LARGE SCALE SEQUENCING CAPACITY RELEASE DATE: January 16, 2003 RFA: HG-03-002 National Human Genome Research Institute (NHGRI) (http://www.nhgri.nih.gov/) LETTER OF INTENT RECEIPT DATE: February 24, 2003 APPLICATION RECEIPT DATE: April 7, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Background o Research Objectives o Mechanism(s) 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 OF THIS RFA The NHGRI invites applications for cooperative agreements to support research centers capable of providing large-scale capacity to sequence the genomes of a variety of organisms of high biomedical interest. It is expected that these large-scale sequencing centers will initially operate at the state of the art in terms of throughput, quality, and cost, and that they will continually improve that state of the art over the period of the award. BACKGROUND The NHGRI initiated a pilot project program to develop the capability for sequencing the human genome in 1995. Based on the success of that program, several large-scale sequencing centers were funded in early 1999 to determine the complete DNA sequence of the human genome by 2005. That effort is now on track to achieve this historic milestone by April 2003. The success of the program was, in significant part, due to improvements in sequencing technology and strategy, and in the organization of the large-scale sequence production efforts. Technology. In 1995, commercially available sequencing machines used polyacrylamide slab gel technology to analyze products of four-color fluorescent cycle sequencing. Those instruments were succeeded in 1999 with 96-capillary sequencers. Use of the new instruments led to major increases in the output of sequence data and reductions in cost because they allowed significant reductions in the amount of labor and reagents required, and increases in the number of runs per day. Their use also resulted in important increases in data quality by eliminating the lane-tracking problem that had plagued slab gel-based sequencing. Other important technological advances, including improved robotics for DNA preparation and sequencing reactions, new purification methods, better project tracking, and incremental improvements in chemistry, also contributed to the increased efficiency and output of large-scale genomic DNA sequencing in this period. Strategy. Important advances were also made in sequencing strategy during this time. The public effort to sequence the human genome initially employed a hierarchical shotgun strategy based on shotgun sequencing of mapped large-insert clones. A different approach, the whole-genome shotgun (WGS) strategy, originally developed for bacterial genomes and proposed for large genomes by Weber and Myers in 1997, was implemented to produce a high quality draft sequence of the Drosophila melanogaster genome in 1999 and was used in assembling a draft version of the human genome in 2000. The development of whole-genome assembly software was critical to the success of whole genome shotgun sequencing. With the publication of two draft versions of the human genome sequence, NHGRI concluded that a hybrid strategy employing both whole genome and hierarchical shotgun components is actually the best way currently available to efficiently achieve an accurate and useful finished assembly of a large genome with a complex repeat structure. Accordingly, a hybrid strategy was used for the sequencing of the mouse genome by the public consortium, which initiated the project with a WGS approach that quickly (15 months) led to a draft version of the genome sequence assembled and refined with one of two publicly available WGS assembly programs. At the same time, a BAC physical map of the mouse genome was developed. Information from this map was used to anchor the sequence scaffolds and improve the whole genome assembly, and individual BAC clones from that map are now being used in the finishing of the mouse genomic sequence. The current state of the art for sequencing whole genomes thus uses both hierarchical and WGS elements in a complementary fashion, varying the proportion of each and customizing the read types, insert sizes, and the use of map information based on the size and other characteristics of the target genome and the end-point being sought (i.e., finished, draft, etc.). Organization. Yet another major contributor to the success of large- scale genome sequencing was the centralization of the effort into a few large sequencing laboratories, as predicted by many at the outset of the HGP. In the case of the NHGRI program, a number of centers were initially funded during a pilot program to develop and test different approaches to large-scale genomic sequencing. Through subsequent rounds of competition, several of the approaches and groups that were most successful in implementing large-scale sequence production were expanded, and three very large-scale, highly efficient NHGRI-funded centers emerged. Similarly, a small number of other very large centers supported by other funding sources have established themselves around the world. Programmatic Conclusions. Several lessons emerged during the sequencing of the human genome. First, by implementing new technologies, sequencing costs in all large-scale centers dropped approximately ten- fold between 1995 and 2002, and it is likely that further significant cost reductions can be gained by additional incremental technology or process improvements. Second, a small number of truly large-scale centers have demonstrated that they can sequence mammalian-sized genomes rapidly and cost-effectively, simplifying the administrative and coordination issues involved in implementing a worldwide program for genomic sequencing. Third, it does not appear that large-scale sequencing centers have yet reached a capacity limit where the efficiencies of scale are no longer realized. On the basis of such experience, the NHGRI has concluded that sufficient capacity is now available so that one, or at most two, large centers can sequence a mammalian genome in one to three years, and there are few compelling reasons to divide a genome project among many centers. NHGRI plans to continue to support genomic sequencing capacity at levels sufficient to meet the demand for sequencing high priority targets. Because experience has shown that programmatic efficiency is obtained by concentrating capacity in a few large centers, the Institute's sequence production program will focus on a small number (three to four) of high-throughput, state-of-the-art centers. The Research Network. The NHGRI large-scale sequencing program has been comprised of a set of cooperative agreements organized as a Research Network. This was necessary at the start of the program when the centers were relatively small and the efforts of several sequencing