Department of Health and Human Services
Part 1. Overview Information
Participating Organization(s)

National Institutes of Health (NIH)

Components of Participating Organizations

National Human Genome Research Institute (NHGRI)

Funding Opportunity Title
Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Phase 1: Data Production Research and Development Centers (UM1 Clinical Trial Not Allowed)
Activity Code

UM1 Research Project with Complex Structure Cooperative Agreement

Announcement Type


Related Notices


Funding Opportunity Announcement (FOA) Number


Companion Funding Opportunity

RFA-HG-21-030 - Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Phase 1: Data Analysis and Validation Centers (U01 Clinical trials not allowed)
RFA-HG-21-031 - Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Phase 1: Data Resource and Administrative Coordinating Center (U24 Clinical trials not allowed)

RFA-HG-22-019 - Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Phase I: Data Analysis and Validation Centers (U01 Clinical trials not allowed)

Assistance Listing Number(s)


Funding Opportunity Purpose

This FOA is one of three issued to create a new program called "Molecular Phenotypes of Null Alleles in Cells (MorPhiC)". The long-term goal of MorPhiC is to develop a consistent catalog of molecular and cellular phenotypes for null alleles for every human gene, using in vitro multicellular systems. The catalog will be made available for broad use by the biomedical community. The program will start with a Phase 1 to optimize available methods to create null alleles and measure their phenotypic effects in a target subset of 1000 protein coding genes across the program. Phase 1 will also assess the scale limitations of such methods, develop common data formats, establish use cases for this catalog, and inform whether and how a potential second phase will be implemented. This specific FOA seeks applications for MorPhiC Data Production Research and Development Centers, which will develop diverse systems and assays and explore and compare approaches to produce MorPhiC data at scale, and to maximize its informativeness.

Key Dates
Posted Date

August 6, 2021

Open Date (Earliest Submission Date)

October 1, 2021

Letter of Intent Due Date(s)

While letters of intent are normally due 30 days prior to the application due date, letters of intent for this FOA are due September 15, 2021

Application Due Date(s)

November 1, 2021

All applications are due by 5:00 PM local time of applicant organization. All types of non-AIDS applications allowed for this funding opportunity announcement are due on the listed date(s)

Applicants are encouraged to apply early to allow adequate time to make any corrections to errors found in the application during the submission process by the due date.

AIDS Application Due Date(s)

Not applicable

Scientific Merit Review

March 2022

Advisory Council Review
Earliest Start Date

September 2022

Expiration Date

November 2, 2021

Due Dates for E.O. 12372

Not Applicable

Required Application Instructions

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed to do otherwise (in this FOA or in a Notice from the NIH Guide for Grants and Contracts). Conformance to all requirements (both in the Application Guide and the FOA) is required and strictly enforced. Applicants must read and follow all application instructions in the Application Guide as well as any program-specific instructions noted in Section IV. When the program-specific instructions deviate from those in the Application Guide, follow the program-specific instructions. Applications that do not comply with these instructions may be delayed or not accepted for review.

Table of Contents

Part 1. Overview Information
Part 2. Full Text of the Announcement

Section I. Funding Opportunity Description
Section II. Award Information
Section III. Eligibility Information
Section IV. Application and Submission Information
Section V. Application Review Information
Section VI. Award Administration Information
Section VII. Agency Contacts
Section VIII. Other Information

Part 2. Full Text of Announcement
Section I. Funding Opportunity Description


The 2020 NHGRI Strategic Vision ( laid out a set of bold predictions for human genomics by 2030 that included: The biological function(s) of every human gene will be known; for non-coding elements in the human genome, such knowledge will be the rule, rather than the exception. In addition, the Strategic Vision states that recent advances in knowledge and technology " provide an unprecedented opportunity to decipher the individual and combined roles of each gene and regulatory element. This must start with establishing the function of each human gene, including the phenotypic effects of human gene knockouts".

Systematically obtaining information about the molecular and cellular phenotypic effects of gene knockouts for all human genes would provide wide-ranging insights into the biological function of genes filling a gap between more direct molecular readouts, such as RNA expression, and whole-organism phenotypes. Such data would provide a foothold for understanding the mechanisms through which genes act to produce phenotypes and would help elucidate the roles and relationships of genes and regulatory elements in pathways and networks, as called out as one of the "compelling genomic research projects" in the NHGRI Strategic Vision.

Based on these considerations, NHGRI is initiating a new program, the Molecular and Cellular Phenotypes of Null Alleles (MorPhiC) Consortium, with the long-term goal of developing a consistent catalog of informative molecular and cellular phenotypes for null alleles for every human gene, using in vitro multicellular systems.

  • The catalog should be consistent, that is, generated using standardized assays and providing a comparable level of phenotype information for each gene. Consistent data enables comparisons between genes, computational modeling, and integration with other functional and phenotypic data.
  • The catalog should include informative molecular and cellular phenotypes. We interpret the word "assays" broadly-- for example, they may go beyond the usual molecular -omics assays to include cell shape and motility, survival/differentiation, and other phenotypes. Genes often have multiple cellular roles and participate in multiple processes, making this goal challenging. MorPhiC therefore does not aim to catalog every function of each gene assayed, but to catalog a core, well characterized "minimal set" of functional information for each gene that is as informative as possible for understanding biological processes. We envision a handoff, where downstream users will combine this information with other functional data to more thoroughly characterize specific genes, or sets of genes, in specific contexts.
  • Null alleles generally, those producing no functional protein are useful as a basis for interpreting other alleles, including regulatory alleles that may have weaker effects (e.g., lower penetrance and expressivity), and gain-of-function alleles. A null allele is also useful for interpreting alleles of other genes that produce similar or opposite phenotypes, and interpreting effects of other perturbations (e.g., small molecule or environmental exposures). Alternatives may be required if the homozygous null cannot be assayed (e.g., is cell lethal in an assay--see below).
  • While the long-term goal of MorPhiC is to be comprehensive with respect to genes, the Phase 1 goal is to target 1000 protein coding genes. This number will be large enough to attain the Phase 1 goals, allowing for diverse genes (with regard to e.g. tissue, functional class, disease relevance) to be tested, and to allow for useful overlap to test the same gene in multiple assays, or for quality assessment.
  • MorPhiC will catalog molecular and cellular phenotypes using multicellular systems that are likely to be informative of human biology, while at the same time having the potential for scalability and reproducibility. This initiative has a strong preference for complex multicellular systems-- such as organoids-- for several reasons. Mainly, they have the potential to more faithfully model human tissue-level phenotypes. Technological advances in this field are well-supported, so the state of the art is likely to improve substantially in the near-term. Moreover, NHGRI (and others) already support multiple other efforts to look at phenotypes in monotypic cell cultures.

Phase 1 of the project will explore the feasibility of developing the MorPhiC catalog and inform its ultimate value. Specifically, the goal of Phase 1 will be to optimize available methods to create null alleles in a target subset of coding genes and to measure their phenotypic effects in multi-cellular systems. It will test the feasibility of integrating the key technical components into a beginning production pipeline. Phase 1 will also assess the scale limitations of such methods, identifying technical and other bottlenecks, and understanding cost drivers. It will develop common data formats. It will examine the ability to use the data to address different kinds of biological questions in order to understand the value of the data, as a whole, and to understand which particular assays may be the most valuable for MorPhiC. All of this will be used to assess the feasibility of a potential second phase.

To achieve the goals of Phase 1 of MorPhiC the following three FOAs are issued:

  • Data Production Research and Development Centers (DPC) RFA-HG-21-029 (this FOA) to develop, implement and compare approaches for obtaining null alleles in human cells, and to assess and catalog the resulting molecular and cellular phenotypes. This FOA is for the DPC component.
  • Data Analysis and Validation Centers (DAV) RFA-HG-21-030 to evaluate and ensure utility of the generated data and to begin to use them in analysis.
  • Data Resource and Administrative Coordinating Center (DRACC) RFA-HG-21-031 to receive, integrate, annotate, and present data for consortium and public use, and provide logistical support for the consortium.

The data and analyses performed in Phase 1 will substantively advance our knowledge of gene function and how to design large-scale approaches to understanding gene function. However, one potential outcome of MorPhiC Phase 1 may be that it is not feasible to achieve the scale, consistency, utility, and interpretability to move to a Phase 2, as evaluated by NHGRI.

