TECHNOLOGIES TO FIND FUNCTIONAL ELEMENTS IN GENOMIC DNA RELEASE DATE: February 21, 2003 RFA: HG-03-004 National Human Genome Research Institute (NHGRI) ( CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.172 LETTER OF INTENT RECEIPT DATE: April 13, 2003 APPLICATION RECEIPT DATE: May 13, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE The purpose of this RFA is to solicit applications to develop new and improved technologies for the efficient, comprehensive, high-throughput identification and verification of all types of sequence-based functional elements, particularly those other than coding sequences, for which adequate methods do not currently exist. This effort is part of a new public research consortium, the Encylopedia of DNA Elements (ENCODE), the intent of which is eventually to identify all functional elements in the human genome sequence. This RFA is being issued in conjunction with the RFA HG-03-003, "Determination of All Functional Elements in Human DNA", which will support a Research Network that will conduct a pilot project to test the ability of current methodologies to exhaustively identify functional elements, focused primarily on transcriptional units, in a targeted region of the human genome. RESEARCH OBJECTIVES Background In April 2003, the sequence of the human genome will be essentially complete. For the scientific community to make the best use of that fundamental information resource, the identity and precise location of all sequence-based functional elements in the genome must be determined. While many of the protein-coding genes are already known, many others remain to be identified. Beyond open reading frames, non- protein-coding genes, transcriptional regulatory elements and determinants of chromosome structure and function remain largely unknown. A comprehensive encyclopedia of all of these features is needed to utilize fully the sequence of the human genome to understand human biology better, to predict potential disease risks, and to stimulate the development of new therapies and other interventions to prevent and treat disease. One of the primary reasons for the success of the Human Genome Project has been the development and use of high-throughput strategies for data generation, and the placement of the data immediately in the public domain. Most of the sequence data, the underlying maps and the sequence assemblies were generated through the use of large-scale automated processes. Now, methods such as sequence analysis of whole genomes, DNA microarray technology and mass spectrometry have been or are being developed as high-throughput approaches for additional types of genomic analyses, such as determining the parameters of gene expression or the location of gene products by the thousands at a time instead of individually. High-throughput methods to determine the location of cis-regulatory elements and, to a lesser extent, other sequence elements, are also beginning to be developed. However, at present, there is no single approach or compilation of approaches that can accurately and efficiently identify every sequence feature in genomic DNA. To address this need, the NHGRI is initiating the Encyclopedia of DNA Elements (ENCODE) project, the goal of which is to comprehensively identify functional elements in the human genome sequence. The ENCODE project will begin with two components. The first is a pilot to test and compare existing methods for the exhaustive identification and verification of functional sequence elements in a fraction (30 Mb) of human genomic DNA. Because the most well developed current methods pertain primarily to coding sequences or transcriptional units, NHGRI anticipates that the initial ENCODE pilot will focus primarily on those two classes. A companion RFA HG-03-003, "Determination of All Functional Elements in Human DNA", is being issued to solicit proposals that address that component of the ENCODE project. The second component of the ENCODE project will address the need for new and improved technologies that will enable the ENCODE project to identify all sequence-encoded functional elements on a genome-wide scale. The current RFA, HG-03-004, "Technologies to Find Functional Elements in Genomic DNA", is intended to solicit proposals to develop novel technologies that take systematic and high-throughput approaches to the comprehensive identification of functional sequence elements in the human genome. It is envisioned that when such a set of technologies is applied in subsequent components of the ENCODE project, it will be possible to fully annotate the human genome with biologic information that will serve as a platform for more in-depth, detailed studies of biological function. Research Scope The purpose of this RFA is to stimulate the development of novel technologies to identify functional elements in the human genome. This is a technology development component of the ENCODE project and is designed to generate a "tool box" of technologies that can be used to comprehensively determine the sequence-encoded functional elements in human DNA ( To be successful, the ENCODE project will eventually need to be able to scan the entire human genome, using high-throughput assays for all types of sequence-encoded functional elements. However, many types of functional elements cannot currently be studied at such large scale, or even at smaller scale, because of the lack of effective, practical high- throughput methods. In addition, newer technologies may improve on established techniques for the identification of more well–studied elements by increasing the accuracy or the efficiency of these methods. This RFA seeks applications for research projects to develop efficient technologies (both experimental and computational) for, but not limited to, the following areas: o Transcribed sequences, including protein-coding sequences but with an emphasis on non-protein coding transcribed sequences. A description of the gene structure with transcriptional start sites, polyadenylation sites, and all alternative transcripts, is an example. o Conserved non-coding sequences that may represent functional elements. o Cis-acting elements that regulate gene expression at either the transcriptional or post-transcriptional levels. These elements include promoters, enhancers, insulators, and those that regulate RNA stability and translation. o Sequence features that affect/control chromosome biology, including chromatin structure. Examples include origins of replication and hot spots for recombination. o Epigenetic changes, such as DNA methylation and chromatin modifications. These few examples are illustrative and should not be considered to be limiting in any way. Novel and innovative technologies to achieve high- throughput, large-scale analyses of any type of sequence-encoded functional elements are sought. The "process" of technology development can be considered to span a spectrum of stages. Initially, it involves the development of an entirely new methodology (or the significant improvement of an existing methodology) to the point of proof of principle. The method must then be reduced to practice. For such a new method to have a significant impact for genomic studies, it also must be shown that it can be used efficiently on a large-scale, or genomic basis, which requires another level of technology development. This RFA is intended to solicit applications that address any of these phases of technology development. The NHGRI will give priority to the development of technologies that will be used to study the human genome. Technology development projects that utilize other eukaryotic organisms will be considered, but direct applicability of these technologies to the analysis of