriptional co-regulation of parasitism-related genes. Few studies have investigated patterns of gene organisation in parasite genomes. Such features are likely fundamental to the genomic basis of parasitism and understanding these 'rules of parasitism' could lead to improved treatment strategies and control mechanisms, for example, by identifying new molecular targets for treatments or vaccine development.

This project will use empirical and bioinformatic approaches to investigate PGIs and their regulation. We hypothesise that PGIs are an important feature of parasitic nematode genomes. We will use long-read genome and transcriptome sequencing to investigate PGIs and PGI-associated features for four Strongyloides parasites and closely related parasitic and free-living nematodes. To investigate how PGIs are regulated we will investigate if changes to 3D chromosome structure and epigenetic markings underscore changes in transcriptional activity at PGIs. Finally, we will investigate if long non-coding RNAs, which are co-localised in PGIs, are involved in regulating PGI activity at the genetic level and if single lncRNAs affect the ability of the parasite to infect a host. Together, the results from this project will determine the precise genomic and genetic features associated with PGIs, and how they are regulated at the chromatin and genetic level.