Proposed Scope and Objectives

The high-level intent of the Phase 1 MorPhiC Consortium is to confront the "Main Barriers" to initiating a full-scale effort, including:

  • What is the optimal way to make null alleles at scale for this purpose? What quality assessment (QA) is needed to ensure these are null alleles? Is there one method that would be compatible with all genes and informative assays? Can existing resources (e.g., libraries of iPSC knock-out lines) be leveraged, or do alleles need to be created? Do we need alternatives to true null alleles in some cases?
  • How can we prioritize the 1000 genes to represent a fair test of generalizability across the genome and organism? What human multicellular systems will be scalable, reproducible, and highly informative about human biology? Are organoids and similar systems currently sufficiently reproducible?
  • What are the best assays, or assay strategies/combinations for measuring molecular and cellular phenotypes? Are assays going to yield readouts that are specific and informative about complex organismal phenotypes? How do we maximize how informative the assays are? Can assays be made more generalizable?
  • How can we anticipate and address, or even take advantage of, potential technical and interpretation issues due to underlying biology, such as: cell- or tissue-type specificity, pleiotropy, cell lethality, haploinsufficiency, cell non-autonomy, natural biological variability?
  • What is the ultimate utility of the data for various purposes? Across all genes, will molecular and cellular assays of null alleles in humans be informative for understanding gene function in basic and clinical applications? Does the proposed catalog provide data in ways that elucidate the roles and relationships of genes and regulatory elements in pathways and networks?
  • What quality and consistency of data is needed? What is the best way to manage and organize the data and present it to the community? What is needed for these data to be interoperable and highly useful in combination with other "perturbation X phenotype" data sets, such as those generated by IGVF ( ), or the Knock Out Mouse Program (KOMP; )?
  • What are the major bottlenecks and cost drivers? Where can costs be reduced?
  • What insights can we gain about the best way to organize a full-scale effort for a potential Phase 2?

This list is not exhaustive. Moreover, some of these challenges are evident now, and some will only become evident as Phase 1 progresses.

This FOA is for the Data Production Research and Development Centers (DPC) component of MorPhiC. MorPhiC DPC's will carry out the following key tasks to address the "Main Barriers" above:

  • Develop--with other MorPhiC components-- an approach that will be informative for how we can eventually generalize and scale to a genome-wide effort.
  • Lead the consortium prioritization of genes including developing a rationale for their prioritization.
  • Produce null alleles in the chosen cellular system. If appropriate, existing libraries of knock-out iPSCs and other cell lines should be leveraged.
  • Test high-throughput cellular and molecular assays in in vitro human system(s). Multicellular complex systems (e.g., organoids derived from iPSCs) are highly preferred, but alternative systems may be proposed with justification for how they achieve the MorPhiC Phase 1 goals. Molecular and cellular assays should be considered based on their throughput and the utility of information they provide. Assays selected--on their own or in combination-- should be able to be more broadly applied to multiple cell types, multiple phenotypes, multiple diseases, etc.
  • Develop methods to ensure comparability and reproducibility, including developing metrics and quality standards; standardize allele and assay validations.
  • Share data, best practices, protocols, methods, software, etc. (see below).
  • Collaborate with other consortia or projects developing complementary data sets.
  • It is important for the proposed experimental designs to explicitly address the broad MorPhiC Phase 1 "Main barriers" outlined above.

Diversity of approaches. Within these constraints, a diversity of approaches will be considered: different ways of generating alleles, different cell systems, different assays, and different approaches to attaining generalizability and the potential for comprehensiveness. For example, the state-of-the-art for organoids may differ between different tissue types. There may be limits on how generalizable any single assay system can be, necessitating alternative strategies such as multiplexing or panel testing of more specific assays; or pre-screening genes (e.g., by cell-type expression; by KOMP phenotype) for subsequent assignment to maximally informative assays. Different approaches may involve different numbers or prioritization of gene targets (up to 1000 per DPC).

Technology optimization. We expect that proposed allele generation, culture systems and assays will be developed enough to begin to test production-scale work within the first year. There may be a need for optimization of the key technical steps proposed (mutagenesis, cellular systems, or assays, e.g., for improved scale/quality/cost, for comparability/reproducibility, for integration). However, MorPhiC Phase 1 will not fund wholly new technology development.

Population diversity. In order to ensure that biological conclusions and potential downstream clinical uses are widely applicable, it is critical that MorPhiC obtain data from samples derived from individuals of diverse ancestry. Applicants must include plans for including such samples.

Consortium Formation and Collaboration

This FOA uses the Cooperative Agreement mechanism. The key objectives of MorPhiC Phase 1 can only be realized by coordinating among what are likely to be diverse approaches, leading to the need to organize MorPhiC into a consortium.

Successful applicants will become members of the MorPhiC Consortium composed of investigators who have been funded in response to one of the three companion FOAs. Awardees are expected to work collaboratively with all members of the consortium towards meeting consortium goals, in addition to the research goals outlined in their individual applications. Synergies among the different components will be identified by the consortium and pursued to generate a better understanding of how to produce the long-term catalog.

For the DPCs, the most important collaborative task will be to prioritize and assay the Phase 1 1000 genes, and to develop standards and methods to ensure comparability, reproducibility, complementarity, etc. of assay results. Once awards are made, successful applicants will be asked to collaborate to develop common plans to prioritize genes, and assay the effects of the null alleles, as efficiently and reproducibly as possible, across the consortium.

Awardees will also be required to work collaboratively with the other MorPhiC components as they are stood up.

At key points during Phase 1, the consortium will be asked to critically evaluate the approaches taken and their potential for long-term inclusion in a full catalog.

Awardee consortium responsibilities will include:

  • Planning experiments, implementing studies, and analyzing results from within component and consortium-wide projects, typically through working groups including all Consortium components.
  • Developing standards and metrics for data, metadata, data quality, and analyses together with the DRACC and DAV.
  • Contributing all data, metadata, protocols, methodologies, analyses, software, and other products to the DRACC and appropriate repositories in specified formats. NHGRI supports the broadest appropriate genomic data sharing with timely data release through widely accessible data repositories. If applicable, awardees are expected to comply with the NIH Genomic Data Sharing (GDS) Policy More information on this expectation can be found on NHGRI's Genomic Data Sharing Policy FAQs.
  • Sharing best practices and lessons learned within the consortium and with the external community.
  • Participating in the development of, and following consortium policies on, data sharing and publication.
  • Taking part in consortium-wide, Steering Committee, and working group meetings.
  • Contributing to outreach efforts, including collaborating with other consortia and projects.

All investigators will be required to attend a kickoff meeting for the consortium that will take place soon after awards are made. A major focus of the kickoff meeting will be establishing the consortium's scientific direction and interactions within and between components. A Steering Committee composed of the funded PDs/PIs and NHGRI staff will be established to guide the overall scientific direction of the consortium. The Steering Committee will meet regularly and be complemented by a set of working groups. NHGRI staff will also recruit outside experts (non-awardees) as an External Scientific Panel to provide advice directly to NHGRI. Applicants should budget adequate funds for collaborative work in all grant years.

Diverse Applicants

NHGRI strongly encourages all investigators with innovative ideas aligned with the goals of this FOA to submit applications. NHGRI especially encourages applicants who are new investigators, experienced investigators who are new to genomic science, investigators that have not previously participated in a NHGRI consortium or program, and investigators from demographic groups or institutions that are generally underrepresented in genomic science, both directly as applicants, and also as part of applications that propose to form diverse collaborations responsive to this FOA.

Non-Responsive Applications

Projects with the following properties will be considered non-responsive, and will not be reviewed:

  • Projects that are not focused on the downstream molecular and cellular phenotypic consequences of null alleles in humans. Projects that test cis-regulation or noncoding variants (except those strategically designed to produce the null alleles) are not responsive. Use of mutations other than nulls may be justified in cases where nulls cannot be assayed (i.e., as an alternative in cases where specific nulls are lethal in the assay system).
  • Projects that are primarily developing new experimental methods.
  • Projects that only aim to accomplish a subset of the key components (e.g., only developing alleles, or only assays) rather than identifying and addressing the key components as an integrated effort.
  • Projects that use non-human model organisms except as a validation of human cell systems. Applications proposing more than 10% of their budget for animal model systems will be considered non-responsive.
  • Projects focused on a single disease; projects that propose approaches focused on a single phenotype, single class of genes, or single specific assay that do not include or is not a part of a clear path to being generalizable e.g., across genes or cell types.
  • Proposed work that does not indicate plans to participate to contribute to consortium-wide, collaborative activities and analyses throughout the course of the project.

Informational 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 for potential applicants. NIH staff will be available to answer questions related to this FOA. The Webinar will occur on September 10, 2021 at 1-3 PM US Eastern DST. Further information will be posted on the NHGRI website: or can be obtained from the Program contact (below). During the webinar, NHGRI staff will present overviews of the FOAs and answer FOA-related questions from prospective applicants. Questions may be submitted in advance to Frequently asked questions will be posted afterwards. 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.

Section II. Award Information
Funding Instrument

Cooperative Agreement: A support mechanism used when there will be substantial Federal scientific or programmatic involvement. Substantial involvement means that, after award, NIH scientific or program staff will assist, guide, coordinate, or participate in project activities. See Section VI.2 for additional information about the substantial involvement for this FOA.

Application Types Allowed


The OER Glossary and the SF424 (R&R) Application Guide provide details on these application types. Only those application types listed here are allowed for this FOA.

Clinical Trial?