groups were necessary to complete the sequence of the genome of a single organism. Although that rationale is no longer applicable and it is anticipated that the awards made under the renewal of this program will be large enough to support a single center to sequence a genome of moderate to large size within the period of the award, NHGRI has determined that it will be useful to maintain the Research Network organization (see Terms and Conditions). It is likely that there will still be benefits to close collaboration between two or more centers on certain large genomes. Most importantly, there is significant scientific benefit to close coordination between several large-scale sequencing centers on issues such as technology development, quality standards, and sequencing strategies. RESEARCH OBJECTIVES The features of a state-of-the-art large-scale sequencing center are: o An automated production pipeline with a minimum throughput of 20 million attempted reads per year and a success rate of at least 80% (successful reads defined as having a minimum of 100 high quality bases, i.e. bases with quality scores of 20 using the phred base- calling program, or the equivalent); o A capacity to finish at least 15Mb of sequence per month; oAn overall average read length for successful reads of at least 550 high quality bases; o A high read pairing rate, if a strategy using paired end reads is employed; o A cost per attempted production read of $1.50 or less. (Production read costs considered here are inclusive of amortized equipment, technology development, informatics, and indirect costs, as detailed below); o The ability to produce both high quality draft genome assemblies and finished genome sequences: o The ability to use multiple genome sequencing strategies, including clone-based and whole genome shotgun approaches, or even more effective strategies; and the ability to adapt and modify approaches as the technology and demands on the center change; o The ability to assemble genomic sequence at all scales (large- insert clone through whole genome); o Expertise in efficiently closing and finishing large genomic regions (of the size of mammalian chromosomes), with a total cost per finished base of $0.05 or less above the cost of draft sequence; o Integrated bioinformatics capabilities to support production, including systems and database administration, laboratory information management, and data handling and deposition; o Ability to perform primary annotation of genomic sequence to maximize its utility for the biological community; o A technology development capability focused on developing and integrating technology improvements (e.g., robotics, chemistries, protocols) that lead to increased efficiency and decreased sequencing cost; o A proven track record in rapidly and efficiently releasing both sequence and trace data to public repositories; o A high degree of flexibility and ability to interact with other publicly funded large-scale sequencing centers, public databases, genome analysis experts, physical mapping groups, and other entities with whom it may be necessary to integrate to be maximally productive in taking on very large projects. The purpose of this RFA is to solicit applications for projects for continued large-scale, state-of-the-art production of genomic sequence, coupled with the likelihood of further improvement in cost, quality, and efficiency of large-scale sequencing over the term of the award. Target choice. The NHGRI large-scale sequencing program has separated the process for selecting organisms to be sequenced from the process for funding the large-scale sequencing centers (see a description of the white paper process for identifying new target genomes at http://www.genome.gov/page.cfm?pageID=10002189). Funded sequencing centers will choose sequencing targets from the list developed through the white-paper process, in consultation with NHGRI and the Scientific Advisory Panel of the large-scale sequencing Research Network (see Definitions below). Therefore, applications submitted in response to this RFA should focus on the technical aspects of production sequencing and should not propose specific sequencing targets. However, the applicant should discuss the center's internal process for choosing sequencing targets based on the white-paper process. The applicant may, if desired, discuss areas of likely interest, including rationales for potential choices; this discussion could illuminate the applicant's motivation for sequencing or approach to using genomic sequence data (e.g., comparative genomics, etc.). Current approaches to large-scale genome sequence production can be conceptualized in four general areas: shotgun sequencing read production (including the associated laboratory management and other informatics infrastructure), sequence finishing, analytical informatics, and technology development. The application should be constructed so that each of these components is broken out and discussed separately. Additionally, the budget requested for each component must be broken out and presented separately. Applicants may propose appropriate collaborations and/or subcontracts for specific elements such as sequence read production, physical map production, assembly, annotation, etc. Specific instructions on how to respond to these sequence production considerations are detailed below in the section SPECIAL APPLICATION GUIDANCE. Shotgun sequence read production. The application should describe the shotgun sequence production component of the proposed center in terms of the role that it will play in the overall sequencing objectives of the center, the strategy or strategies the center will take to generate shotgun sequence, the projected throughput, expected or needed read characteristics and quality, assembly strategy and all other pertinent factors. The discussion should take into account the fact that NHGRI objectives will require that different genomic sequences will need to be finished to different degrees and that, therefore, it cannot be known until a genomic sequencing project is initiated what the requirements for finishing that particular sequence will be. In the presentation of the shotgun-sequencing component, the applicant should discuss all pertinent informatics issues. These include, but are not limited to, the informatics infrastructure proposed for the center, such as the basic IT infrastructure/system administration, lab information management, and data handling/deposition, as well as the informatics required for the assembly of the shotgun sequence data up to the point at which it is handed off to the finishing component. In all cases, software development should be described in detail. Finished sequence production. The applicant should describe all pertinent aspects of sequence finishing, defined