Generating the next generation of genomics resources for biomedical investigation using a powerful and cost-effective genome assembly strategy

使用强大且具有成本效益的基因组组装策略生成用于生物医学研究的下一代基因组资源

• 批准号: 9294805
• 负责人: Richard Edward Green
• 金额: $ 28.79万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-17 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294805
• 关键词: Biomedical Research; Cactaceae; Cataloging; Catalogs; Cell Line; Chromatin; Chromosomes; Communities; Comparative Genomic Analysis; Consent; DNA; Data; Disease; Genetic; Genetic Variation; Genome; Genomics; Goals; Graph; Haploidy; Haplotypes; Health; High-Throughput Nucleotide Sequencing; Human; Human Genetics; Human Genome; Hybrids; In Vitro; Investigation; Knowledge; Length; Libraries; Ligation; Maps; Modeling; Molecular Weight; Pan Genus; Pan paniscus; Phase; Pongidae; Population; Price; Primates; Recommendation; Research Subjects; Resources; Sampling; Shapes; Shotguns; Speed; Technology; Time; Unmarried person; Variant; base; biomedical resource; comparative; comparative genomics; cost effective; cost effectiveness; falls; genetic analysis; genetic variant; genome-wide; human data; human reference genome; improved; innovation; next generation; nonhuman primate; public health relevance; reference genome; scaffold

 DESCRIPTION (provided by applicant) Unravelling the genetic basis of human health and disease requires high-quality genome information. Heretofore, the community has relied on a single, haploid human reference sequence that does not represent the actual genome sequence of any single person. While this resource has been enormously beneficial for mapping many of the genetic variants responsible for human normal and disease variation, it can limit many types of analyses. Further, this single-reference model can cause uneven power to analyze genetic variation across all human populations. Similarly, non-human primate genomes are also fundamentally important for understanding our own genome. While many draft primate genome assemblies are available, including for all great apes, these genomes are all of lower quality and contiguity than the human reference genome. Importantly, chromosome-scale scaffolding of these genomes was often done by comparison to the human reference. While this approximation is generally correct, knowing where this is wrong is critically important. Using a radically innovative and simple approach, we can now generate highly contiguous de novo assemblies of human and non-human primate genomes. The approach requires sub- microgram quantities of DNA and can be carried done from start to finish within a few months, including sequencing time. Our approach uses genome contiguity information as derived from proximity ligation of in vitro assembled chromatin. It harnesses the speed and cost-effectiveness of high-throughput sequencing to generate large amounts of haplotype-phased contiguity data spanning well over 100 kilobases in length. Using this approach we will generate de novo assembled genomes from 50 humans and 12 non-human primates of high accuracy, partially haplotype phased, with scaffold N50s expected to be between 10 and 20 Mb in length.

 描述（由申请人提供） 阐明人类健康和疾病的遗传基础需要高质量的基因组信息。迄今为止，社区一直依靠一个单倍体参考顺序，该顺序不代表任何一个人的实际基因组序列。尽管该资源对绘制许多负责人正常和疾病变异的遗传变异非常有益，但它可以限制许多类型的分析。此外，这种单参考模型可能会导致不平衡的功率分析所有人类种群的遗传变异。同样，非人类灵长类动物基因组对于理解我们自己的基因组也很重要。尽管有许多灵长类动物基因组，包括所有伟大的猿类，但这些基因组的质量和连续性都比人类参考基因组低。重要的是，这些基因组的染色体规模脚手架通常是通过与人类参考进行比较来完成的。尽管这种近似通常是正确的，但要知道这是错误的地方至关重要。使用根本创新和简单的方法，我们现在可以生成人类和非人类灵长类动物基因组的高度连续的从头组装。该方法需要亚微图数量的DNA，并且可以在几个月内从头到尾进行，包括测序时间。我们的方法使用基因组连续性信息，这些信息是从体外组装染色质的接近性结扎中得出的。它利用高通量测序的速度和成本效益，以产生大量基于单倍型的连续性数据，长度超过100千倍。使用这种方法，我们将从50人和12个非人类精确度的非人类素质中产生从头组装的基因组，部分单倍型分阶段，脚手架N50的长度预计在10至20 MB之间。