Broad-Color: The Genome Center for the Future of All of Us

ABSTRACT The AU of Us Research Program is building a national biomedical research resource from an historically diverse population to empower and accelerate the understanding, diagnosis, and treatment of human diseases in a representative and equitable way. The Broad Institute of MIT & Harvard has a 35-year track record of delivering on transformative projects in the field of

genomics. Beginning with the Human Genome Project in the 1990s, our center has played a leadership role in the design, data generation, and methods development in almost every major genomic resource initiative that the NIH has launched. Over the last two decades, Broad has sequenced the genomes of over 630,000 people, with >290,000 of those being for participants of

All of Us. Similarly, we have genotyped - 1.8 million samples with - 180,000 of those being AoU participants. Color Health's clinical programming brings improved risk assessment, identification, and disease management directly to large populations. Color's genetic services laboratory (Color Dx) has sequenced and retumed clinical results to >200,000 individuals, with

as many as 10,000 results in a single month's time. Together Broad and Color propose to continue to serve as a genome center and clinical validation laboratory for the All of Us Program. Our group has a proven track record of high quality data generation, collaboration across the AoU ecosystem, scaled capacity for retum of

results, and driving innovation through a suite of pilots, demo, and driver projects. We propose to leverage our economies of scale to allow the program to meet all its commitments and maximize value while also delivering new and powerful data types into the hands of the scientific community. We propose an aggressive cost reduction and cost sharing plan to meet these goals.

We further offer a vision, for a future where additional funding is available, to accelerate the adoption of the All of Us cohort data by providing a diverse set of pilot and demo project proposals across the spectrum from innovative multiomic data generation, to longitudinal studies, to elucidation of the interplay between exposures a participant may have had to markers

in their genetic, epigenetic, or proteomic profiles. Our group brings together expertise in management of large scale genomics projects, novel assay development, interpretation of human variation, clinical validation, regulations, information security, and scientific vision. We also bring our network of scientific colleagues and

collaborators for the analysis of expression, long read, and proteomic data and for future studies to further elucidate the mechanisms of complex traits and genes x environment interactions. Specifically, for this award we propose to support the core genomic assays of whole genome sequencing and genotyping at the desired scales, utilizing the same validated, secure,

and compliant workflows we have used over the last 5-years. We further propose to complete the suite of innovative multiomic assays we have started on a core set of participants. We further propose a variety of pilot, demo and driver projects that could be prioritized for future adoption should additional funding be sourced.