The primary aim for the use of these Research Grant funds is to support small-to-medium scale projects with a well-defined scope that will complement GREGoR’s ongoing efforts to develop novel approaches to identify candidate variants/genes underlying rare genetic diseases and phenotypes, particularly those that remain unsolved following whole exome sequencing.
Any investigator who is not part of a funded GREGoR center (i.e., does not have ‘core member’ status in GREGoR) is eligible for this funding call. An awardee may, however, be at the same institution as a GREGoR center.
Researchers from academic institutions within and outside the US are welcome to apply. Multiple applications from the same institution and principal investigator are allowed provided the proposals are sufficiently distinct scientifically. Diversity in institutions and investigators, and early-stage career status will be taken into consideration for funding decisions depending on the number of meritorious applications.
Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Principal Investigator(s) (PI(s)) is invited to work with their organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are encouraged to apply for these funding opportunities.
If you have questions regarding eligibility or the appropriateness of your research idea, we strongly encourage you to email firstname.lastname@example.org.
Priority will be given to proposed projects that use experimental or analytical approaches that complement ongoing efforts by the GREGoR Consortium. Focus areas of each Research Center can be found here. GREGoR samples span a wide spectrum of rare diseases, and we encourage proposals focused on a broad range of phenotypes, disease areas, and organ systems. Note: Pre-submission inquiries, Letters of Intent (LOIs), and applications may be shared confidentially with members of the GREGoR Opportunity Fund Committee to review for fit and alignment with GREGoR goals.
Proposals that are non-responsive (not eligible) for this funding announcement are described below:
- Proposals to carry out routine diagnostic sequencing are not eligible.
- Proposals that focus on common genetic variation or phenotyping of existing models without modeling new candidate genes/variants will be considered non-responsive.
- Proposals to carry out sequencing and/or analysis of individuals whose samples are not part of a GREGoR center's study cohort are not eligible. Researchers or clinicians who would like to collaborate with GREGoR Research Centers on these types of projects can find information here on ways to collaborate with the GREGoR Consortium or can email the Consortium’s Data Coordinating Center at <email@example.com>.
- Functional validation or follow-up studies only applicable to a small set of genes are not eligible.
Priority research areas that are appropriate for this funding announcement include but are not limited to:
Experimental approaches for functional validation or prioritization of GREGoR candidate genes and/or variants
- The Consortium is currently using a number of methods to establish or refute the causality – and further biological understanding – of candidate genes and variants. Broadly, these include: generation of disease models, RNA-sequencing, saturation genome editing, metabolomics, epigenetic assays, splicing assays, and induced neuronal cell and induced cardiomyocyte phenotyping. Consortium-generated disease models principally involve CRISPR-generated human cell lines including iPS cells, induced neural lines, and induced cardiomyocytes, but also fly, mouse, and zebrafish organism models.
- To supplement these largely “one-gene/variant-at-a-time” approaches, we are soliciting proposals that would test the functional effect of variants in >50 genes (or of >50 variants in a smaller number of genes) at a time – ideally in a single experiment.
- Proposals should test variants that have been found in human patients, at least some of which would be variants identified by GREGoR as potentially causally impactful for rare disease (to be determined via discussion with the Consortium in the first quarter of the award) but may also include additional genes/variant candidates derived from other rare disease sources.
- Successful proposals may overlap with the above approaches or those of other consortia, so long as there is novelty to the experimental design and/or set of genes/variants to which it is applied, as well as no overlapping funding.
- Proposals that will be applied to noncoding, repetitive, or complex structural candidate variants will be given highest priority.
New genomic technologies / molecular assays that can be applied to unsolved cases
- Projects to pilot the use of emerging or novel genomic technologies that could help resolve existing GREGoR samples that have remained unsolved after exhaustive sequencing and analysis (e.g. spatial sequencing, benchmarking experiments). Assays already run on many GREGoR samples include short read exome/genome sequencing (Illumina), RNA-seq, and long read (PacBio and Nanopore) genome sequencing, metabolomics and Optical Genome Mapping (Bionano platform). Available samples likely include banked DNA, banked RNA, frozen cells/tissue (in select cases), and patient-derived cell lines (in select cases).
- If a new assay is being developed on non-GREGoR samples, proposals must demonstrate that the assay would also have utility for GREGoR cases (i.e. unsolved after genome sequencing at a minimum).
User-friendly interfaces for interactive or batch annotation and interpretation of candidate variants in non-coding regions. Such an interface should provide tools and accompanying interpretation guidance (cutoff scores/ranks/etc.) that are easily utilized by a broad range of clinicians and researchers.
- Given genomic coordinates of a (typically non-coding) single nucleotide variant (SNV) or indel:
- Does the variant add or remove a transcription factor binding site; is the predicted change in the transcription factor binding likely to have a large effect on gene regulation consistent with a monogenic cause of disease?
- For which gene(s) is the variant predicted to decrease or increase expression, by how much, and in which tissues?
- Create a comprehensive set of annotations of predicted regulatory elements for specific tissues/developmental stages of interest for Mendelian conditions evaluated by GREGoR that could be used to identify candidate regions for novel/unsolved Mendelian phenotypes (e.g. developmental heart defect, cerebellar malformation, limb malformation, skin, immune system, malformation of reproductive organs, muscular dystrophy, cornea, neurodevelopmental conditions, and holoprosencephaly).
