Optimizing HaploSeq for whole-genome phased haplotypes in biomedical applications

描述（由申请人提供）：DNA测序技术的惊人进步已经能够系统地识别人类个体的遗传变异，最近FDA对第一个下一代基因组测序仪的上市许可标志着药物基因组学和个性化医疗新时代的到来。然而，DNA测序本身无法提供关于个体遗传组成的完整信息，因为人类基因组中存在两组同源染色体。母亲和父亲的副本，或单倍型的描绘，是决定一个人的遗传组成，并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，基因组规模的单体型分析，或DNA变异的“定相”，长期以来一直是一个难以实现的目标。现有的方法过于昂贵，技术上具有挑战性，需要专门的仪器，或远远达不到重建染色体跨越单倍型。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。作为一种具有成本效益的简化技术，HaploSeq有望成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的定相能力，通过开发新的“智能映射”计算模块来扩展HaploSeq算法的能力，以同时提供来自相同来源测序数据的基因型和单倍型，HaploSeq在与加州大学圣地亚哥分校的临床研究合作者合作进行的下一代遗传关联研究中的效用的演示和基准测试。我们的研究目标的成功完成将为正在进行的人类遗传变异如何影响心脏生物学和疾病中涉及的基因调控网络的研究提供宝贵的新知识，并将大大提高HaploSeq在各种研究，生物医学和临床测序应用中的商业可行性。HaploSeq有望大大提高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。

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.