Optimizing HaploSeq for whole-genome phased haplotypes in biomedical applications

优化生物医学应用中全基因组定相单倍型的 HaploSeq

• 批准号: 8833411
• 负责人: KELLY A FRAZER
• 金额: $ 35万
• 依托单位: ARIMA GENOMICS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8833411
• 关键词: Affect; Agriculture; Algorithms; Authorization documentation; Benchmarking; Biology; Biomedical Research; Biotechnology; Cardiac; Cells; Child; Chromosomes; Clinical Research; DNA; DNA Sequence; Data; Data Sources; Digestion; Disease; Enzymes; Generations; Genetic; Genetic Variation; Genome; Genomics; Genotype; Goals; Haplotypes; Health; Human; Human Genetics; Human Genome; Individual; Investigation; Knowledge; Laboratories; Ligation; Long QT Syndrome; Maps; Marketing; Methods; National Heart, Lung, and Blood Institute; Parents; Patients; Pharmacogenomics; Phase; Protocols documentation; Regulator Genes; Research; Resolution; Role; Sampling; Sequence Analysis; Signal Transduction; Source; Structure; Technology; TimeLine; Variant; clinical sequencing; cohort; cost effective; falls; genetic association; genetic makeup; genetic variant; genome sequencing; genome-wide; improved; innovation; instrumentation; mammalian genome; next generation; novel strategies; personalized medicine; programs; public health relevance; rare variant; research and development; research study; restriction enzyme; tool

DESCRIPTION (provided by applicant): Phenomenal advances in DNA sequencing technologies have enabled systematic identification of genetic variants in human individuals, and the recent FDA marketing authorization of the first next-generation genome sequencer signals the arrival of a new era of pharmacogenomics and personalized medicine. Nevertheless, DNA sequencing alone fails to provide complete information on the genetic makeup of an individual, as two homologous sets of chromosomes are present in the human genome. Delineation of both maternal and paternal copies, or haplotypes, is critical for determining an individual's genetic composition, and for understanding the structure and function of the human genome and its role in health and disease. Yet genome- scale haplotyping, or "phasing" of DNA variants, has long remained an elusive goal. Existing approaches are prohibitively expensive, technically challenging, require specialized instrumentation, or fall far short of reconstructing chromosome-spanning haplotypes. Arima Genomics has recently developed an innovative new approach for whole-genome haplotyping, combining proximity-ligation and DNA sequencing with a probabilistic algorithm for haplotype assembly. This new method, known as HaploSeq, achieves chromosome-spanning haplotypes with high completeness, resolution, and accuracy in mammalian genomes. As a cost-effective, streamlined technology, HaploSeq is poised to underpin a new standard in genome sequencing in biomedical applications and other markets from pharmacogenomics to agricultural biotechnology. The objectives of Arima Genomics' proposed R&D efforts involve improvement of HaploSeq's ability to phase rare variants in human cells by adapting the protocol to achieve more uniform genome coverage, extension of the HaploSeq algorithm's capabilities to provide genotypes concurrently with haplotypes from the same source sequencing data by developing a new "smart-mapping" computational module, and demonstration and benchmarking of HaploSeq's utility in ongoing next-generation genetic association studies in partnership with clinical research collaborators at UC San Diego. Successful completion of our research aims will contribute invaluable new knowledge to ongoing investigations of how human genetic variation influences the gene regulatory networks involved in cardiac biology and disease, and will substantially advance the capabilities of HaploSeq toward commercial viability in diverse research, biomedical, and clinical sequencing applications. HaploSeq promises to greatly enhance our understanding of human genetics in health and contribute to the realization of personalized medicine.

描述（由申请人提供）：DNA 测序技术的显着进步已经能够系统地识别人类个体的遗传变异，并且最近 FDA 对第一台下一代基因组测序仪的营销授权标志着药物基因组学和个性化医疗新时代的到来。然而，仅 DNA 测序无法提供有关个体基因构成的完整信息，因为人类基因组中存在两组同源染色体。母本和父本拷贝或单倍型的描述对于确定个体的遗传组成、了解人类基因组的结构和功能及其在健康和疾病中的作用至关重要。然而，基因组规模的单倍型分析，或 DNA 变体的“定相”，长期以来一直是一个难以捉摸的目标。现有的方法非常昂贵，技术上具有挑战性，需要专门的仪器，或者远远不能重建跨染色体单倍型。 Arima Genomics 最近开发了一种创新的全基因组单倍型分析方法，将邻近连接和 DNA 测序与单倍型组装的概率算法相结合。这种被称为 HaploSeq 的新方法在哺乳动物基因组中实现了具有高完整性、分辨率和准确性的跨染色体单倍型。作为一种经济高效的简化技术，HaploSeq 有望在生物医学应用以及从药物基因组学到农业生物技术的其他市场中奠定基因组测序的新标准。 Arima Genomics 提出的研发工作的目标包括通过调整协议以实现更均匀的基因组覆盖来提高 HaploSeq 对人类细胞中罕见变异进行定相的能力，扩展 HaploSeq 算法的能力以同时提供来自同一源测序数据的基因型和单倍型通过开发新的“智能绘图”计算模块，并与临床研究合作，在正在进行的下一代遗传关联研究中展示 HaploSeq 的实用性并对其进行基准测试加州大学圣地亚哥分校的合作者。成功完成我们的研究目标将为正在进行的人类遗传变异如何影响涉及心脏生物学和疾病的基因调控网络的研究贡献宝贵的新知识，并将大大提高 HaploSeq 在各种研究、生物医学和临床领域的商业可行性。测序应用。 HaploSeq 有望大大增强我们对人类健康遗传学的理解，并为实现个性化医疗做出贡献。