Tools may be:
- Web portals for annotating small numbers of variants
- Command line executables applicable to genome-scale data (e.g. VCFs)
Novel analytical approaches useful for analyzing GREGoR molecular data (these data include, but are not limited to: short-read DNA and RNA sequencing, long-read Nanopore and PacBio sequencing, methylation array and sequencing, metabolomics, optical genome mapping)
- Head-to-head comparisons of available bioinformatics tools for calling/discovery or pathogenicity prediction.
- Development or piloting of new computational tools for variant filtration/analysis. This is especially needed for data types newly/recently applied for rare disease research such as RNA-Seq data and methylation data from long read (Nanopore or PacBio) sequencing.
- Bioinformatics tools that integrate analysis of two or more types of data. For instance, multi-omic approaches that enable coordinated variant prioritization across short-read DNA and RNA sequencing or across short-read DNA and long read sequencing.
Development of software that increases the utility of the GREGoR Combined Consortium Dataset for rare disease research by providing summary/aggregate genotype and phenotype information
- The Consortium Data is hosted on the NHGRI AnVIL platform and is structured to conform with the GREGoR Consortium Data Model. Proposed software should leverage the GREGoR Data Model which is designed to integrate family, clinical and phenotype information with experimental metadata and quality control information.
- Highly desirable are applications that propose software compatible with or executable on AnVIL and that enable sophisticated and semantically integrated queries (e.g. cohort building or case matching based on phenotypic similarity), and analysis across variant, gene, disease, and phenotype data as structured in the GREGoR Consortium Data Model
- Proposed software must be open source, well documented, and freely available for use or modification by others.
Deadline Dates and Submission Details
|Deadline Date and Time||Submission November|
|November 10, 2023 by 11:59 p.m. Pacific Time (PT)||Letter of Intent (LOI) due|
|December 1, 2023||Eligible applicants are notified and invited to submit an application (see next steps below)|
|January 12, 2024 by 11:59 p.m. PT||Applications due|
|March 1, 2024||Awards announced|
|April 1, 2024||Start date of awards|
|March 31, 2025 for 1-year awards or March 31, 2026 for 2-year awards||Deadline by which research needs to be completed|
The GREGoR Consortium’s Data Coordinating Center will facilitate a scientific review similar to that performed by the National Institutes of Health. The review will be performed by experts in Mendelian genomics and potentially others with relevant areas of expertise who are not active members of the GREGoR Consortium. With input from Consortium leadership, NHGRI will make the final funding decisions for these awards. GREGoR Consortium members on the Opportunity Fund Sub-Committee may be given access to application materials and asked to provide input during the application review process. All application materials are confidential to NHGRI, the Data Coordinating Center and the members of the Opportunity Fund Sub-Committee.
Requirements to Issue an Award
To issue an award, upon award notification the following will need to be provided:
- IRB approval (for Human or Animal research).
- Project Narrative statement: maximum 3 sentences describing your project. Use plain language for a general audience.
- Contact information for the fiscal person at your University.
- Signed agreement between the University of Washington and your University - this will be initiated by the UW business office.
- Agreement to follow the GREGoR Consortium Publications Policy.
- Agreement to follow the GREGoR Data Sharing Agreement.
- GREGoR Partner Membership: Research Grant Awardees automatically become Partner Members during the term of their award.
- Current Facilities and Administrative Cost Rates (overhead) rate agreement: if your institution does not have a negotiated rate, we will use the de minimis rate allowed by federal regulations.
- Institutions are required to have a unique entity ID (UEI) issued by System for Award Management (SAM.gov) at the institutional level - not the individual level.
- Reporting requirements for awardees will include: initial presentation about your Research Grant project and goals to GREGoR Consortium members at a GREGoR Science Seminar (virtual).
- Presentation on the progress of your project at a GREGoR Science Seminar, likely in the December - February range at the end of the first award year, and subsequent years for multi-year awards.
- If requested: a brief written report at the conclusion of your project/funding period or towards the end of each award year.
Next Steps After LOI Submitted - Grant Application Required Materials
Based on LOI submissions received by the deadline, eligible applicants who propose research of high interest to the Consortium will be invited via email to submit a Research Grant application. DO NOT email application materials for the GREGoR Research Grants to the GREGoR DCC.
Below is a sample of the materials required for the Research Grant Application:
- Administrative Information
- Format of pdf file: “YOURLASTNAME_First Initial_2024_admin.pdf”
- Project title
- University affiliation
- Contact information for the Contact PI, including name, title, and email address
- Name(s) and affiliation(s) of other investigators and key personnel
- Description of each participating investigator’s role in the project
- Detailed budget form with budget justification
- Letter of Institutional Support
- If your institution has a standard letter that is acceptable
- Biosketch and Proposal Information
- Format of pdf file: “YOURLASTNAME_First Initial_2024_proposal.pdf”
- Abbreviated Biosketch template (will be provided; maximum 1 page per key personnel)
- Please provide eRA commons ID only if available. If you do not have one, it can be obtained during the award process
- Proposal (maximum 3 pages including references, if applicable)
- Research Grant Priority Areas of Interest