Not Allowed: Only accepting applications that do not propose clinical trials)

Need help determining whether you are doing a clinical trial?

Funds Available and Anticipated Number of Awards

NHGRI intends to commit $7M total in FY 2022 to fund 4-5 awards.

Award Budget

Application budgets must not exceed $1.1M direct costs per year.

Award Project Period

The maximum project period is five years.

NIH grants policies as described in the NIH Grants Policy Statement will apply to the applications submitted and awards made from this FOA.

Section III. Eligibility Information
1. Eligible Applicants
Eligible Organizations

Higher Education Institutions

  • Public/State Controlled Institutions of Higher Education
  • Private Institutions of Higher Education

The following types of Higher Education Institutions are always encouraged to apply for NIH support as Public or Private Institutions of Higher Education:

o Hispanic-serving Institutions

o Historically Black Colleges and Universities (HBCUs)

o Tribally Controlled Colleges and Universities (TCCUs)

o Alaska Native and Native Hawaiian Serving Institutions

o Asian American Native American Pacific Islander Serving Institutions (AANAPISIs)

Nonprofits Other Than Institutions of Higher Education

  • Nonprofits with 501(c)(3) IRS Status (Other than Institutions of Higher Education)
  • Nonprofits without 501(c)(3) IRS Status (Other than Institutions of Higher Education)

For-Profit Organizations

  • Small Businesses
  • For-Profit Organizations (Other than Small Businesses)


  • State Governments
  • County Governments
  • City or Township Governments
  • Special District Governments
  • Indian/Native American Tribal Governments (Federally Recognized)
  • Indian/Native American Tribal Governments (Other than Federally Recognized)
  • Eligible Agencies of the Federal Government
  • U.S. Territory or Possession


  • Independent School Districts
  • Public Housing Authorities/Indian Housing Authorities
  • Native American Tribal Organizations (other than Federally recognized tribal governments)
  • Faith-based or Community-based Organizations
  • Regional Organizations
  • Non-domestic (non-U.S.) Entities (Foreign Institutions)
Foreign Institutions

Non-domestic (non-U.S.) Entities (Foreign Institutions) are eligible to apply.
Non-domestic (non-U.S.) components of U.S. Organizations are eligible to apply.
Foreign components, as defined in the NIH Grants Policy Statement, are allowed.

Required Registrations

Applicant Organizations

Applicant organizations must complete and maintain the following registrations as described in the SF 424 (R&R) Application Guide to be eligible to apply for or receive an award. All registrations must be completed prior to the application being submitted. Registration can take 6 weeks or more, so applicants should begin the registration process as soon as possible. The NIH Policy on Late Submission of Grant Applications states that failure to complete registrations in advance of a due date is not a valid reason for a late submission.

  • Dun and Bradstreet Universal Numbering System (DUNS) - All registrations require that applicants be issued a DUNS number. After obtaining a DUNS number, applicants can begin both SAM and eRA Commons registrations. The same DUNS number must be used for all registrations, as well as on the grant application.
  • System for Award Management (SAM) Applicants must complete and maintain an active registration, which requires renewal at least annually. The renewal process may require as much time as the initial registration. SAM registration includes the assignment of a Commercial and Government Entity (CAGE) Code for domestic organizations which have not already been assigned a CAGE Code.
  • o NATO Commercial and Government Entity (NCAGE) Code Foreign organizations must obtain an NCAGE code (in lieu of a CAGE code) in order to register in SAM.
  • eRA Commons - Applicants must have an active DUNS number to register in eRA Commons. Organizations can register with the eRA Commons as they are working through their SAM or registration, but all registrations must be in place by time of submission. eRA Commons requires organizations to identify at least one Signing Official (SO) and at least one Program Director/Principal Investigator (PD/PI) account in order to submit an application.
  • Applicants must have an active DUNS number and SAM registration in order to complete the registration.

Program Directors/Principal Investigators (PD(s)/PI(s))

All PD(s)/PI(s) must have an eRA Commons account. PD(s)/PI(s) should work with their organizational officials to either create a new account or to affiliate their existing account with the applicant organization in eRA Commons. If the PD/PI is also the organizational Signing Official, they must have two distinct eRA Commons accounts, one for each role. Obtaining an eRA Commons account can take up to 2 weeks.

Eligible Individuals (Program Director/Principal Investigator)

Any individual(s) with the skills, knowledge, and resources necessary to carry out the proposed research as the Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) is invited to work with his/her organization to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH support.

For institutions/organizations proposing multiple PDs/PIs, visit the Multiple Program Director/Principal Investigator Policy and submission details in the Senior/Key Person Profile (Expanded) Component of the SF424 (R&R) Application Guide.

2. Cost Sharing

This FOA does not require cost sharing as defined in the NIH Grants Policy Statement.

3. Additional Information on Eligibility
Number of Applications

Applicant organizations may submit more than one application, provided that each application is scientifically distinct.

The NIH will not accept duplicate or highly overlapping applications under review at the same time. This means that the NIH will not accept:

  • A new (A0) application that is submitted before issuance of the summary statement from the review of an overlapping new (A0) or resubmission (A1) application.
  • A resubmission (A1) application that is submitted before issuance of the summary statement from the review of the previous new (A0) application.
  • An application that has substantial overlap with another application pending appeal of initial peer review (see NOT-OD-11-101).

Although this RFA allows multiple applications per institution, please see section V.2, Review and Selection Process.

Section IV. Application and Submission Information
1. Requesting an Application Package

The application forms package specific to this opportunity must be accessed through ASSIST, Workspace or an institutional system-to-system solution. Links to apply using ASSIST or Workspace are available in Part 1 of this FOA. See your administrative office for instructions if you plan to use an institutional system-to-system solution.

2. Content and Form of Application Submission

It is critical that applicants follow the Research (R) Instructions in the SF424 (R&R) Application Guide, except where instructed in this funding opportunity announcement to do otherwise. Conformance to the requirements in the Application Guide is required and strictly enforced. Applications that are out of compliance with these instructions may be delayed or not accepted for review.

Letter of Intent

Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review.

By the date listed in Part 1. Overview Information, prospective applicants are asked to submit a letter of intent that includes the following information:

  • Descriptive title of proposed activity
  • Name(s), address(es), and telephone number(s) of the PD(s)/PI(s)
  • Names of other key personnel
  • Participating institution(s)
  • Number and title of this funding opportunity

The letter of intent should be sent to:

Adam Felsenfeld
Telephone: 301-496-7531

Page Limitations

All page limitations described in the SF424 Application Guide and the Table of Page Limits must be followed with the following exceptions or additional requirements: For this specific FOA, the Research Strategy section is limited to 30 pages overall. Four sections are required, with no specific page limits for each section of the Research Strategy.

Instructions for Application Submission

The following section supplements the instructions found in the SF424 (R&R) Application Guide and should be used for preparing an application to this FOA.

SF424(R&R) Cover

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Project/Performance Site Locations

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Other Project Information

All instructions in the SF424 (R&R) Application Guide must be followed.

SF424(R&R) Senior/Key Person Profile

All instructions in the SF424 (R&R) Application Guide must be followed.

R&R Budget

All instructions in the SF424 (R&R) Application Guide must be followed. For single PD/PI applications, the PD/PI is expected to devote at least 3 person months, based on a 12-month calendar. If multi-PDs/PIs are proposed, then each PD/PI is expected to commit sufficient time to serve his/her proposed role, with a minimum aggregate PD/PI effort of 3 person months, and at least one PI devoting 2 months. The appropriateness of the effort of key personnel must be justified in the budget justification.

Budgets should include support for a dedicated Project Manager who will devote a minimum of 4 person months, based on a 12-month calendar, to oversee the day-to-day activities of the center, coordinate metadata and data submissions to the DRACC, coordinate across center sites, if applicable, and be responsible for promptly providing requested reporting information to NHGRI Program Staff. A PD/PI may serve as the Project Manager.

Budgets should include funds for the PD(s)/PI(s) and key personnel to attend the initial consortium kickoff meeting, and for the PD(s)/PI(s) and 2-6 members of the center to attend annual consortium meetings thereafter that start in year 1. Budgets should also include funds for the PD(s)/PI(s) to attend mid-year, in-person Steering Committee meetings.

Budgets should include any funds required to support sharing of genomic data under this FOA (e.g., to obtain samples with explicit informed consent for future research use and broad data sharing, or to prepare the data for submission to appropriate repositories). In all years, reasonable costs must be allocated to support shared work with other consortium components, with specific tasks to be determined in consultation with NHGRI staff. This work is anticipated to further both the needs of the funded centers and the consortium.

R&R Subaward Budget

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Cover Page Supplement

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS 398 Research Plan

All instructions in the SF424 (R&R) Application Guide must be followed, with the following additional instructions:

Specific Aims: Describe the specific goals of the Production Center and its role in achieving the overall objectives of the MorPhiC Consortium.

