Maintaining, improving, and providing the human reference

项目总结(项目1：维护、改进和提供人员参考) 我们建议将当前最好的方法和实践与实用的、可扩展的模型相结合，以创建 并共享一个广泛有用的泛人类基因组参考(“泛基因组”)，该参考基于组件和 基因组生产中心提供的原始数据。我们提出的泛基因组参考并不完全 替换现有的GRCh38引用，相反，它在很大程度上建立在它的基础上，以创建引用资源 这包含了更丰富的人类遗传多样性的代表。为了实现这一计划，我们有 聚集了一群拥有互补专业知识的强大个人，他们将共同构建、共享、 维护和改进最先进的人类泛基因组资源。将初始基因组转换为 组装成高质量的人类基因组参考队列我们将执行组装质量控制， 纠错和验证，反映了我们为维护和验证而创建的成功流程 改进现有的人类参考基因组。为了使此程序集集合具有可比性，我们将 然后创建一张它们之间存在的基因组变异的综合图谱。利用人类基因组 参考队列和变异图，我们将创建一个有三个 互补和基本部分：(I)以非冗余的方式对基因组进行编码的序列图 通过将共享序列合并在一起的方式；(Ii)序列中单倍型的可搜索编码 图形，图形本身不能捕捉到的东西；以及(Iii)使之成为可能的坐标系 平等地引用所有变体，同时保留与GRCh38的向后兼容性。要构建这个图表， 我们将使用我们开发并在整个社区工作的工具来测试和制作该方法的原型， 发布稳定的和版本化的泛基因组参考。我们还提出了一项计划来处理来自 联盟和更广泛的社区，并通过数据分析、整理和修复参考文献中的错误 定向测序。我们将遵循完全开放的模式来确保所有数据-主要数据、基因组 组件和泛基因组参考-可通过砧板同时获得，并可通过 适当的国际数据库。我们将通过创建一套核心的泛基因组来增加这一资源的价值 功能注释，主要集中在基因上。使用并迁移到建议的 泛基因组参考简单明了，我们将促进创建新的和更新的工具。我们的战略 通过与工具开发人员合作来利用社区，特别是建立和促进交流 格式和创建基准，以促进同类最佳的社区方法。

PROJECT SUMMARY (Project 1: Maintaining, improving, and providing the human reference) We propose to combine the best current methods and practices with a practical, scalable model to create and share a broadly useful pan-human genome reference (the "pan-genome") based on the assemblies and raw data delivered by the genome production center. The pan-genome reference we propose does not wholly replace the existing GRCh38 reference, rather it substantially builds upon it to create a reference resource that incorporates a much richer representation of human genetic diversity. To deliver this plan, we have assembled a strong group of individuals with complementary expertise that together will construct, share, maintain and improve a state-of-the-art human pan-genome resource. To convert the initial genome assemblies into a high-quality human genome reference cohort we will perform assembly quality control, error correction and validation, mirroring the successful processes we have created for maintaining and improving the existing human reference genome. To make this collection of assemblies comparable, we will then create a comprehensive map of the genomic variants that exist among them. Using the human genome reference cohort and variation map, we will create a human pan-genome reference that has three complementary and essential parts: (i) a sequence graph that encodes the genomes in a non-redundant manner by merging together shared sequences; (ii) a searchable encoding of the haplotypes in the sequence graph, something that the graph itself does not capture; and (iii) a coordinate system that makes it possible to refer to all the variation equally while preserving backwards compatibility with GRCh38. To build this graph we will use tools that we have developed and work across the community to test and prototype the approach, releasing stable and versioned pan-genome references. We also propose a plan to handle error reports from the consortium and broader community, and to fix errors in the references via data analysis, curation and targeted sequencing. We will follow a completely open model to ensure all data – primary data, genome assemblies and pan-genome reference – are simultaneously available via AnVIL and accessioned through appropriate international databases. We will add value to this resource by creating a core set of pan-genome functional annotations, focusing primarily on genes. To make working with and migrating to the proposed pan-genome reference straightforward, we will foster the creation of new and updated tools. Our strategy harnesses the community by working with tool developers, in particular establishing and promoting exchange formats and creating benchmarks to promote best-of-breed community methods.