High-density linkage map to find snail genes that block schistosome transmission

高密度连锁图谱寻找阻止血吸虫传播的蜗牛基因

• 批准号: 8960339
• 负责人: Michael Scott Blouin
• 金额: $ 14.6万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-11-01 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8960339
• 关键词: Binding; Biochemical; Biomphalaria; Candidate Disease Gene; Chromosome Mapping; Chromosomes; Chronic; Chronic Disease; Communities; Complement; Country; Culicidae; DNA; Development; Disease; Dose; Drug resistance; Elements; Epidemiology; Evolution; Foundations; Genes; Genetic Markers; Genetic Variation; Genome; Genomic Segment; Genomics; Goals; Health; Helminths; Human; Immune response; Immune system; Immunity; Infection; Link; Malaria; Maps; Methods; Modeling; Molecular; Outcome; Parasites; Parasitic Diseases; Pharmaceutical Preparations; Phenotype; Plasmodium; Population; Population Genetics; Praziquantel; Research; Research Personnel; Resistance; Resources; Schistosoma; Schistosomatidae; Schistosomiasis; Snails; Staging; System; Therapeutic; Vaccines; Variant; Water; Work; base; density; design; disability; disability-adjusted life years; effective therapy; functional genomics; gene discovery; genome sequencing; genome wide association study; immune function; innovation; interest; novel strategies; reference genome; resistance gene; study population; success; therapeutic target; trait; transmission process

DESCRIPTION (provided by applicant): 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 concern. Schistosomes are transmitted by aquatic snails. Understanding the molecular mechanisms by which snails and schistosomes interact is key for new strategies to interrupt transmission. To this end, the genome of the snail Biomphalaria glabrata was recently sequenced. However, because >50% of the 0.9 Gb genome is highly repetitive, it remains very poorly assembled. It consists of >500,000 contigs, with half the genome contained on contigs under 43 kb (N50 = about the size of a gene). As a result, any genetic markers that associate with parasite immunity are unlikely to be found on the same contig as the causal gene to which they are linked. Six markers linked to schistosome resistance are known in B. glabrata. But most of the genes linked to those markers remain a mystery owing to the inadequate genome assembly. Thus, one of the most important goals of the Biomphalaria research community, to find genes associated with immunity, is currently severely hampered. Fortunately, there is an alternative to complete genome assembly. The repetitive portion of the genome is of little epidemiological importance because we expect it to contain few functional elements or useful genetic markers. The non-repetitive regions of the genome, which include the vast majority of genes, can be assembled with a high-density linkage map via the powerful new method of targeted sequence capture. We are uniquely poised to develop this map, given our preliminary work with linkage mapping in B. glabrata and our past success with high-density targeted capture in other systems. The specific objectives of this application are (1) to generate a high-density linkage map of the non-repetitive fraction of the B. glabrata genome, and then (2) use that map to identify genes surrounding resistance markers. This map will employ ~40,000 genetic markers to unite >99% of the unique genomic sequence, including >95% of genes, into large linkage groups corresponding to the 18 snail chromosomes. Innovation: Targeted capture is a new approach that has never been used with Biomphalaria. Focusing on just the single-copy, gene-containing fraction of the genome sidesteps the challenge of assembling such a repetitive genome, while creating a high-quality genomic resource for trait mapping. This approach should also be a model for other poorly-assembled genomes. Significance: The snail genome project has thus far failed to facilitate trait mapping as expected. This linkage map will remove the last barrier to rapidly identifying genes that control snail immunity and other phenotypic traits. Understanding snail immunity will reveal new ways to potentially interfere with the parasite (e.g. therapeutics targeting parasite molecules that are targeted by the snail immune system) or to manipulate snail populations to make them into less competent hosts.

描述（由申请人提供）：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），现在耐药性是一个问题。血吸虫通过水生蜗牛传播。了解蜗牛和寄生虫相互作用的分子机制是阻断传播的新策略的关键。为此，最近对光滑双脐螺的基因组进行了测序。然而，由于>50%的0.9 Gb基因组是高度重复的，它仍然非常差地组装。它由> 500，000个重叠群组成，其中一半的基因组包含在43 kb以下的重叠群上（N50 =大约基因的大小）。因此，任何与寄生虫免疫相关的遗传标记都不太可能在与它们所链接的致病基因相同的重叠群上发现。在B中已知6个标记与染色体抗性连锁。光滑的但是，由于基因组组装不充分，与这些标记相关的大多数基因仍然是一个谜。因此，Biomphalaria研究界最重要的目标之一，找到与免疫相关的基因，目前受到严重阻碍。幸运的是，有一种替代完整基因组组装的方法。基因组的重复部分在流行病学上没有什么重要性，因为我们认为它包含的功能元件或有用的遗传标记很少。基因组的非重复区域，其中包括绝大多数基因，可以通过强大的新方法，有针对性的序列捕获组装与高密度的连锁图谱。鉴于我们在B区进行的连锁作图的初步工作，我们是唯一准备开发这一图谱的人。glabrata和我们过去在其他系统中高密度靶向捕获的成功。本申请的具体目的是（1）产生非重复性的高密度连锁图谱， B的分数。glabrata基因组，然后（2）使用该图谱鉴定抗性标记周围基因。该图谱将采用~ 40，000个遗传标记将>99%的独特基因组序列（包括>95%的基因）联合成对应于18条蜗牛染色体的大连锁群。创新：靶向捕获是一种从未用于Biomphalaria的新方法。只关注基因组的单拷贝、包含基因的部分，可以避开组装这种重复基因组的挑战，同时为性状作图创造高质量的基因组资源。这种方法也应该成为其他组装不良基因组的模型。意义：迄今为止，蜗牛基因组计划未能像预期的那样促进性状作图。这个连锁图将消除最后的障碍，以迅速确定基因控制蜗牛免疫力和其他表型性状。了解蜗牛免疫力将揭示潜在干扰寄生虫的新方法（例如针对蜗牛免疫系统靶向的寄生虫分子的治疗方法）或操纵蜗牛种群使其成为较弱的宿主。

项目成果

Allelic variation partially regulates galactose-dependent hydrogen peroxide release from circulating hemocytes of the snail Biomphalaria glabrata.

• DOI: 10.1016/j.fsi.2017.10.037
• 发表时间: 2018-01
• 期刊: Fish & shellfish immunology
• 影响因子: 4.7
• 作者: Allan ERO;Blouin MS
• 通讯作者: Blouin MS

A Targeted Capture Linkage Map Anchors the Genome of the Schistosomiasis Vector Snail, Biomphalaria glabrata.

• DOI: 10.1534/g3.117.041319
• 发表时间: 2017-07-05
• 期刊: G3 (Bethesda, Md.)
• 作者: Tennessen JA;Bollmann SR;Blouin MS
• 通讯作者: Blouin MS