the human genome must be evident. An important feature of any newly developed technology will be the ease with which it can be exported into other laboratories, or in other ways made readily accessible to investigators. The development of computational methods for the study of genomic function is encouraged under this solicitation. It is anticipated that there will be several kinds of large-scale datasets relevant to the ENCODE project available for developing new computational analyses, including, e.g., genomic sequences of regions syntenic to the ENCODE target regions from diverse species and full- length cDNAs sequences from most human and mouse genes. Since the technologies to be developed under this RFA need to be able to be applied to the entire genome, applications proposing to analyze a particular gene, gene product or non-coding functional element will not be considered to be responsive to this RFA. To encourage the consideration of novel approaches, applicants responding to this RFA are not required to have preliminary data. However, the research project must be well designed, must be scientifically and technically sound, and should propose alternative solutions. In the absence of preliminary data, applicants are encouraged to present any other information that can be considered as evidence of feasibility. As the work funded under this RFA progresses, the P.I.s will be encouraged to interact with the ENCODE pilot project consortium and its members. If work supported under this RFA, such as a computational analysis, results in the generation of data pertaining to the complete set of target regions of the ENCODE project, the P.I. may be invited to join the consortium (see for a description of the consortium). Among other requirements, this would involve sharing of the data with the members of the consortium, as participation involves concurrence with a specific data release policy (see RFA HG-03-003 for a detailed description of that policy). Applicants to HG-03-004 may wish to address their approach to data release in their proposal. MECHANISM OF SUPPORT This RFA will use NIH investigator-initiated research project grant (R01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation in FY2003 (see FUNDS AVAILABLE below). Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 2003. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application (see This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at FUNDS AVAILABLE The NHGRI intends to commit approximately $2,000,000 in FY 2003 to fund 4 to 8 grant applications in response to this RFA. An applicant may request a project period of up to 3 years and a budget for direct costs of up to $350,000 per year. Awards pursuant of this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is anticipated that this RFA will be reissued in FY 2004 to allow potential applicants to consider the development of creative and novel technologies that may require additional preparation time prior to submission. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution 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 programs. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Elise Feingold, PhD or Peter Good, PhD Program Directors Division of Extramural Research NHGRI Building 31, Room B2B07 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: or o Direct your questions about peer review issues to: Rudy Pozzatti, PhD Scientific Review Administrator Division of Extramural Research NHGRI Building 31, Room B2B37 Bethesda, MD 20892-2032 Telephone: (301) 402-0838 FAX: (301) 435-1580 Email: o Direct your questions about financial or grants management matters to: Jean Cahill Chief, Grants Administration Branch Division of Extramural Research NHGRI Building 31, Room B2B34 Bethesda, MD 20892-2031 Telephone: (301) 301-435-7858 FAX: (301) 402-1951 Email: Prospective Applicant Meeting. There will be a combined meeting at the Natcher Conference Center on the NIH campus from 9:00 a.m. to approximately 2:00 p.m. on March 7, 2003 to launch the ENCODE project and to answer questions about the RFA from prospective applicants. Attendance at this meeting is not a prerequisite for responding to the RFA or for participation in the ENCODE consortium. For more information about this meeting, see or send an email request for information to LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA 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. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Peter Good, PhD Program Director Division of Extramural Research NHGRI Building 31, Room B2B07 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 Email: SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at includes step- by-step guidance for preparing modular grants. Additional information on modular grants is available at USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three signed, photocopies, in one package to: Center For Scientific Review National Institutes Of Health 6701 Rockledge Drive, Room 1040, MSC 7710 Bethesda, MD 20892-7710 Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Rudy Pozzatti, PhD Scientific Review Administrator Division of Extramural Research NHGRI Building 31, Room B2B37 Bethesda, MD 20892-2033 Telephone: (301) 402-0838 FAX: (301) 435-1580 Email: APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes. While the investigator may still benefit from the previous review, the RFA application is not to state explicitly how. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHGRI. Incomplete applications will be returned to the applicant without further consideration. And, if the application is not responsive to the RFA, NIH staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next appropriate NIH review cycle. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NHGRI in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Advisory Council for Human Genome Research. REVIEW CRITERIA The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. The application must be directed toward attaining the programmatic goals as stated under RESEARCH OBJECTIVES. The following criteria will be used by peer review groups to evaluate these applications: (1) SIGNIFICANCE: Does the application address the problem outlined in this RFA? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project as outlined in this RFA? Are potential problem areas acknowledged and alternative tactics considered? Does the technical approach have the potential to be applied efficiently and cost-effectively at large scale? (3) INNOVATION: Does the project employ novel concepts, approaches, or methods for identifying and verifying sequenced-based functional elements? Does your project challenge existing paradigms or develop new methodologies or technologies? Does the project develop new methods or technologies to reduce costs or increase quality or throughput? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: April 13, 2003 Application Receipt Date: May 13, 2003 Peer Review Date: July 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 30, 2003 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic priorities, including both the likelihood that the proposed technology could be applied to the ENCODE project in a timely manner and the range of technologies that could be developed under this component of the ENCODE project. REQUIRED FEDERAL CITATIONS INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (; a complete copy of the updated Guidelines are available at 2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at The PHS strongly encourages all grant recipients to provide a smoke- free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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