as starting at handoff from the draft-sequencing component and proceeding through finishing projects and data deposition. The applicant should also discuss map closure. Informatics and software development integral to this component should be discussed. NHGRI appreciates that the needs for production of draft and finished sequence are no longer coupled many genomes will be sequenced to draft quality, but will not need to be finished, or could even be partly or completely finished by a different center than produced the draft. In addition, we anticipate that the quality of a draft genome is likely to become sufficiently high that there will be even less demand for finished sequence. However, for the foreseeable future, there is a clear need for the Institute's program to maintain some amount of finishing capacity and to maintain an appropriate balance of finishing and production activities among the funded centers as a group. If an applicant chooses to propose only shotgun sequence production, then the question of how the necessary finishing needs can be met must be addressed, including how the draft product and any substrates for finishing will be archived or transferred. Applications proposing a substantial finishing component in addition to shotgun sequence production should include a brief discussion of their ability to finish draft data generated by other groups, if desired. Applications proposing finishing without a substantial and efficient draft sequence production component will not be considered responsive to this RFA; while the demands for draft sequence are clear, there is currently no separate, well-defined backlog or pipeline of draft genomes that could be used by a stand-alone finishing center. Analytical informatics. Most large-scale sequencing centers currently perform automated annotation of the genome sequences they produce. The appropriate level of annotation in sequencing centers strikes a balance between, on the one hand, providing a minimal level of annotation necessary to provide a useful product for the community and, on the other, rapidly releasing that sequence to the community to make it available for more extensive and complete annotations and analyses. The appropriate types of annotation carried out by sequencing centers usually include annotation of gaps, low quality bases, and other sequence quality measures; automated annotation of repeat sequences; and automated annotation of genes. Additionally, a modest amount of analysis of annotation features to perform quality assessment of sequence may be appropriate. Applicants to this RFA may propose appropriate automated annotation and, if so, should provide details in the application about the extent of annotation to be done, justifying choices based on the utility of the annotated sequence to the user community, and defining the point at which primary annotation (of projects, genome assemblies, finished genomes, etc.) will be considered to be complete enough for hand-off to the community. More extensive analyses of biological features of sequence beyond those needed for assembly and appropriate primary annotation should not be requested in responses to this RFA. Technology development. Incremental technology improvements within centers have played an important role in increasing the efficiency and decreasing the cost of large-scale sequencing. NHGRI encourages such technology development activities in this RFA. Plans and costs for technology improvement within the center must be well described and justified in terms of leading to a reduction in sequencing costs. The cost of such technology development should be clearly described so that its contribution to the overall sequence production costs can both be reflected in read or per base costs, and be separately identified and evaluated. Crosscutting issues to be explicitly discussed in the application. In addition to the four components outlined above, there are a number of other issues important to the successful operation of a state-of-the- art large-scale sequencing center that should be discussed separately in the application: 1) Physical maps. If the proposed approach to genomic sequencing requires a physical map, the application must describe how the maps will be generated or acquired, and made available. The cost of production or acquisition of such maps must be clearly described so that its contribution to the overall sequence production costs can both be reflected in read or per base costs, and be separately identified and evaluated. 2) Sequence quality. The applicant should describe how s/he will ensure the quality of, or otherwise validate, the genomic sequence that will be produced, and all intermediate products (maps, libraries, reads, paired ends, assemblies, and finished or other end products). Evidence of the effectiveness of such quality assessment programs should be included. 3) Sequence cost. The applicant should describe plans for achieving continued reduction in sequencing cost. Proposed cost analyses should be described in the same terms used in the format for reporting prior costs (see SPECIAL APPLICATION GUIDANCE), that is, in terms of the total costs, the fully loaded costs of shotgun reads, and the incremental costs per base of finishing. The calculated costs of sequencing must take into account all of the expenses associated with sequence production (that is, the total costs for the grant). In addition, the portion of shotgun read costs and finishing costs that are attributable to informatics infrastructure, assembly, annotation, and technology development should be identified. 4) Management Plan. The management of a sequencing center requires a significant commitment by the Principal Investigator (P.I.) of the project. The P.I. of a large-scale project funded under this RFA is expected to devote at least 30% effort to the project. The application should describe the management plan for the proposed center, and how it will support the goals proposed. It should describe the organization of the proposed center and its management structure, including integration of the separate components to form an efficient pipeline, key personnel, section leaders, and reporting relationships. Recruitment and training of personnel should be discussed. The plan should describe how the various components of the proposed center will be integrated, and how collaborations or subcontracts, if proposed, will be managed. The issue of how any other, ongoing large-scale sequencing projects would be integrated with the one to be funded under this RFA should be discussed. 