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。目前还没有疫苗，唯一有效的治疗方法是重复服用单一药物（吡喹酮），而现在耐药性成为一个问题。血吸虫由水生蜗牛传播。了解蜗牛和血吸虫相互作用的分子机制是阻断传播新策略的关键。为此，最近对光滑 Biomphalaria glabrata 蜗牛的基因组进行了测序。然而，由于 0.9 Gb 基因组的 50% 以上是高度重复的，因此其组装情况仍然很差。它由超过 500,000 个重叠群组成，其中一半基因组包含在 43 kb 以下的重叠群中（N50 = 大约一个基因的大小）。因此，任何与寄生虫免疫相关的遗传标记不太可能在与其相关的致病基因相同的重叠群上找到。光滑拟杆菌中已知有六种与血吸虫抗性相关的标记。但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个谜。因此，生物指螺研究界最重要的目标之一，即寻找与免疫相关的基因，目前受到严重阻碍。幸运的是，有一种替代方法可以完成基因组组装。基因组的重复部分在流行病学上没有什么重要性，因为我们期望它包含很少的功能元件或有用的遗传标记。基因组的非重复区域（包括绝大多数基因）可以通过强大的靶向序列捕获新方法组装成高密度连锁图谱。鉴于我们在光滑 B. glabrata 连锁图谱方面的初步工作以及我们过去在其他系统中高密度靶向捕获的成功，我们已经做好了开发这张图谱的独特准备。该应用程序的具体目标是（1）生成非重复的高密度连锁图 光滑 B. glabrata 基因组的一部分，然后 (2) 使用该图谱来识别抗性标记周围的基因。该图谱将采用约 40,000 个遗传标记，将 >99% 的独特基因组序列（包括 >95% 的基因）联合成与 18 条蜗牛染色体相对应的大型连锁群。创新：靶向捕获是一种从未用于生物脐螺的新方法。仅关注基因组中包含基因的单拷贝部分可以避开组装此类重复基因组的挑战，同时为性状作图创建高质量的基因组资源。这种方法也应该成为其他组装不良的基因组的模型。意义：迄今为止，蜗牛基因组计划未能如预期那样促进性状图谱绘制。该连锁图谱将消除快速识别控制蜗牛免疫和其他表型性状的基因的最后障碍。了解蜗牛免疫将揭示潜在干扰寄生虫的新方法（例如针对蜗牛免疫系统所针对的寄生虫分子的治疗方法）或操纵蜗牛种群以使它们成为能力较差的宿主。

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