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测序技术的惊人进步已使人对人类遗传变异的系统识别，以及最近的第一代下一代基因组测序仪的最新FDA营销授权，信号表明了药物基因组学和个性化药物的新时代和个性化医学时代的到来。然而，单独的DNA测序无法提供有关个体遗传构成的完整信息，因为人类基因组中存在两组同源染色体。描述母体和父亲副本或单倍型对于确定个人的遗传组成以及理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，基因组量表单倍型或DNA变体的“相分化”一直是一个难以捉摸的目标。现有的方法非常昂贵，在技术上具有挑战性，需要专门的仪器，或者远远不足重建跨染色体的单倍型。 Arima Genomics最近为全基因组单倍型型开发了一种创新的新方法，将接近度结合和DNA测序与单倍型组装的概率算法相结合。这种称为Haploseq的新方法可在哺乳动物基因组中具有高完整性，分辨率和准确性，实现了跨染色体的单倍型。作为一种具有成本效益的精简技术，Haploseq有望为生物医学应用和从药物基因组学到农业生物技术的其他市场中的基因组测序的新标准构成。 Arima基因组学提出的研发工作的目标涉及改善Haploseq通过调整协议来实现更均匀的基因组覆盖范围，扩展Haploseq算法的能力，从而提高人类细胞中稀有变异的能力，从而扩展Haploseq算法，通过与同一源序列数据共同开发基因组合的基因组，从而提供“新型”序列型号的基因组合，并将“ smart and smart smart”计算的“计算”计算为“ smart”计算。 Haploseq与加州大学圣地亚哥分校的临床研究合作者合作进行下一代遗传关联研究的实用性。成功完成我们的研究目标将为对心脏生物学和疾病涉及的基因调节网络的持续研究提供宝贵的新知识，并将大大提高Haploseq在多元化研究，生物医学和临床测序应用方面的商业生存能力。 Haploseq有望大大增强我们对健康遗传学的理解，并有助于实现个性化医学。