5) Data release. NHGRI strongly endorses rapid release of genomic data and materials. The NHGRI policy on release of sequence data is available at http://www.genome.gov/page.cfm?pageID=10000910. Applicants should also be familiar with the NIH statements regarding intellectual property of resources developed with Federal funds (http://www.ott.nih.gov/policy/rt_guide_final.html). Responses to this RFA should propose a plan for data release, as quality of the data release plan will be a criterion in the review of the application. Appropriate data release plans will be made a condition of the awards made as a result of this RFA. Each of the following items should be discussed separately: o Release of sequence read and trace data o Release of assembled projects (large-insert clone assemblies) o Release of whole genome shotgun assemblies o Release of annotation performed by the center o Availability of map information o Availability of software developed with funds from this award o Availability of resources developed (eg, 10kb libraries, fosmids) o Availability of technologies developed with funds from this award 6) Training. The applicant must propose a plan in response to NHGRI's Action Plan for increasing the number of underrepresented minorities in genome research. Please see http://www.genome.gov/page.cfm?pageID=10003996 for a description of the Action Plan. An application that is rated highly for its scientific program will not be funded until its response to the Action Plan is deemed to be adequate by peer review. NHGRI recognizes that it is possible that by the time applications are submitted to this RFA there may be superior alternatives to the current state-of-the-art of technology platforms; if so, NHGRI encourages applicants to propose incorporating such technology as the core of a large-scale sequencing center. In that case, the applicant must provide justification, including any preliminary data supporting the new technology, that such new technology would result in a sequence production process that would equal, or exceed, the current process in terms of throughput, success rate, quality, and cost per read (or cost per base). In summary, applicants for awards under this RFA: o should focus primarily on all aspects of genome sequence production, explicitly describing how the proposed center will attain or exceed the current state-of-the-art in throughput, quality, and cost using the information requested under the SPECIAL GUIDANCE FOR APPLICANTS (below) as a format; o should describe how the center will improve on the state-of-the-art, with the goal of reducing costs; o should use explicit milestones and timelines when describing production goals; o should discuss major production goals in relation to the state-of- the-art outlined above; o should use the web-based progress and cost reporting spreadsheets as described in the SPECIAL GUIDANCE FOR APPLICANTS; o should propose appropriate technology development that will improve efficiency; o should explicitly discuss informatics infrastructure needed for sequence production; o should propose assembly and/or primary annotation, but not extensive biological analyses; o should explicitly discuss center management and how various components of the center will be integrated; o should provide information about the applicant's prior experience in large-scale genomic sequencing and available resources; o should propose a plan for assessing the quality of sequence and sequence assemblies; o should discuss the general approaches or strategies to be used for sequencing large genomes, and also rationales or motivations that will be used to select genomes identified by the NHGRI white paper process (see http://www.genome.gov/page.cfm?pageID=10002189), without choosing in advance a specific target genome; o should discuss interactions, collaborations, or subcontracts that may be appropriate (eg, in support of sequencing large genomes, for interactions with interested model organism communities, for physical mapping, assembly, etc.); o should propose a comprehensive data release plan; o should propose a plan for training, especially of under-represented minorities. MECHANISM OF SUPPORT This RFA will use the NIH Specialized Center -- Cooperative Agreement (U54) award mechanism. This RFA is a one-time solicitation. The anticipated award date is November 2003. The U54 is a cooperative agreement award mechanism in which the Principal Investigator retains the primary responsibility and dominant role for planning, directing, and executing the proposed project, with NIH staff being substantially involved as a partner with the Principal Investigator, as described under the section "Cooperative Agreement Terms and Conditions of Award" FUNDS AVAILABLE Three to four large-scale sequencing centers will be funded for a three-year term. Toward the end of this period, the NHGRI large-scale sequencing effort will be evaluated to determine the priority of genomic sequence and improvements in sequencing technology with other research priorities. The NHGRI large-scale sequencing effort was funded at a level of about $190M in fiscal year 2002. The planning process that NHGRI is currently undergoing has highlighted many other vital and exciting research opportunities that have been afforded by the availability of genomic sequence data. As the planning process has not been completed at the time of the publication of this RFA, it is not yet possible to definitively state the proportion of the NHGRI budget that will be used for large-scale sequencing. However, it is not expected to increase, and indeed may decrease somewhat as new research priorities are defined. In spite of this, the expectation is that the output of the NHGRI sequencing program will not decrease and it is hoped it will increase because of reduced sequencing costs. If more precise information about the funds available to support awards made in response to this RFA is available before the applications are due, an updated notice will be published in the NIH Guide for Grants and Contracts. Awards pursuant to this RFA are contingent on the availability of funds appropriated to the NHGRI and the receipt of a sufficient number of meritorious applications. 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 Foreign institutions are not eligible. 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 his/her 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. SPECIAL REQUIREMENTS In describing the research plan, the applicant must address the issues and questions in the format described in the Special Guidance to Applicants section below. Cooperative Agreement Terms and Conditions of Award The following terms and conditions will be incorporated into the award statement and will be provided to the Principal Investigator, as well as the appropriate institutional official, at the time of award. The following special terms of award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines, HHS grant administration regulations at 45 CFR Parts 74 and 92 [Part 92 is applicable when State and local Governments are eligible to apply], and other HHS, NIH, and NIH grant administration policies: 1. The administrative and funding instrument used for this program will be the Specialized Center -- Cooperative Agreement (U54). The cooperative agreement is an "assistance" mechanism (rather than an "acquisition" mechanism), in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during the performance of the activity. Under the Cooperative Agreement, the NIH purpose is to support and/or stimulate the recipient's activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the study will be shared among the awardee(s) and the NHGRI Program Director. 