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.