Research Strategy: In the Research Strategy, applicants should propose plans, approaches, and potential alternative strategies for carrying out the goals of the Production Center. Applications should address all the key elements in an integrated way. The Research Strategy must consist of the following subsections uploaded as a single PDF attachment:

1) Center Overview and Management

2) Mutagenesis, Biological Samples/Systems, and Experimental Assays

3) Data Management and Analysis

4) Integration

Details about what should be discussed in each section are described below.

1) Center Overview and Management

Provide an overview of the proposed Production Center and how it will be structured to achieve the center’s goals and the major objectives of the FOA. This should include a high-level description of the strategic approach proposed (choice/generation of alleles, cell systems, assays), along with the high-level rationale behind those choices, with details to be covered in the subsections below. The overview should provide a sense of how the proposed Phase 1 effort will contribute data, methods, and knowledge about feasibility and organization of a potential MorPhiC catalog, and, more generally, contribute to the understanding or interpretation of gene and/or pathway function or other biological processes. Any planned technical, strategic, methodological, analytical, or other innovation may be highlighted.

Outline the expertise of the research team (without duplicating information in the Biosketches) and explain how their expertise aligns with the key components of the FOA (e.g., mutagenesis; organoids or other cellular systems; assays; data integration, see above).

Describe the management structure of the proposed center, including the role of the Project Manager responsible for day-to-day operations, components of the center and how they will be integrated to form a cohesive center, key personnel and their responsibilities (such as those responsible for data collection, data analyses, and data submission), and overall center leadership.

Discuss how the encouragement of diversity in both samples and investigators has been addressed.

Discuss past experiences (if any) in working as part of interdisciplinary teams and/or large collaborative research efforts. Describe how consortium activities will be managed including how this proposed center will work collaboratively with other components of the consortium in component-specific and consortium-wide activities such as finalizing prioritization of the 1000 target genes, establishing a data collection strategy, comparing across approaches, and planning joint analyses. This should include descriptions of consents or material transfer agreements that allow for sharing of samples and data with other consortium-supported centers and projects. This should also include plans for management of any external collaborations, if relevant.

As part of the management plan, applicants should give an overview of how they will ensure the essential elements of reproducibility in their own laboratories, and also propose the key elements for ensuring reproducibility and comparability among consortium members, including e.g., overlap in genes tested and assays. Details about ensuring reproducibility should be included in the appropriate sections below.

Include a detailed timeline and milestones for tracking all aspects of the center and the proposed studies. Whenever feasible, milestones should provide quantitative metrics for assessing the center’s progress. Milestones will be reviewed and updated, as needed, in consultation and with the approval of NHGRI.

2) Mutagenesis, Biological Samples/systems, and Experimental Assays

The elements A-E below must be clearly addressed in the application. However, applicants may use a different order (or combine or split elements) if the rationale for each, and the factors to be considered in integrating them, will be clearer or will fit better with their proposed approach.

Because MorPhiC Phase 1 will be a pilot project for a potential scaled Phase 2, it is expected that all methods proposed will be ready, or close to being ready, for use in a rudimentary but integrated production pipeline. Choices should be supported by publications or preliminary data.

For the elements A-E below, both the individual elements, and their integration, should be described. Descriptions should address how approaches have the potential to generalize across genes and tissues, and their potential to scale. Consider how the elements overall will balance throughput and interoperability/utility of the data, its relevance to human phenotypes, and otherwise address the "Main Barriers" described in the "Scope and Objectives" section above. Describe potential problems, alternative strategies, how you will evaluate whether the element is successful (including benchmarks), and how you will respond if issues arise.

This FOA encourages applicants to propose innovative solutions to address the "Main Barriers" discussed above, and others that may be identified by applicants, where they are needed. Proposed innovations should be justified, e.g., in terms of improved methods, scale, interpretability/utility of data, integration between key elements; etc.

A. Provide the rationale for the choice of genes and number of genes to be targeted in this center. Although the ultimate prioritization within Phase 1 will be done as a consortium, each applicant should propose a prioritization scheme that best fits with their proposal, with examples, for up to 1000 genes. This section should state where the proposal is open to flexibility about gene priorities, and may propose factors to be considered when the consortium-level prioritization is done (e.g., including allowing for overlap, allowing for allocation based on assays, etc.).

B. Describe how samples will be obtained and alleles produced along with the rationale for these choices. Plans should include how samples will be obtained in a way that the work can begin in a timely fashion with minimal delay. Applicants may propose to generate new null alleles, or may use existing resources (for example, available libraries of CRISPR/Cas9 alleles in iPSCs that can be differentiated into systems for assays; siRNA libraries, etc.). Applicants need not be strictly limited to actual genetic knockouts, as long as the alleles are functionally equivalent to a null (i.e. do not produce functional protein) and otherwise aid in attaining the FOA goals. Applicants must describe how alleles will be ascertained/QC'd to ensure they are null and stable enough to work in assays. Plans should discuss potential artifacts or confounders (e.g. genetic compensation for certain alleles; cases in which the homozygous null is cell lethal in their assays) and how they will be addressed. Once the Consortium is formed, MorPhiC standards will be developed for allele QC.

In the context of this FOA, any cell lines generated or used will need to be transferable (to be available to the community), and data from them will need to be sharable. See Data Sharing Plan and Resource Sharing Plan below. We assume that there will be genome sequence available for these samples as part of their basic characterization (either available in advance or produced for MorPhiC). Other kinds of data that will facilitate analyses may be available as well, including disease status or other phenotype data. Where these are present, they should be made available in a way that can be associated with the MorPhiC sample data.

This FOA also requires that cell lines originate from, or samples be chosen from, participants from diverse human populations, and that are balanced with regard to sex. This section should include a plan for how those samples will be obtained, along with the rationale for the choices and how this will impact the research plan and how such sampling will be considered in analysis. Applicants should also plan to collect information on age of the sample donor and consider how they will control for this factor, as well as any other subject-level factors the applicant considers, as appropriate.

If new samples will be obtained, the consent process should be described. If using existing samples, applicants should address how the consents will allow wide use of the data and cell lines (see Resource Sharing, below).

C. Describe and provide a detailed rationale and justification for the cellular systems that will be assayed and how they will be produced and characterized. The FOA has a preference for complex multicellular systems such as organoids but others may be proposed if they are justified, including 2D culture systems if necessary. It is important to address issues with reproducibility and biological variability, and in the context of MorPhiC, potential for scale and comparability with results from other assay systems. Non-human systems (including whole organisms) may only be used for validation (10% of the budget, maximum). We encourage applicants to make use of existing data for validation, especially the KOMP resource. All choices should be clearly justified in terms of the FOA goals.

D. Describe and provide a detailed rationale for the molecular and cellular assays and how they will be carried out, including information about controls/comparisons. Assays should be well-justified in terms of their potential to scale, and to provide useful, interpretable information related to human phenotypes. Applicants should discuss rationales for assay choice (individually and in combination) and balance between number of genes versus number of assays per gene. In choosing, describing, and justifying the assays, applicants should refer to the factors discussed in the "Main Barriers" section of the Scope and Objectives, and elaborated here:

  • What are the best assays, or assay strategies/combinations? How can informativeness be maximized? What are the factors driving this question? Are assays going to yield readouts that are specific, faithful to, and informative about complex organismal phenotypes? How do we maximize how informative the assays are? Can assays be made more generalizable? Multiplexed? Are iterative/pre-screening or panel testing strategies useful? During the Concept development stage for MorPhiC, some reviewers were concerned that null alleles would produce non-specific phenotypes that would be too difficult to relate to specific, informative gene functions or biological processes. How will the assay strategy and interpretation address that potential concern?
  • How can the effort anticipate, address, and learn from potential biological, technical and interpretation issues such as: cell- or tissue-type specificity, pleiotropy, cell lethality, cell non-autonomy, haploinsufficiency, cell lineage, and natural biological variability? What are other potential complicating factors (or learning opportunities)?
  • What is the ultimate utility of the data for various purposes? For example, across all genes, will molecular and cellular assays of null alleles in humans be as informative for understanding gene function in basic and clinical applications as assumed in the background to this FOA and in the NHGRI Strategic Vision? Will these data be interoperable and highly useful in combination with other "perturbation X phenotype" data?

This section should include details about considerations in overall project design, including measuring or accounting for natural and technical variability, application of statistical methods (both data processing and study power) and generally how the data will be interpreted.

E. (Optional) Describe plans and rationale for technology and methods optimization. This FOA will not provide funds for development of new technologies or wholly new methods related to any of the elements in this section. However, applicants may request up to 10% funds for adoption and optimization of new technologies and methods into their pipelines. Requests should be justified in terms of adding value to the data or throughput/cost, etc. Plans should include a description of how the improvements will be evaluated and incorporated into the existing pipeline.