2. P.I. Rights and Responsibilities: The P.I. will have the primary responsibility for defining the details for the sequencing production center within the guidelines of RFA HG- 03-002 and for performing the scientific activities. The P.I. will agree to accept close coordination, cooperation, and participation of NHGRI staff in those aspects of scientific and technical management of the project as described under "NIH Program Staff Responsibilities." The P.I. of a genome sequencing production center will: o Determine experimental approaches, design protocols, set project milestones and conduct experiments; o Provide goals for throughput, quality, and cost to the NHRI as requested (usually at the outset of the award and in six-month progress reports, but also at other times as requested by NHGRI program staff); o Ensure that the genomic sequence produced meets the quality standards and costs agreed upon at the time of award; o Ensure that the sequence data (reads, assemblies) are deposited in the appropriate public database (e.g., GenBank or other, as specified by NHGRI program staff), that resources developed as part of this project are made publicly available according to NHGRI policies, and that results are published in a timely manner; o Adhere to the NHGRI policies regarding intellectual property, data release and other policies that might be established during the course of this activity; o Integrate with the NHGRI large-scale sequencing white paper process for selecting target genomes (see http://www.genome.gov/page.cfm?pageID =10002189); o Submit data for quality assessment in any manner specified by the Steering Committee or the Scientific Advisory Panel; o Submit periodic progress reports in a standard format, as agreed upon by the Steering Committee and the Scientific Advisory Panel; o Accept and implement any other common guidelines and procedures developed for the NHGRI large-scale sequencing program and approved by the Steering Committee and the Scientific Advisory Panel; o Accept and participate in the cooperative nature of the Genome Sequencing Research Network; o Coordinate and collaborate with other U.S. and international groups sequencing large genomes; o Inform the Program Director of all major interactions of members of the Steering Committee; o Attend Steering Committee meetings; o Lead the center's efforts to respond to the NHGRI Action Plan for increasing the representation of under-represented minorities in genome research. 3. NHGRI Program Staff Responsibilities: The NHGRI Program Director will have substantial scientific/programmatic involvement during the conduct of this activity through technical assistance, advice and coordination. However, the role of NHGRI will be to facilitate and not to direct the activities. It is anticipated that decisions in all activities will be reached by consensus of the Genome Sequencing Research Network and that NHGRI staff will be given the opportunity to offer input to this process. One NHGRI Program Director shall participate as a member of the Steering Committee and will have one vote. The Program Director will: o Participate (with the other Steering Committee members) in the group process of setting research priorities, deciding optimal research approaches and protocol designs, and contributing to the adjustment of research protocols or approaches as warranted. The Program Director will assist and facilitate the group process and not direct it; o Negotiate throughput, quality, and cost goals with the awardees as necessary; o Serve as a liaison between the awardees and the Scientific Advisory Panel, the National Advisory Council for Human Genome Research, and the larger community in helping the awardee(s) select targets from the list developed by the white paper process; o Coordinate the efforts of the awardees with other participants in the NHGRI large-scale sequencing program, including other awardees under this RFA and those awardees involved in the NHGRI BAC library programs (library production, characterization, and construction of physical maps; see URL http://www.genome.gov/page.cfm?pageID=10001691); with other U.S. large-scale sequencing efforts, and with the international sequencing community; as well as with the larger biological community; o Attend all Steering Committee meetings as a voting member and assist in developing operating guidelines, quality control procedures, and consistent policies for dealing with recurrent situations that require coordinated action. o Schedule the time for, and prepare concise (3 to 4 pages) summaries of, the Steering Committee meetings, which will be delivered to members of the group within 30 days after each meeting; o Periodically report progress to the Director, NHGRI; o Lend relevant expertise and overall knowledge of NHGRI- sponsored research to facilitate the selection of scientists not affiliated with the awardee institutions who are to serve on the Scientific Advisory Panel and the Steering Committee; o Serve as liaison between the Steering Committee and the Scientific Advisory Panel; o Serve on subcommittees of the Steering Committee and the Scientific Advisory Panel, as appropriate; o Provide advice in the management and technical performance of the investigation; o Assist in promoting the availability of the genome sequence and related resources developed in the course of this project to the scientific community at large; o Participate in data analyses, interpretations, and where warranted, co-authorship of the publication of results of studies conducted through the Genome Sequencing Research Network; o Assist awardees in the development, if needed, of policies for dealing with situations that require coordinated action; o Retain the option to recommend, with the advice of the Scientific Advisory Panel, the withholding or reduction of support from any cooperative agreement that substantially fails to achieve its goals according to the milestones agreed to at the time of award, fails to maintain state-of-the-art capabilities, or fails to comply with the Terms and Conditions of the award. An NHGRI Program Director will be responsible for the normal stewardship of this award; this same Program Director may, in addition, be substantially involved as described above. 