A new genetic mechanism in snails that controls transmission of schistosomes

血吸虫病是迄今为止人类最重要的蠕虫寄生虫病。没有疫苗， 唯一有效的治疗方法是重复服用一种药物（吡喹酮），现在是药物 阻力是一个主要问题。血吸虫需要水生蜗牛传播。了解 蜗牛和寄生虫相互作用的分子机制是新策略的关键， 传输几十年来，人们对蜗牛与寄生虫相容性的分子基础进行了艰苦的研究， 只得到了少量的候选基因或机制。利用全基因组关联图谱 通过这种方法，我们最近发现了蜗牛基因组的一个小区域，即光滑双脐螺，其中 未知基因的等位基因变异对曼氏血吸虫的抗性具有非常强的影响。这 区域包含10个推定的编码基因，其中没有一个是以前已知的免疫相关的， 软体动物这个建议的目的是明确地确定该区域中的哪些基因是因果关系。 首先，候选基因将根据其作为因果基因的可能性进行排序。排名将基于 抗性与易感单倍型上的等位基因（区域的版本）是否在（a） 表达水平或（B）氨基酸序列，以及推定基因功能的信息。那么对于 每个剩余的候选人按排名顺序，我们将功能测试是否等位基因变异在该基因座 实际上控制着阻力。这将使用RNA干扰（RNAi）和等位基因特异性RNAi来实现。 (i.e.敲除杂合子中的一个等位基因或另一个等位基因）。这些互补的方法使人们能够 评估表达水平或氨基酸序列不同的等位基因的因果关系。创新： 通过致病基因的功能鉴定进行关联作图说明了一种新的方法， 双脐螺遗传学领域。使用具有RNAseq（全基因组表达）数据的近交系， 在假设检验框架下的等位基因特异性RNAi也是新颖的。意义：识别新 抗性途径将指示潜在干扰寄生虫传播的新途径（即， 蜗牛阻碍了寄生虫在宿主体内探测、穿透或成功发育的能力。识别 螺类中的抗性基因对于评估螺类种群的遗传操作是否 可能成为阻断传播的可行方法。了解蜗牛的抵抗力也有助于 寻找寄生虫中控制宿主特异性的基因。最后，软体动物是 许多疾病在世界范围内具有重要的医学和经济意义。关联区域中的基因 先前已被确定为与软体动物免疫相关。因此，无论哪种基因被证明是因果关系， 它将在这一重要的疾病传播群体中确定一种新的抗病机制 有机体

Schistosomiasis is by far the most important helminth parasitic disease of humans. Vaccines are unavailable, the only effective treatment involves repeated dosing with a single drug (praziquantel), and now drug resistance is a major concern. Schistosomes require aquatic snails for transmission. Understanding the molecular mechanisms by which snails and schistosomes interact is key for new strategies to interrupt transmission. Decades of painstaking research on the molecular basis of snail-schistosome compatibility have yielded just a handful of candidate genes or mechanisms. Using a genome-wide association mapping approach, we recently identified a small region of the genome of the snail, Biomphalaria glabrata, in which allelic variation at an unknown gene has a very strong effect on resistance to Schistosoma mansoni. This region contains 10 putative coding genes, none of which was previously known to be immune relevant in molluscs. The goal of this proposal is to unambiguously identify which of the genes in this region is causal. Firstly, candidate genes will be ranked by their likelihood of being the causal gene. Ranking will be based on whether or not alleles on the resistant versus susceptible haplotypes (versions of the region) differ in (a) expression levels or (b) amino acid sequence, together with information on putative gene function. Then, for each remaining candidate in ranked order, we will functionally test whether allelic variation at that locus actually controls resistance. This will be accomplished using RNA interference (RNAi) and allele-specific RNAi (i.e. knock down one allele or the other in heterozygotes). These complementary approaches allow one to evaluate causality for alleles that differ in either expression level or amino acid sequence. Innovation: Association mapping through functional identification of a causal gene illustrates a fresh new approach in the field of Biomphalaria genetics. The use of inbred lines with RNAseq (whole-genome expression) data, RNAi and allele-specific RNAi in a hypothesis testing framework is also novel. Significance: Identifying new resistance pathways will indicate new ways to potentially interfere with parasite transmission (i.e. how do some snails block schistosomes' ability to detect, penetrate or successfully develop within a host?). Identifying resistance genes in snails is also essential for evaluating whether genetic manipulation of snail populations might become a viable approach for blocking transmission. Understanding resistance in snails should also aid the search for genes in the parasite that control host specificity. Finally, molluscs are intermediate hosts for many diseases of medical and economic importance worldwide. None of the genes in the region of association have been previously identified as immune-relevant in molluscs. Thus, whichever gene turns out to be causal, it will identify a new mechanism of disease resistance in this important group of disease-transmitting organisms.