Section I. Notice of Funding Opportunity Description Purpose The National Human Genome Research Institute (NHGRI) supports the Human Genome Reference Program (HGRP), which is transforming the original human genome reference by incorporating data from over 350 diverse, high quality, haplotype resolved genomes in a pangenome representation. This NOFO seeks applications from eligible small business concerns (SBCs) for the development of informatics tools with commercial potential to facilitate uptake and scientific use of the human pangenome reference. This NOFO calls for innovative Phase I SBIR applications from SBCs to demonstrate proof of principle or viability of informatics tools for use of the pangenome. Emphasis for this NOFO will be on development of tools for compelling use cases for the pangenome that are relevant to particular sectors of the genomics community, e.g., clinical, population, and functional genomics. Tools should demonstrate commercial potential and enable other genomics researchers to adopt and use the pangenome in their scientific endeavors. Projects may also build upon existing infrastructure tools in use by the Human Pangenome Reference Consortium (HPRC), but should not aim to create entirely new infrastructure. Small business applicants interested in submitting a Small Business Technology Transfer (STTR) grant application should submit to the related funding opportunity, PAR-25-309 Background A human genome reference sequence is an accepted representation of the human genome used as a standard to align and assemble genome sequence data. It also serves as a consensus coordinate system for reporting results. Since the completion of the Human Genome Project, the genome reference has been steadily improved over time by resolving errors and adding information from new assemblies. The HGRP was established by NHGRI in 2019 to further improve the human genome reference by using new methods for more complete assemblies, increasing genetic diversity, and transforming the reference to represent hundreds of diverse genomes in an accessible and usable resource. In the ensuing five years, funded investigators formed the Human Pangenome Reference Consortium (HPRC), established an embedded ELSI team which guided the HPRC on issues such as consent and participant community engagement, and initiated collaborations with international partners to develop a resource representative of global populations. An initial draft pangenome consisting of nearly 50 human genome assemblies was released on May 10th, 2023; currently over 140 assemblies have been produced and will soon be incorporated into the pangenome, working towards a total of 350 to be available within the next six months. These efforts constitute a strong foundation for the further improvement of the human pangenome reference. In October 2022, NHGRI hosted The Human Genome Reference Program (HGRP) Planning Meeting to identify future directions for the HGRP. Meeting participants strongly encouraged the continuation of the program, with key recommendations emerging from the participants' individual input including: Prioritize utility over quantity and focus on sample selection and data generation of highest benefit to the broader genomics research community. Emphasize adoption of the new pangenome by identifying use cases, building user-friendly tools, and minimizing disruption to existing workflows. Establish partnerships with international organizations and global participant communities and strive to ensure equitable benefit of the pangenome. Integrate ethical, legal and social implications (ELSI) at all stages of research including project design, recruitment, adoption, dissemination, and access. Considering these recommendations, NHGRI renewed the program. The goals for the renewal include: 1) continuing to maintain and improve the pangenome reference, adding diverse, reference quality sequence assemblies; 2) facilitating adoption of the pangenome reference by the research and clinical genomics communities; 3) fostering the development and deployment of informatics tools for the pangenome; 4) embedding ELSI research; and 5) forming international partnerships to maximize the chances that the human pangenome reference will represent populations worldwide, and encourage the collaboration of scientists worldwide in its creation and use. Overall, there will be a shift in emphasis towards evaluating HGRP progress in terms of how useful the pangenome resource is for clinical and basic genomics research communities. The overall goal of the HGRP during the renewal will be to produce a human pangenome reference that optimizes both the population genetic diversity represented, and also the utility for, and adoption by, the genomics research community. As a component of the program, four U01 awards were made for informatics tools development. Research and development performed by small businesses is an important element to achieving the goal or optimizing the utility of the HGRP. Importantly, commercial bioinformatics products and services may help enhance the applicability and widespread adoption of genomics in expanded settings. Commercial products offer robust genomic data analysis and interpretation