4. Collaborative Responsibilities Steering Committee The Steering Committee will serve as the main governing board of the Genome Sequencing Research Network. The Steering Committee membership will include the NHGRI Program Director and the P.I. of each awarded cooperative agreement. Additional members may be added by action of the Steering Committee. Other government staff may attend the Steering Committee meetings, if their expertise is required for specific discussions. The Steering Committee will: o Discuss progress in meeting the research community's need for genomic sequence. o Help to develop uniform procedures and policies, for example for data quality measures and assessment, nomenclature and annotation conventions for data depositions, and so forth. Members of the Steering Committee will be required to accept and implement the common guidelines and procedures approved by the Steering Committee, program director and Scientific Advisory Panel. o Serve as a venue for coordination on improving the state of the art, for example by reporting progress, disseminating best practices and collectively evaluating new procedures, resources, and technologies. o Serve, in appropriate subgroups, as a coordinating body in cases where two or more centers are collaborating closely on sequencing a single large genome, where for example common policies and data exchange are critical to the success of the effort. 5. Scientific Advisory Panel The Scientific Advisory Panel (SAP) will be responsible for reviewing and evaluating the progress of the members of the Genome Sequencing Research Network toward meeting their individual and collective goals. The SAP will provide recommendations to the Director, NHGRI, about continued support of the components of the Genome Sequencing Research Network. The Advisory Panel is composed of four to six senior scientists with relevant expertise who are not P.I.s of a cooperative agreement involved in the Genome Sequencing Research Network. The membership of the Scientific Advisory Panel may be enlarged permanently, or on an ad hoc basis, as needed. The Scientific Advisory Panel will meet at least once a year. During part of this meeting, there will be a joint meeting with the Steering Committee to allow the Scientific Advisory Panel members to interact directly with the awardees. Annually, the Scientific Advisory Panel will make recommendations regarding progress of the Genome Sequencing Research Network and present advice about changes, if any, which may be necessary in the Genome Sequencing Research Network program to the Director, NHGRI. 5. Arbitration Process Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NHGRI may be brought to arbitration. An Arbitration Panel will be composed of (i) a designee of the Steering Committee chosen without the NHGRI staff voting, (ii) one NHGRI designee, and (iii) a third designee with relevant expertise who is chosen by the other two (in the case of an individual disagreement, the first member may be chosen by the individual awardee). The Arbitration Panel will help resolve both scientific and programmatic issues that develop during the course of work and that restrict progress. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with NIH regulations 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 6. Yearly Milestones Each awardee will be asked to define a set of yearly milestones at the time of the award and to update these milestones annually at the anniversary date. These will be made a condition of the award. In accord with the procedures described above, NHGRI may withhold or reduce funds for a project that substantially fails to meet its milestones or to maintain the state of the art. 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 programmatic/ scientific, peer review, and financial or grants management issues: Direct inquiries regarding programmatic issues to: Dr. Jane L. Peterson or Dr. Adam Felsenfeld Division of Extramural Research National Human Genome Research Institute National Institutes of Health Building 31, Room B2B07 MSC 2033 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 E-mail: Jane_Peterson@nih.gov; Adam_Felsenfeld@nih.gov Direct inquiries regarding peer review issues to: Dr. Rudy Pozzatti Scientific Review Administrator Office of Scientific Review National Human Genome Research Institute National Institutes of Health Building 31, Room B2B37, MSC 2032 Bethesda, MD 20982-2032 Telephone: (301) 402-0838 Fax: (301) 435-1580 E-mail: Rudy_Pozzatti@nih.gov Direct inquiries regarding fiscal matters to: Ms. Jean Cahill Grants Management Officer Grants Administration Branch National Human Genome Research Institute Building 31, Room B2B34, MSC 2031 Bethesda, MD 20892-2031 Telephone: 301-435-7858 FAX: (301) 402-1951 E-mail: Jean_Cahill@nih.gov 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: Dr. Jane L. Peterson Division of Extramural Research National Human Genome Research Institute National Institutes of Health Building 31, Room B2B07 MSC 2033 Bethesda, MD 20892-2033 Telephone: (301) 496-7531 FAX: (301) 480-2770 E-mail: Jane_Peterson@nih.gov 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 http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. Applicants must use the web-based cost reporting format and are encouraged to use the progress report format as described in the SPECIAL GUIDANCE FOR APPLICANTS as part of the Progress Report and Research Proposal sections. 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: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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: Dr. Rudy Pozzatti Scientific Review Administrator Office of Scientific Review National Human Genome Research Institute National Institutes of Health Building 31, Room B2B37, MSC 2032 Bethesda, MD 20982-2032 Telephone: (301) 402-0838 Fax: (301) 435-1580 E-mail: Rudy_Pozzatti@nih.gov APPLICATION PROCESSING: Applications must be received by 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. 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. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and for 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, CSR 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 the 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 the application's overall score, weighting them as appropriate for each application. The 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, it may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does the proposal address the Research Objectives outlined in this RFA? How much will the proposed center contribute to the NHGRI-supported large-scale genomic sequencing program? What is the potential for further increases in the efficiency of large-scale sequencing beyond current practices? Will the output of the proposed center make a significant contribution to the availability of genome sequences to the community? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Are they likely to lead to successful attainment of the stated goals? Does the applicant acknowledge potential problem areas and consider alternative tactics? Are the proposed milestones reasonable? Is the quality assessment/validation plan adequate? (3) INNOVATION: Does the project employ novel concepts, approaches or methods to improve technology for genomic sequencing, aimed at reducing costs and/or increasing throughput or quality? (4) INVESTIGATOR: Is the applicant appropriately trained and well suited to carry out this work? (5) ENVIRONMENT: Does the scientific environment in which the proposed work will be done contribute to the probability of success? Does the proposed center 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, applications received in response to RFA HG-03-002 will also be reviewed with respect to the following: o The likelihood that the proposed center can produce high-quality genome sequence, based on past experience and future plans for generating high quality read data, accurate subassemblies and whole genome assemblies, and finished sequence at and beyond state-of-the- art levels of throughput, quality, and cost. o The quality of the plan to continue increasing throughput while lowering costs. o The quality of the plan for technology development and identifying and solving critical integration problems. o The quality of the plans for bioinformatics, including infrastructure/laboratory information management, assembly, and primary annotation. o The quality of the applicant's approach to sequencing, including considerations for choosing target genomes, sequencing approach/strategy, degree of completion, and considerations that may arise due to the variety of potential target genomes available. o The quality of the plan for release of sequence data, including evidence that the systems are in place to support data release, and the plans for release or distribution of other resources, software, or technologies developed under this award. o The quality of the plans to coordinate efforts with other large- scale sequencing centers in the U.S. and abroad, and with appropriate subcontractors or collaborators that may be needed. o The track record of the Principal Investigator and other key personnel in large-scale genomic sequencing. o The reasonableness of the proposed budget, milestones, timelines, and goals in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 24, 2003 Application Receipt Date: April 7, 2003 Peer Review Date: May/June 2003 Council Review: September 2003 Earliest Anticipated Start Date: November 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, both as a matter of achieving balance within the sequencing program to ensure a balanced program for meeting variable sequencing target goals, and between the sequencing program and other NHGRI activities; o The likelihood that the proposed center will make a significant contribution to the availability of high-quality sequenced genomes to the community; o The prospect for attaining and improving the state-of-the-art in genome sequencing with regard to throughput, quality, and cost. 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 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_ 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 http://grants.nih.gov/grants/funding/children/children.htm. 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. This policy announcement can be found in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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 http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA 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 http://www.health.gov/healthypeople. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.172, 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 http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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. SPECIAL GUIDANCE FOR APPLICANTS The NHGRI has conducted several competitions for large-scale sequencing projects during the course of the human sequencing effort. It has been our experience that there are specific information items and presentation formats that the reviewers have found to be critical to their assessment of large-scale sequencing proposals. The following guidance summarizes that experience in the form of a format that the applicant must use to provide that information. If there is additional information, not addressed in this Guidance, that the applicant wishes to present, the applicant is encouraged to provide it concisely in addition to the information requested here. Please note that, in addition to the textual description requested below, the applicant should also complete the indicated standardized formats to report recent sequence production and costs in a consistent manner; these are available at URL: http://www.genome.gov/Pages/Grants/RFAHG-03-002-Format. I. The Progress Report. The progress report section should adequately describe the applicant's past experience in large-scale sequence production. This section of the application should include both textual and graphic information, as follows: Section A. Text. The total length for this section must not exceed 15 pages (5000-7500 words). Brief, concise summaries are encouraged. Please base the report on the center's past accomplishments, rather than on future plans. In addition to the discussion in this section, please complete the Progress Report and Cost Format spreadsheet available at URL: http://www.genome.gov/Pages/Grants/RFAHG-03-002-Format. 