3) Data Management and Analysis

Applicants should propose data management and analysis plans including data processing/QC, and ensuring completeness, appropriate tracking, preservation, integration, and availability of the data, data wrangling, and transmission to the DRACC. For this section, please describe your laboratory information management system, how it will be implemented for this project, why it will be adequate over the life of the project (e.g., to pilot scale), and what incremental improvements may be needed. Please include a "sample/data flow" diagram illustrating the path that data generated internally will follow, from sample logging and data generation, to internal lab management systems, to analysts, to deposition.

If not already detailed in the elements above, please discuss any specialized analytical software and algorithms to be used, for example, in processing raw molecular and cellular phenotype data.

Applicants are encouraged to identify analytical or data processing steps that are likely to represent common challenges across DPC's, and that represent opportunities to develop solutions that are more uniform or reproducible across the consortium.

The funding available in this FOA for analyses is limited, so applicants should narrowly prioritize analyses that are designed to characterize the quality and utility of their data for downstream applications (e.g., consistency, biological and technical variability). Analyses that include, for example, looking for correlations between assay data types, or comparisons integrating outside data (e.g., KOMP, other "perturbation X phenotype") are acceptable as long as they are mainly used to help characterize the performance of the system or demonstrate utility. Describe any software that will be used to support the analyses, if not described elsewhere. Proposed analyses should be described and justified.

Analysis plans should take into account the data from samples provided by diverse participant populations. Applicants should also take into account that the MorPhiC DAV will be doing analyses of their own choosing, using the data. This means that it will be useful to have coordination within the consortium on proposed analyses.

4) Integration

Provide additional information on how the elements in #1-3 above will be integrated without duplicating information in above sections. Describe how the elements will be brought together; how a production "pipeline" could be created and improved; how critical bottlenecks to scale will be identified and resolved; how costs will be analyzed (per gene? per screen?); how opportunities for improvement will be systematically identified. How will the overall effort contribute to lessons about how, and whether, to pursue a potential genome-wide effort?

Describe plausible routes by which your overall plan (including number of samples and assays) could work in combination with those of other MorPhiC Production Centers to ultimately produce high quality, consistent data across the program for a combined 1000 genes. Although the details of the other centers cannot be known in advance, applicants should discuss the potential for their proposed alleles and assays to be used by others, for example to allow comparisons between centers or to maximize the number of assays per gene.

Resource Sharing Plan: Individuals are required to comply with the instructions for the Resource Sharing Plans as provided in the SF424 (R&R) Application Guide, with the following modification:

  • Consistent with the goals of this program, Resource Sharing Plans are required for this FOA. Applicants must address all the points below.
  • In their Resource sharing Plans, applicants should indicate their willingness to abide by all resource sharing policies developed by the Consortium's Steering Committee and approved by NHGRI staff. Awardees are expected to develop such policies as members of the consortium's Steering Committee in collaboration with NHGRI and should indicate their willingness to participate in the development of such policies and to accept them. These policies will remain consistent with NIH and NHGRI policies on data and resource sharing.

Plan for Data Sharing: A key long-term goal of the MorPhiC Consortium is to build a durable community resource of data, models, and tools designed and built to enable future adoption in building a full catalog. At the same time, we expect the Phase 1 data on their own will be included in the catalog and will be used by researchers for diverse analyses. Applicants should propose a data sharing plan consistent with this goal that addresses rapid data sharing with the community and describes plans to adhere to the FAIR Guiding principles (Findable, Accessible, Interoperable, Reusable), including:

  • Data and metadata assigned unique and persistent identifiers.
  • Data and metadata retrievable using standardized protocols/APIs.
  • Data pass strict quality metrics.
  • Data have clear provenance.
  • Rich metadata are collected with all data.

Wherever possible, community-standard formats, vocabularies, ontologies, quality metrics are to be used. For this consortium, data will be sent initially to the DRACC. It may be required to send data to other repositories, either directly or via the DRACC. Note that, once the consortium is formed, we expect to develop cross-consortium policies for data sharing; this will be led by the DRACC (see Companion FOA HG-2021-31).

Selection of Biological Samples and Ability to Share Sample Data with Community: In order to maximize the utility of the data, all human biological samples to be studied that are derived from specimen or cell line sources are expected to have been obtained using a documented informed consent process that explicitly allows for future research use and broad data sharing (NOT-HG-20-011). Sources with participant consent for unrestricted access is strongly encouraged. Sources consented for sharing through a controlled-access environment, such as General Research Use (GRU) or Health, Medical, and Biomedical (HMB) without additional restrictions, will also be considered and should be well justified. The consent process for human biological samples should be described at a high level in the Research Plan and detailed in the Data and Resource Sharing Plans.

Studies must include samples or cell lines that are derived from individuals of diverse ancestry and allow for consideration of sex as a biological variable.

Plan for Software and Data Analysis Sharing: NHGRI is committed to the timely release of open source software and well-documented data analyses including models and tools developed from proposed studies. Applicants should include plans for open dissemination of methods, protocols, software, and tools to the community such that they are readily usable and extensible, where applicable. These should be made freely available to biomedical researchers and educators. There is no prescribed license for software produced by applications responding to this announcement, but any software license selected by applicants should allow for unrestricted redistribution and modification of software.

Methods, protocols, tools, and software should be well-documented and where applicable made available via version-controlled public repositories.

Where applicable, applicants should describe solutions for portable implementations.

Solutions that enhance reproducibility when used by the community and ability of the community to integrate into automated pipelines should be emphasized.

Plan for Sharing Other Resources: NHGRI intends that, in addition to data, software, and analyses, any physical resources, such as DNA clones and cell lines, generated by awardees, should be made rapidly available to the research community and that such sharing plans should follow the same principles and spirit as data, software, and analysis release plans. The applicant should provide specific plans for such resource sharing and distribution in the application. If the application will use pre-existing commercially available resources (e.g., knockout iPSC lines) the terms of availability of these lines should be described. Key factors for this are availability to the community at reasonable cost and on equal terms; and use terms with lack of reach-through with regard to claims on downstream discoveries. Applicants should also propose plans for sharing experimental protocols and methods.

After initial review, NHGRI program staff will conduct an additional administrative review of the plans for sharing data, software, data analysis, and resources and may negotiate modifications of these plans with the prospective awardee. The final negotiated version of these plans will become a term and condition of the award of the cooperative agreement.


Only limited Appendix materials are allowed. Follow all instructions for the Appendix as described in the SF424 (R&R) Application Guide.

PHS Human Subjects and Clinical Trials Information

When involving human subjects research, clinical research, and/or NIH-defined clinical trials (and when applicable, clinical trials research experience) follow all instructions for the PHS Human Subjects and Clinical Trials Information form in the SF424 (R&R) Application Guide, with the following additional instructions:

If you answered Yes to the question Are Human Subjects Involved? on the R&R Other Project Information form, you must include at least one human subjects study record using the Study Record: PHS Human Subjects and Clinical Trials Information form or Delayed Onset Study record.

Study Record: PHS Human Subjects and Clinical Trials Information

All instructions in the SF424 (R&R) Application Guide must be followed.

Delayed Onset Study

Note: Delayed onset does NOT apply to a study that can be described but will not start immediately (i.e., delayed start).

All instructions in the SF424 (R&R) Application Guide must be followed.

PHS Assignment Request Form

All instructions in the SF424 (R&R) Application Guide must be followed.

Foreign Institutions

Foreign (non-U.S.) institutions must follow policies described in the NIH Grants Policy Statement, and procedures for foreign institutions.

3. Unique Entity Identifier and System for Award Management (SAM)

See Part 1. Section III.1 for information regarding the requirement for obtaining a unique entity identifier and for completing and maintaining active registrations in System for Award Management (SAM), NATO Commercial and Government Entity (NCAGE) Code (if applicable), eRA Commons, and

4. Submission Dates and Times

Part I. Overview Information contains information about Key Dates and times. Applicants are encouraged to submit applications before the due date to ensure they have time to make any application corrections that might be necessary for successful submission. When a submission date falls on a weekend or Federal holiday, the application deadline is automatically extended to the next business day.

Organizations must submit applications to (the online portal to find and apply for grants across all Federal agencies). Applicants must then complete the submission process by tracking the status of the application in the eRA Commons, NIH’s electronic system for grants administration. NIH and systems check the application against many of the application instructions upon submission. Errors must be corrected and a changed/corrected application must be submitted to on or before the application due date and time. If a Changed/Corrected application is submitted after the deadline, the application will be considered late. Applications that miss the due date and time are subjected to the NIH Policy on Late Application Submission.

Applicants are responsible for viewing their application before the due date in the eRA Commons to ensure accurate and successful submission.

Information on the submission process and a definition of on-time submission are provided in the SF424 (R&R) Application Guide.

5. Intergovernmental Review (E.O. 12372)

This initiative is not subject to intergovernmental review.

6. Funding Restrictions

All NIH awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Pre-award costs are allowable only as described in the NIH Grants Policy Statement.

7. Other Submission Requirements and Information

Applications must be submitted electronically following the instructions described in the SF424 (R&R) Application Guide. Paper applications will not be accepted.

