The Broad-LMM-Color Genome Center for All of Us

以30年来在大规模基因组学和科学资源创造方面的记录为基础 社区，我们建议结合远大研究所(BROAD)、色彩基因组学(色彩)、 和分子医学合作伙伴医疗实验室(LMM)为我们所有的研究提供服务 程序(AoURP)(图1)。广泛基因组学平台已经对100,000个全基因组进行了测序，以 Date，在CLIA/CAP环境中运行，并在许多大型NIH中发挥核心作用 首创精神。COLOR和LMM都是CLIA认证的诊断实验室，在 临床测序和变异解释，总共有150,000个样本和32,000多个样本 经临床解释并提交给ClinVar的变体。联合这三个实体的理由是 汇聚远大在基因组数据生成方面的无与伦比的经验和规模，Color的创新 结合计算和临床专业知识，提供低成本、易于使用的临床测序面板 在人口规模上，以及LMM在领先的高质量变体解释和数据方面的国际声誉 共同努力。 这三个组织已经成对合作，布罗德和LMM共同支持几个 临床基因组学项目(例如Emerge、BabySeq、临床诊断)；LMM和COLOR合作 在过去的一年里，通过克莱根方案进行了变体口译；以及《博大与色彩》 在产生和应用多基因风险评分的科学项目上进行合作。此外，这三个 Sites Together成功地完成了拟议的AoURP基因组中心工作流程的试点。 布罗德将在第一年为100,000个样本和整个基因组生成阵列基因数据 &gt；20,000个样本的序列(WGS)。我们将以475美元的价格直接执行WGS(总计635美元)，使我们能够 将RFA要求的第一年基因组数量增加一倍。(在方案C中，五年平均WGS成本 将直接支付275美元(总计350美元)。布罗德用于数据处理和变量调用的生物信息学管道将 在与正在建设的AoURP数据资源中心(DRC)相同的平台环境中运行 通过范德比尔特、维莉莉和布罗德的合作。 COLOR将对ACMG59基因列表中的所有罕见变异进行解释(与正交表一起 确认所有致病和可能的致病变异)，为阳性参与者发布可操作的报告， 并将生成药物基因组学(PGx)、血统，如果AoURP需要，还将生成多基因风险分数 (PRS)所有参与者的结果。 LMM将审查具有挑战性的变体(例如，在主要策展人不确定的情况下或解释 与ClinVar的其他提交者冲突)通过其变体裁决委员会(VAC)和将 与Clingen变式口译差异工作组以及Clingen专家小组合并 以获取更多针对特定疾病的变异解释专业知识。 BRED、COLOR和LMM已经在 AoURP所需的规模，提供立即准备发射的能力。在这一雄心勃勃的计划中取得成功 研究项目将需要在许多复杂、综合的领域拥有深厚的专业知识。

Building on a 30-year track record in large-scale genomics and resource creation for the scientific community, we propose to combine the strengths of the Broad Institute (Broad), Color Genomics (Color) , and the Partners Healthcare Laboratory for Molecular Medicine (LMM) to serve the All of Us Research Program ( AoURP ) (Figure 1). The Broad Genomics Platform has sequenced >100,000 whole genomes to date, operates in a CLIA/CAP environment and has played a central role in numerous large-scale NIH initiatives. Color and LMM are both CLIA-accredited diagnostic laboratories with extensive experience in clinical sequencing and variant interpretation, with combined volume of >150,000 samples and over 32,000 variants interpreted clinically and submitted to ClinVar. The rationale to unite these three entities is to bring together Broad’s unparalleled experience and scale in genomic data generation, Color’s innovative combination of computational and clinical expertise to offer low-cost, easy-access to clinical sequencing panels at population scale, and LMM’s international reputation in leading high-quality variant interpretation and data sharing efforts. These three organizations already work together pairwise , with Broad and LMM jointly supporting several clinical genomics programs (e.g. eMERGE, BabySeq, clinical diagnostics); LMM and Color working together over the past year on variant interpretation and through the ClinGen program; and Broad and Color collaborating on scientific projects on generation and application of polygenic risk scores. Moreover, the three sites together successfully completed a pilot of the proposed AoURP Genome Center workflow. ● Broad will generate in Year 1 array genotype data for >100,000 samples and Whole Genome Sequence (WGS) for > 20,000 samples . We will perform WGS for $475 direct ($635 total), allowing us to double the number of Year 1 genomes required by the RFA. (In Scenario C, the five-year average WGS cost will be $275 direct ($350 total)). Broad’s bioinformatics pipeline for data processing and variant calling will operate in the same platform environment as the AoURP Data Resource Center (DRC), which is being built through a partnership between Vanderbilt, Verily, and Broad. ● Color will perform interpretation of all rare variants in the ACMG59 gene list (with orthogonal confirmation of all pathogenic and likely pathogenic variants), issue actionable reports for positive participants, and will generate pharmacogenomics (PGx), ancestry, and if desired by the AoURP, polygenic risk score (PRS) results for all participants . ● LMM will review challenging variants (e.g. where a primary curator is uncertain or the interpretation conflicts with other submitters to ClinVar) through its Variant Adjudication Committee (VAC) and will integrate with the ClinGen Variant Interpretation Discrepancy Working Group as well as ClinGen Expert Panels for additional disease-specific variant interpretation expertise. Broad, Color, and LMM already perform high-quality sequencing, genotyping, and interpretation at the scale required by the AoURP , providing an immediate ready-to-launch capability . Success in this ambitious research program will require deep expertise in numerous complex, integrated areas.