solutions to researchers and scientists outside the smaller subset of research groups with highly specialized computational genomics skillsets. Commercial computational approaches are also required to lower the barriers to adoption of the pangenome in clinical settings, providing robust and user-friendly clinical tools to enhance the diagnostic capabilities of genomics data and improve health outcomes. Research Objectives Tools for using the pangenome For this NOFO NHGRI seeks applications from SBCs proposing to develop informatics tools that will allow the full range of biomedical community that uses genomic data to use the human pangenome reference being developed by the HGRP. Proposed projects can be wholly new tools that take advantage of the new information in the pangenome reference, and its graph representation to produce improved results, or modifications of existing tools to enable important use cases of the pangenome. The current representations are graph-based, but other representations (e.g. k-mer) may evolve to accommodate scale and complexity and strategies for compression and efficient data structures may be relevant. NHGRI supports development of genomics methods, tools, and technologies that can be used by the community of biomedical researchers. This NOFO has a focus on developing tools that will catalyze routine use of the human pangenome by a broad range of genomics researchers. These tools are expected to break the path for scientists to benefit from the pangenome reference. Ideally such tools will be usable by investigators or clinicians with a range of genomics informatics expertise and resources. Emphasis will be on tools for compelling use cases that are relevant to different sectors of the genomics research community: clinical, population, functional genomics, etc. Applications may propose wholly new tools, or modifications of existing tools. Proposed tools may facilitate the use and uptake of the pangenome as a whole or any aspect of it (e.g. high quality assemblies from diverse individuals, reference representations, annotations, etc...). However, applications should not aim to re-create new versions of existing infrastructure for creating the pangenome itself (e.g. new assemblers, new whole pangenome annotation pipelines, new graph reference representations, etc?) unless they are integral to the development of tools to address identifiable uses for a particular set of pangenome end-users. Possible examples of tools include applications that use the human pangenome reference for: Selecting the best subset of linear genomes or paths along the pangenome graph for use in genome alignments of short read sequence data Creating a data visualization tool to aid in identifying structural variation in the pangenome Using the distribution of genetic variation in the pangenome to inform population genetic or comparative genomic analysis Integrating the pangenome with multi-omic or functional genomic data to improve variant characterization in genomically diverse populations Integration of pangenome information into existing genomics tools such as variant calling or assemblers Visualizing regulatory elements, or other functional genomic features within the pangenome Using the pangenome reference to improve fine mapping and polygenic risk scores Using the pangenome to annotate disease associations or clinically relevant variants Integrating controlled access genomic data with open access pangenome data in ways that enable secure and private use of protected data. While Phase I SBIR projects focus on early-stage development of products and services, demonstrating feasibility and technical merit of the approach, the informatics tool being developed in the application should also demonstrate commercial potential and a clearly defined potential user-base. Awardees from this NOFO will be eligible to become associate members of the Human Pangenome Reference Consortia (HPRC) and are encouraged to attend the HPRC annual meeting. Responsiveness The following applications will be considered non-responsive to this NOFO: Applications that do not focus on developing tools for use of the pangenome produced by the HGRP Applications that propose tools that are applicable to only one or a small number of diseases or biological systems Applications that propose extensive wet-lab data generation, other than a small amount (10% of direct costs) that may be needed to validate the tool. Webinar All applicants are strongly encouraged to contact NHGRI Staff to discuss the responsiveness and alignment of their proposed work with the goals of this program. An informational webinar will be held in January, 2025. NIH staff will be available to answer questions related to this NOFO. Time, date, and dial in information will be provided at https://www.genome.gov/Funded-Programs-Projects/Human-Genome-Reference-Program#events. During the webinar, NHGRI staff will present overviews of the program and answer RFA-related questions from prospective applicants. The informational webinar is open to all prospective applicants, but participation is not a prerequisite for submission of an application. See Section VIII. Other Information for award authorities and regulations.
