PROJECT SUMMARY The human reference genome is the most widely used resource in genetics and is due for an update. Its current structure is a linear composite of genome segments from roughly 20 people, contains gaps, biases and errors, and does not allow for fluid representation of global genomic variation. The Human Pangenome Reference Consortium (HPRC) aims to create a more sophisticated and complete human reference genome with a graph-based, telomere-to-telomere representation of global genomic diversity. For this effort to be successful and responsive to the needs of diverse populations as partners in the creation of this resource for genomics, the newly assembled ‘embedded ELSI’ team has been a critical component of the HPRC to facilitate decision-making that is equitable, respectful of ethical frameworks, laws, and cultural norms. Over the last year, the ELSI leadership team established the HPRC-ELSI working group by recruiting nationally and internationally recognized experts in relevant disciplines such as research ethics, law, social sciences, demography, population genetics, international data sharing, and Indigenous sovereignty. The ELSI leadership team (which consists of Dr. Alice Popejoy, University of California, Davis; Dr. Barbara Koenig, University of California, San Francisco; Dr. Bob Cook-Deegan, Arizona State University; Dr. Karen Miga, University of California, Santa Cruz; and Dr. Nanibaa’ Garrison, University of California, Los Angeles) and the newly formed HPRC-ELSI working group members advise the HPRC in real time through participation in standing working group calls and consortium-wide meetings. This embedded ELSI team provides guidance about concerns—both anticipated and unanticipated—related to consent procedures, ethical and scientific selection of study samples, engagement of communities, and definition(s) of diversity that will be used in selecting and reporting on genetic diversity. We are building partnerships and collaborations while actively pursuing opportunities for community engagement and tribal consultations, toward the goal of developing community-informed recruitment protocols such as informed consent and sample population descriptors. There is a critical need to build additional capacity within the HPRC to anticipate and respond to ELSI issues. Our ‘embedded ELSI’ approach will continue to build the foundational knowledge base, policy infrastructure, and strategic partnerships to make evidence-based choices. These include sample selection, facilitating expansion of diversity and inclusion efforts, encouraging adoption of the pangenome reference among research partner organizations and clinical genetics laboratories, and further enhancing long-term ELSI capacity within the HPRC structures and systems. This administrative supplement will support building a rigorous and formal embedded ELSI infrastructure to complement and enhance HPRC’s ongoing technical and scientific efforts. We aim to conduct research acr...