Applicants must complete all required registrations before the application due date. Section III. Eligibility Information contains information about registration.

For assistance with your electronic application or for more information on the electronic submission process, visit How to Apply Application Guide. If you encounter a system issue beyond your control that threatens your ability to complete the submission process on-time, you must follow the Dealing with System Issues guidance. For assistance with application submission, contact the Application Submission Contacts in Section VII.

Important reminders:

All PD(s)/PI(s) must include their eRA Commons ID in the Credential field of the Senior/Key Person Profile Component of the SF424(R&R) Application Package. Failure to register in the Commons and to include a valid PD/PI Commons ID in the credential field will prevent the successful submission of an electronic application to NIH. See Section III of this FOA for information on registration requirements.

The applicant organization must ensure that the DUNS number it provides on the application is the same number used in the organization’s profile in the eRA Commons and for the System for Award Management. Additional information may be found in the SF424 (R&R) Application Guide.

See more tips for avoiding common errors.

Upon receipt, applications will be evaluated for completeness and compliance with application instructions by the Center for Scientific Review and responsiveness by components of participating organizations, NIH. Applications that are incomplete, non-compliant and/or nonresponsive will not be reviewed.

Post Submission Materials

Applicants are required to follow the instructions for post-submission materials, as described in the policy. Any instructions provided here are in addition to the instructions in the policy.

Section V. Application Review Information
1. Criteria

Only the review criteria described below will be considered in the review process.

Applications submitted to the NIH in support of the NIH mission are evaluated for scientific and technical merit through the NIH peer review system.

Overall Impact

Reviewers will provide an overall impact score to reflect their assessment of the likelihood for the project to exert a sustained, powerful influence on the research field(s) involved, in consideration of the following review criteria and additional review criteria (as applicable for the project proposed).

Scored Review Criteria

Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field.


Does the project address an important problem or a critical barrier to progress in the field? Is the prior research that serves as the key support for the proposed project rigorous? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field?

Specific to this FOA:

  • Will the proposed project contribute to understanding the feasibility and potential organization of a future full-scale effort to develop a catalog of cellular and molecular phenotypes of null alleles in humans? Does the application identify and address the key questions, and scientific, scale, and other barriers to doing this?
  • Has the application adequately considered work on all the major components of such an effort?
  • Will the proposed assays, considered together with the other key components of the work, produce data that has high potential to inform human phenotypes and biological processes, and be of high utility to the community?
  • Will the proposed project contribute to the consortium goals, including the need to compare data and approaches and to ensure reproducibility?
  • Do the plans for identifying samples and analysis plans adequately consider the need for generating data from participants from diverse populations? Are there adequate plans for use of these data in analyses?

Are the PD(s)/PI(s), collaborators, and other researchers well suited to the project? If Early Stage Investigators or those in the early stages of independent careers, do they have appropriate experience and training? If established, have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? If the project is collaborative or multi-PD/PI, do the investigators have complementary and integrated expertise; are their leadership approach, governance and organizational structure appropriate for the project?

Specific to this FOA:

  • Has the team demonstrated a track record in interdisciplinary research and/or team science?
  • Has adequate leadership for the day-to-day project management activities (e.g., a project manager or sufficient PD(s)/PI(s) effort) been described? Does the management plan clearly describe how the effort will be managed? Are there clearly described roles and reporting relationships for key personnel?
  • Does the applicant indicate a willingness to work with other centers and participate in Consortium activities?

Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed?


Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Have the investigators included plans to address weaknesses in the rigor of prior research that serves as the key support for the proposed project? Have the investigators presented strategies to ensure a robust and unbiased approach, as appropriate for the work proposed? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? Have the investigators presented adequate plans to address relevant biological variables, such as sex, for studies in vertebrate animals or human subjects?

Specific to this FOA:

  • Please evaluate whether the proposed approach will successfully address the "Main Barriers" (defined in the "Scope and Objectives" section) to the development of a catalog of informative molecular and cellular phenotypes of null alleles in human cells. These include:
  • Plans for developing data that are specific, faithful to, and informative about complex organismal (human) phenotypes or biological processes.
  • Potential for the approach to be generalizable across e.g. genes and tissue or cell types; applications to different diseases, etc.
  • Consideration and adoption of strategies that anticipate and address potential biological, technical and interpretation issues such as: cell- or tissue-type specificity, pleiotropy, cell lethality, cell lineage, cell non-autonomy, haploinsufficiency, natural biological variability; ability to learn from these and other potential complicating factors/opportunities).
  • Identifying, over the course of the work, the major bottlenecks to scale, and cost drivers. Work towards development of a production pipeline.
  • Demonstrating the utility of the data for various purposes.
  • Has the applicant adequately raised and addressed potential additional questions or barriers?
  • Are the proposed elements (for example, sampling, mutagenesis, cell/assay systems, assays, and data) well-justified and are plans adequate for their integration? Are they ready, or nearly ready, for generation of high-quality data to address the MorPhiC Phase 1 goals (approximately 1000 genes across the program)?
  • Are plans for developing, or acquiring existing (e.g., libraries of knockout iPSCs), alleles adequate? Are plans for validating/QCing these adequate? Note that applicants may propose alternatives to genetic nulls as long as they are demonstrably functionally equivalent (e.g., make no functional protein and are stable). In addition, applicants may propose alternatives to null alleles for specific genes where the null cannot be analyzed due e.g. to cell lethality.
  • Do plans for obtaining samples give confidence that sufficient samples will be available in a timely fashion so that work can begin at the earliest opportunity?
  • Are any proposed technical or methodological modifications or optimizations clearly justified, and is there a plan for evaluating them and incorporating them into the pipeline? Although wholly new technology development is outside the scope of this FOA, applicants have the option to adopt new technologies or methods as they become mature. Are any proposed plans for such adoption adequate?
  • Are there adequate plans for the informatics infrastructure to support proposed work, including data processing, handling/integration, analyses, and deposition?
  • Are statistical methods and expertise that may be needed adequately considered (for example, relevant to data processing, study design, biological or other variability, etc.)?
  • Are the plans for quality assessment and quality control, and ensuring data reproducibility, reasonable and adequate?
  • Are the Resource Sharing plans adequate? Do they address how the applicants will ensure rapid release of data, including metadata, in a way that will be useful to the community? Do the applicants consider the role of the Data Resource and Administrative Coordinating Center (DRACC) described in companion FOA RFA-HG-21-031)? Have the applicants adequately considered release/availability of other products (e.g., software, cell lines) of the proposed work? Are plans for resource sharing practical within the budget limitations? Is there a commitment to work within the MorPhiC consortium to develop and adopt policies relating to resource sharing and data quality?
  • Are the milestones, timelines and goals proposed for the research project reasonable and realistic?
  • Are there reasonable and appropriate plans to work with the Consortium to undertake collaborative efforts (including exchange/handoff of samples; routes to enhancing the likelihood of complementarity of approaches, comparability) and to take into account Consortium strategy over the course of the project?

If the project involves human subjects and/or NIH-defined clinical research, are the plans to address

1) the protection of human subjects from research risks, and

2) inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion or exclusion of individuals of all ages (including children and older adults), justified in terms of the scientific goals and research strategy proposed?


Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements?

Additional Review Criteria

As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact score, but will not give separate scores for these items.

Protections for Human Subjects

For research that involves human subjects but does not involve one of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate the justification for involvement of human subjects and the proposed protections from research risk relating to their participation according to the following five review criteria: 1) risk to subjects, 2) adequacy of protection against risks, 3) potential benefits to the subjects and others, 4) importance of the knowledge to be gained, and 5) data and safety monitoring for clinical trials.

For research that involves human subjects and meets the criteria for one or more of the categories of research that are exempt under 45 CFR Part 46, the committee will evaluate: 1) the justification for the exemption, 2) human subjects involvement and characteristics, and 3) sources of materials. For additional information on review of the Human Subjects section, please refer to the Guidelines for the Review of Human Subjects.

Inclusion of Women, Minorities, and Individuals Across the Lifespan

When the proposed project involves human subjects and/or NIH-defined clinical research, the committee will evaluate the proposed plans for the inclusion (or exclusion) of individuals on the basis of sex/gender, race, and ethnicity, as well as the inclusion (or exclusion) of individuals of all ages (including children and older adults) to determine if it is justified in terms of the scientific goals and research strategy proposed. For additional information on review of the Inclusion section, please refer to the Guidelines for the Review of Inclusion in Clinical Research.

Vertebrate Animals

The committee will evaluate the involvement of live vertebrate animals as part of the scientific assessment according to the following criteria: (1) description of proposed procedures involving animals, including species, strains, ages, sex, and total number to be used; (2) justifications for the use of animals versus alternative models and for the appropriateness of the species proposed; (3) interventions to minimize discomfort, distress, pain and injury; and (4) justification for euthanasia method if NOT consistent with the AVMA Guidelines for the Euthanasia of Animals. Reviewers will assess the use of chimpanzees as they would any other application proposing the use of vertebrate animals. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section.


Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed.


Not applicable.


Not applicable.


Not applicable.

Additional Review Considerations

As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact score.

Applications from Foreign Organizations

Reviewers will assess whether the project presents special opportunities for furthering research programs through the use of unusual talent, resources, populations, or environmental conditions that exist in other countries and either are not readily available in the United States or augment existing U.S. resources.

Select Agent Research

Reviewers will assess the information provided in this section of the application, including 1) the Select Agent(s) to be used in the proposed research, 2) the registration status of all entities where Select Agent(s) will be used, 3) the procedures that will be used to monitor possession use and transfer of Select Agent(s), and 4) plans for appropriate biosafety, biocontainment, and security of the Select Agent(s).

Authentication of Key Biological and/or Chemical Resources:

For projects involving key biological and/or chemical resources, reviewers will comment on the brief plans proposed for identifying and ensuring the validity of those resources.

Budget and Period of Support

Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research.

2. Review and Selection Process

Applications will be evaluated for scientific and technical merit by (an) appropriate Scientific Review Group(s) convened by NHGRII, in accordance with NIH peer review policy and procedures, using the stated review criteria. Assignment to a Scientific Review Group will be shown in the eRA Commons.

As part of the scientific peer review, all applications:

  • May undergo a selection process in which only those applications deemed to have the highest scientific and technical merit (generally the top half of applications under review) will be discussed and assigned an overall impact score.
  • Will receive a written critique.

Appeals of initial peer review will not be accepted for applications submitted in response to this FOA.

Applications will be assigned to the appropriate NIH Institute or Center. Applications will compete for available funds with all other recommended applications submitted in response to this FOA. Following initial peer review, recommended applications will receive a second level of review by the National Advisory Council on Human Genome Research. The following will be considered in making funding decisions:

  • Scientific and technical merit of the proposed project as determined by scientific peer review.
  • Availability of funds.

Relevance of the proposed project to program priorities.

These include:

  • Program balance, meaning the need for this program to include multiple comparable approaches studying diverse cell and tissue types, with consideration of the potential throughput and capacity of the approaches; and potential for synergy between MorPhiC components towards the Phase 1 goals of testing 1000 genes.
  • Potential to work effectively in large collaborative efforts or research consortia, which may be based on previous experience with NIH-funded research consortia, if applicable.
  • Adequacy of data sharing, software and analysis sharing and resource sharing plans.
  • Whether samples to be used are derived from participants from diverse populations. Does the application, considered together with others, advance the imperative to ensure that the results are applicable across populations?
  • Expansion of the community of genomic science to include new investigators, experienced investigators who are new to this field, and investigators from demographic groups or institutions that are generally underrepresented in genomic science.
  • Inclusion of new investigators and experienced investigators that are new to NHGRI consortia.
  • Whether an applicant or applicant institution will be funded as a PD/PI through this or the other FOAs in the MorPhiC Consortium to encourage participation from a broader representation of the research community.
3. Anticipated Announcement and Award Dates

After the peer review of the application is completed, the PD/PI will be able to access his or her Summary Statement (written critique) via the eRA Commons. Refer to Part 1 for dates for peer review, advisory council review, and earliest start date.

Information regarding the disposition of applications is available in the NIH Grants Policy Statement.

Section VI. Award Administration Information
1. Award Notices

If the application is under consideration for funding, NIH will request "just-in-time" information from the applicant as described in the NIH Grants Policy Statement.

A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the grants management officer is the authorizing document and will be sent via email to the recipient’s business official.

Awardees must comply with any funding restrictions described in Section IV.5. Funding Restrictions. Selection of an application for award is not an authorization to begin performance. Any costs incurred before receipt of the NoA are at the recipient's risk. These costs may be reimbursed only to the extent considered allowable pre-award costs.

Any application awarded in response to this FOA will be subject to terms and conditions found on the Award Conditions and Information for NIH Grants website. This includes any recent legislation and policy applicable to awards that is highlighted on this website.

Institutional Review Board or Independent Ethics Committee Approval: Recipient institutions must ensure that protocols are reviewed by their IRB or IEC. To help ensure the safety of participants enrolled in NIH-funded studies, the awardee must provide NIH copies of documents related to all major changes in the status of ongoing protocols.

2. Administrative and National Policy Requirements

All NIH grant and cooperative agreement awards include the NIH Grants Policy Statement as part of the NoA. For these terms of award, see the NIH Grants Policy Statement Part II: Terms and Conditions of NIH Grant Awards, Subpart A: General and Part II: Terms and Conditions of NIH Grant Awards, Subpart B: Terms and Conditions for Specific Types of Grants, Recipients, and Activities. More information is provided at Award Conditions and Information for NIH Grants.

Recipients of federal financial assistance (FFA) from HHS must administer their programs in compliance with federal civil rights laws that prohibit discrimination on the basis of race, color, national origin, disability, age and, in some circumstances, religion, conscience, and sex. This includes ensuring programs are accessible to persons with limited English proficiency. The HHS Office for Civil Rights provides guidance on complying with civil rights laws enforced by HHS. Please see and

HHS recognizes that research projects are often limited in scope for many reasons that are nondiscriminatory, such as the principal investigator’s scientific interest, funding limitations, recruitment requirements, and other considerations. Thus, criteria in research protocols that target or exclude certain populations are warranted where nondiscriminatory justifications establish that such criteria are appropriate with respect to the health or safety of the subjects, the scientific study design, or the purpose of the research. For additional guidance regarding how the provisions apply to NIH grant programs, please contact the Scientific/Research Contact that is identified in Section VII under Agency Contacts of this FOA.

Please contact the HHS Office for Civil Rights for more information about obligations and prohibitions under federal civil rights laws at or call 1-800-368-1019 or TDD 1-800-537-7697.

In accordance with the statutory provisions contained in Section 872 of the Duncan Hunter National Defense Authorization Act of Fiscal Year 2009 (Public Law 110-417), NIH awards will be subject to the Federal Awardee Performance and Integrity Information System (FAPIIS) requirements. FAPIIS requires Federal award making officials to review and consider information about an applicant in the designated integrity and performance system (currently FAPIIS) prior to making an award. An applicant, at its option, may review information in the designated integrity and performance systems accessible through FAPIIS and comment on any information about itself that a Federal agency previously entered and is currently in FAPIIS. The Federal awarding agency will consider any comments by the applicant, in addition to other information in FAPIIS, in making a judgement about the applicant’s integrity, business ethics, and record of performance under Federal awards when completing the review of risk posed by applicants as described in 45 CFR Part 75.205 Federal awarding agency review of risk posed by applicants. This provision will apply to all NIH grants and cooperative agreements except fellowships.

Cooperative Agreement Terms and Conditions of Award

The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.S. Office of Management and Budget (OMB) administrative guidelines, U.S. Department of Health and Human Services (DHHS) grant administration regulations at 45 CFR Part 75, and other HHS, PHS, and NIH grant administration policies.

The administrative and funding instrument used for this award will be managed as a cooperative agreement, an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH programmatic involvement with the awardees is anticipated during the performance of the activities. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients' activities by involvement in and otherwise working jointly with the award recipients in a partnership role; it is not to assume direction, prime responsibility, or a dominant role in the activities. Consistent with this concept, the dominant role and prime responsibility resides with awardee. Specific tasks and activities may be shared among the awardees, within the consortium and with the NHGRI staff as defined below

The PD(s)/PI(s) will have the primary responsibility for:

  • Determining research approaches, designing protocols, setting project milestones and timelines, and conducting research.
  • Ensuring that the data, software, resources, materials, etc. produced as part of this project are released appropriately according to the Resource Sharing Plan.
  • Preparing abstracts, presentations, and publications in a timely manner.
  • Adhering to policies regarding sharing of genomic and other types of data, data access, and standardized formats; timely publication; and intellectual property established by the NIH, NHGRI, and the consortium.
  • Not disclosing confidential information.
  • Interacting with other relevant NHGRI and NIH activities, as needed, to promote synergy and consistency among similar or related projects.
  • In order for the collaboration to be effective, PDs/PIs are responsible for:
  • Collaborating with the Data Resource and Administrative Coordinating center (DRACC) and other members of the consortium.
  • Ensuring that the grantee receives the appropriate approvals for sharing data between the DRACC and selected data repositories such as, AnVIL,?dbGaP, GEO, ?ClinVar and other appropriate public databases.
  • Transferring, in a timely manner, detailed (sequence, variant, other genomic, functional, phenotypic) and related data and metadata, as appropriate, to the DRACC, using agreed-upon formats and processes, to facilitate dissemination of data more broadly through databases such as?AnVIL,?dbGaP, GEO or?ClinVar, and other appropriate databases.
  • Collaborating with the DRACC to establish data formats and standards, to track and document collaborations and incoming samples, report findings, etc.
  • Submitting periodic progress or summary reports in a standard format, including data production summaries and metrics of the use and impact on the community, agreed on with the NHGRI Project Scientist/Scientific Officer (PS/SO) or the Steering Committee (SC; see below).
  • Sharing research resources, tools, and data of interest with other members of the consortium, consistent with achieving the goals of the project.
  • Assessing and disseminating data, protocols, consent materials, and methods developed for or derived from the DRACC within and outside the Consortium.
  • Abiding by common definitions, protocols, and procedures.
  • Attending and participating in SC and other working group meetings and accepting and implementing decisions made by the SC and/or PS/SO.

