Genetics and genomics of schistosome resistance in snails

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SUMMARY Transmission of human schistosome parasites depends on availability of suitable aquatic snail intermediate hosts. If no schistosome-transmitting snails are present, or snails no longer support schistosome development, there will be no schistosomiasis. Developing snail-targeted genetic control programs has long been advocated, but hampered by the lack of necessary genetic knowledge and effective germline manipulation tools. The objective of this project is to exploit our recently developed genetic and genomic resources, in combination with application of emerging powerful technologies, to address fundamental mechanisms of schistosome resistance of snails in two snail-schistosome systems, Biomphalaria spp.–Schistosoma mansoni and Bulinus spp.–S. haematobium, which are involved in transmission of intestinal and urogenital schistosomiasis, respectively. The two snail-schistosome systems are responsible for approximately 99% of human schistosomiasis transmission in the world. We propose to employ two new snail models, Bi. glabrata– S. mansoni and Bu. truncatus–S. haematobium to represent the two systems for the study. In Aim 1, we will apply whole genome sequencing (WGS) to scan single nucleotide polymorphisms (SNPs) of individual recombination inbred lines (RILs) to generate high-resolution genetic maps of schistosome resistance in juvenile and adult Bi. glabrata, the best-studied snail model of schistosomiasis. The RILs have been bred from our new model that consists of two homozygous lines of Bi. glabrata, one fully susceptible to, and the other completely resistant to, S. mansoni, the most important causative agent of intestinal schistosomiasis. In Aim 2, we will employ RNA sequencing (RNAseq) to investigate differential expression and allelic variation of genome-wide genes using our newly developed genetic resources (i.e., RIL snails and their two homozygous parent snails). A comprehensive analysis of RNAseq data coupled with genes identified in the fine resistance loci will lead to accurate identification of small number of resistance candidates, which will be used for subsequent studies, including genetic variation of resistance genes in natural populations in endemic areas proposed in this aim. In Aim 3, we will use a combined approach of functional and comparative genomics to identify syntenic regions between Bi. glabrata and Bu. truncatus and reveal the genomic basis of schistosome resistance in Bu. truncatus, an intermediate host of S. haematobium. Paradoxically, S. haematobium, despite being the most abundant of all schistosome species infecting people, has received very little attention with respect to its interactions with its bulinid snail hosts. In Aim 4, we will utilize RNAi (RNA interference) and CRISPR (clustered regularly interspaced short palindromic repeats) to functionally verify the candidate genes affecting snail compatibility to S. mansoni or S. haematobium. This study will lead to a much deeper understanding of schistosome resistance in Bi. glabrata, provide the first molecular insight into the genomic basis underpinning competence of bulinid snails to schistosome, and help develop more effective and novel methods for controlling schistosomiasis.