NHGR staff have substantial programmatic involvement that is above and beyond the normal stewardship role in awards, as described below:

The Project Scientist/Scientific Officer (PS/SO) at NHGR is a dual role held by a NHGRI Program Director (PD). In the Project Scientist role, the Program Director will have substantial scientific and programmatic involvement during the conduct of this activity through technical assistance, advice, and coordination. In the Scientific Officer role, the Program Director will be responsible for the normal scientific and programmatic stewardship of the award and manages concerns about bias as it affects the project. The role of NHGRI PS/SO will be to facilitate and not to direct the activities. The PS/SO will be named in the Notice of Award.

The PS/SO will have the following substantial involvement:

  • Serving as a liaison, helping to coordinate activities among and for the awardees, including acting as a liaison to the NHGRI and as an information resource for the awardees about genome research activities. The PS/SO will also coordinate the efforts of the grantee(s)with other groups conducting similar studies.
  • Reporting periodically on the progress of the grantees to the NHGRI Director and to the National Advisory Council for Human Genome Research.
  • Assisting awardee(s) in the development, if needed, of policies for dealing with situations that require coordinated action, including coordination with other NIH, national or international efforts.
  • Providing advice on the management and technical performance of the award.
  • Assisting in promoting the availability of the data and related resources developed in the course of the award to the scientific community.
  • Being responsible for the normal scientific and programmatic stewardship of the award, including assessments of how well the awardee has met any milestones required for each year of funding.
  • Curtailing, withholding or reducing support for any awardee that fails to make satisfactory progress toward the work scope that NHGRI approved, has ethical or conflict of interest issues, or fails to comply with the Terms and Conditions of Award.
  • Involving NIH or NHGRI staff who may assist the awardee(s) as designated by the PS/SO.
  • Where warranted and consistent with authorship and conflict of interest requirements of journals in which the Consortium/Network decides to publish, co-authoring manuscripts through their role in scientific program management.
  • External Scientific Panel. The NHGRI PS/SO may engage external scientists with relevant scientific and consortium experience, who are not funded as part of the project and who agree to a confidentiality policy, to provide input and advice to the NHGRI PS/SO about the project. The PS/SO will appoint 4-6 scientists to the ESP and will determine the durations of service. Activities of the ESP could include:
  • Participating, as appropriate, in consortium meetings, Steering Committees calls, and the annual grantees meetings; a subset of ESP members may also meet remotely at other times during the project period, as needed.
  • Reviewing and evaluating the progress of grantees (individually or as a group) in achieving the goals of the project.
  • Recommending changes in priorities based on scientific advances within and outside the consortium.
  • Providing individual recommendations regarding any changes in the project or grant(s) as necessary. The PS/SO will use these recommendations to make project changes, as appropriate.

Areas of Joint Responsibility:

If there are multiple awards working toward a common goal, close interaction between the participating grantee(s) and the PS/SO will be required, to manage, assess, and implement the award(s), goals of the consortium, etc. This is accomplished by:

  • Establishing a Steering Committee (SC): The SC will be the main governing body of the Consortium. The purpose of the SC will be to recommend directions for the consortium consistent with achieving the project goals, develop consortium policies to build synergy and improve communication and collaboration between the projects, and to provide a forum for discussing progress, challenges, and opportunities for the consortium.
  • Each funded cooperative agreement within the consortium will designate one senior investigator to participate in and be responsible for reporting at SC calls/meetings. Other members of each group may attend at the discretion of the designated representative, as needed to cover specific topics. For decisions that require a vote, each grant in the consortium will have one vote. The PS/SOs will be SC members, with one vote total for NHGRI.
  • Responsibilities of the SC will include:
  • Developing its own operating procedures.
  • Determining meeting (frequency and format).
  • Sharing information on data resources, methodologies, analytical tools, data analyses, preliminary results, etc.
  • Establishing best practices for data QC, integration and collaborative analyses as appropriate.
  • Setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted.
  • Generating responses to ESP recommendations by deadlines agreed upon by the SC and ESP members.
  • The PS/SO will assist and facilitate the group process and not direct it.

The SC may establish subcommittees to oversee the development and implementation of consortium policies including data, software, or other releases, publications and standards, etc. and to coordinate analyses. Subcommittees may be either permanent or time limited, may include additional experts, depending on the needs of the research. The PD(s)/PI(s) will be expected to play an active role in these working groups, as appropriate.

It is expected that most of the decisions on the activities of the SC will be reached by consensus. If a vote is needed, at least 60% of the voting members must vote in favor of the proposal.

NIH staff will review and approve policies developed by the SC. Awardees will be required to accept and implement policies approved by the SC. The PS/SO will assist and facilitate the group process and not direct it.

Any disagreements that may arise in scientific or programmatic matters (within the scope of the award) between award recipients and the NHGRI may be addressed by convening a Dispute Resolution Panel. It will be composed of three members: a designee of the SC chosen without NIH staff voting, one NIH designee, and a third designee with expertise in the relevant area who is chosen by the other two; in the case of disagreement for one award, the first member may be chosen by that awardee.?This special dispute resolution procedure does not alter the awardee's right to appeal an adverse action that is otherwise appealable in accordance with PHS regulation 42 CFR Part 50, Subpart D and DHHS regulation 45 CFR Part 16.

3. Reporting

When multiple years are involved, awardees will be required to submit the Research Performance Progress Report (RPPR) annually and financial statements as required in the NIH Grants Policy Statement.

A final RPPR, invention statement, and the expenditure data portion of the Federal Financial Report are required for closeout of an award, as described in the NIH Grants Policy Statement.

The Federal Funding Accountability and Transparency Act of 2006 (Transparency Act), includes a requirement for awardees of Federal grants to report information about first-tier subawards and executive compensation under Federal assistance awards issued in FY2011 or later. All awardees of applicable NIH grants and cooperative agreements are required to report to the Federal Subaward Reporting System (FSRS) available at on all subawards over $25,000. See the NIH Grants Policy Statement for additional information on this reporting requirement.

In accordance with the regulatory requirements provided at 45 CFR 75.113 and Appendix XII to 45 CFR Part 75, recipients that have currently active Federal grants, cooperative agreements, and procurement contracts from all Federal awarding agencies with a cumulative total value greater than $10,000,000 for any period of time during the period of performance of a Federal award, must report and maintain the currency of information reported in the System for Award Management (SAM) about civil, criminal, and administrative proceedings in connection with the award or performance of a Federal award that reached final disposition within the most recent five-year period. The recipient must also make semiannual disclosures regarding such proceedings. Proceedings information will be made publicly available in the designated integrity and performance system (currently FAPIIS). This is a statutory requirement under section 872 of Public Law 110-417, as amended (41 U.S.C. 2313). As required by section 3010 of Public Law 111-212, all information posted in the designated integrity and performance system on or after April 15, 2011, except past performance reviews required for Federal procurement contracts, will be publicly available. Full reporting requirements and procedures are found in Appendix XII to 45 CFR Part 75 Award Term and Conditions for Recipient Integrity and Performance Matters.

Section VII. Agency Contacts

We encourage inquiries concerning this funding opportunity and welcome the opportunity to answer questions from potential applicants.

Application Submission Contacts

eRA Service Desk (Questions regarding ASSIST, eRA Commons, application errors and warnings, documenting system problems that threaten submission by the due date, and post-submission issues)

Finding Help Online: (preferred method of contact)
Telephone: 301-402-7469 or 866-504-9552 (Toll Free)

General Grants Information (Questions regarding application instructions, application processes, and NIH grant resources)
Email: (preferred method of contact)
Telephone: 301-945-7573 Customer Support (Questions regarding registration and Workspace)
Contact Center Telephone: 800-518-4726

Scientific/Research Contact(s)

Adam L. Felsenfeld
National Human Genome Research institute (NHGRI)
Telephone: 301-496-7531

Peer Review Contact(s)

Rudy Pozzatti, Ph.D.
National Human Genome Research Institute (NHGRI)
Telephone: 301-402-8739

Financial/Grants Management Contact(s)

Lisa Oken
National Human Genome Research Institute (NHGRI)
Telephone: 301-402-8739
Telephone: 301-496-7531

Section VIII. Other Information

Recently issued trans-NIH policy notices may affect your application submission. A full list of policy notices published by NIH is provided in the NIH Guide for Grants and Contracts. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement.

Authority and Regulations

Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR Part 52 and 45 CFR Part 75.

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