1. Shotgun sequence production. The applicant should describe the center's current shotgun sequencing pipeline, starting from large- insert clones (hierarchical approach) or genomic DNA (whole genome approach). This part of the discussion is limited to genomic sequencing capacity, but the center's total capacity (i.e., human and other organisms, whether funded by NHGRI or other sources) should be included. The discussion must address data throughput, data quality, and cost, and should include, but not be limited to, the following: a. Data Generation: i. The amount of genomic shotgun sequence produced in the past twelve months in terms of reads, both the number of attempted reads and the number of successful reads, as well as the frequency of successfully paired end reads from sequencing double ended inserts (if applicable); ii. The proportions of the production sequencing that are whole genome shotgun reads and BAC-based shotgun reads; iii. The average length of production sequencing reads (in bases of phred 20 or equivalent quality) and the average useable read length; iv. The amount of that data deposited in a public database (bases deposited in a public nucleotide sequence database and reads deposited in a trace archive). NB: All sequence claimed as evidence of past production must be available to the reviewers; v. The center's total current monthly production capacity. This number should be based on an average of the last six months of sequencing and should include number of attempted and successful reads, the number of base pairs per read of at least phred 20 or equivalent quality, and the frequency of double ended reads (if appropriate); vi. The internal metrics (e.g., reads per month, failed lanes, base pairs per lane, etc.) that the center has found to be most useful in evaluating and managing progress in sequence production. b. Sequence assembly: The applicant should discuss the center's experience in assembling genome sequence at all scales (e.g., large-insert clones through genomes). The progress report should include any draft genome assemblies that have been deposited to a public database or otherwise made available (including any conditions on the use of pre-publication data). 2. Finishing. The applicant should describe the center's finishing process starting from draft-level sequence or whole genome shotgun assemblies. The discussion should include any experience in closing gaps and building contiguous finished sequence. a. The report should include the amount of finished genomic sequence (in finished base pairs) that the center produced in the last twelve months and how much of that, if any, was deposited in a public database. N.B. All sequence claimed as evidence of past production must be available to the reviewers. b. The report should include the center's current monthly finishing capacity. This number should be based on an average of the last six months of sequencing. 3. Quality. The applicant should report the center's procedures for maintaining and checking the quality of the sequence and sequence assemblies it produces, at all scales (reads, shotgun assemblies, finished sequence, and finished genomes). In the event that NHGRI and the reviewers wish to assess the data quality in more detail, the applicant must be prepared to submit sequence data produced in the last six months, including sequence traces, success rates, and information about data tracking, during the review process 4. Technology Development. The progress report should describe any experience the center has in developing and improving production- sequencing technology. The discussion should describe, in quantitative terms, the effect that such technology development has had in decreasing the center's sequencing costs and improving its efficiency 5. Prior experience in attaining milestones. The applicant should discuss the center's experience in defining and meeting useful milestones for a sequencing project. 6. Cost analysis. Using the cost portion of the Progress Report and Cost Format spreadsheet provided at URL: http://www.genome.gov/Pages/Grants/RFAHG-03-002-Format, the applicant must report the current cost per attempted lane for shotgun sequencing, for finished sequence, and for other aspects of sequencing, as well as breaking out the specific costs for technology development and informatics. The progress report should also include a description of the process by which the center's production effort is monitored internally with respect to costs. Section B. Graphical and Tabular Material. Please provide the following: 1. Graphs showing, for the past six months, the number of lanes attempted per week, the number of successful lanes per week, and the weekly success rate. 2. If the proposal includes a component to produce finished sequence, please also provide a graph indicating monthly depositions of finished sequence for the past six months (non-cumulative). II. The Research Proposal. This section (a maximum of 50 pages) comprises the applicant's proposal for operating and further developing the sequencing center during the next funding period. The organization suggested below for this section of the application is based on the NHGRI staff's current understanding that the most efficient strategy for generating a finished genomic sequence involves a shotgun phase to generate draft sequence, followed by a finishing phase. The applicant is free to propose an alternative strategy, but in doing so, must address all of the issues raised below. A. Shotgun sequence production. 1. Data generation. The applicant must present a clear plan, including concrete milestones, for (1) achieving the proposed level of sequence production, and (2) increasing the efficiency of production. The following must be addressed: a. All phases of the sequence production pipeline, starting with sub-cloning of large clones and/or generation of a whole genome shotgun library through release of the trace data to a Trace Archive and sequence to a public sequence database. The following should be included: i. the number attempted and successful sequencing reads and definition of a successful read; ii. the overall projected throughput of the proposed center and how it will be attained, increased or maintained; iii. potential bottlenecks or other problems that can be anticipated as well as proposals as to how they will be addressed; iv. timelines and quantitative milestones where appropriate. v. plans for improving efficiency; the discussion of expected costs should be expressed in the same way as in the progress report cost format, i.e., as fully loaded costs per read and per finished base. It is imperative that projections of cost reduction be fully justified, and to the extent possible based on data that are provided in the application. To report overall proposed production costs, applicants should use the Projected Cost Format spreadsheet available at URL http://www.genome.gov/Pages/Grants/RFAHG-03-002-Format. b. Sequencing targets. The applicant should assume that the specific sequencing targets will be determined on the basis of the white paper process described above and subject to negotiation with the sequencing centers, and that the NHGRI genomic sequencing program will be interested in sequencing different target genomes to different levels of completion (draft through finished). Thus, the applicant should not propose specific sequencing targets. However, the application should include: i. a discussion of strategies and approaches that the center will employ to achieve the goal identified for any particular genome; ii. a discussion of the expected characteristics of the assembled (or finished) products with regard to contiguity, order/orientation, and completeness; iii. a discussions of how issues such as genome size, repeat content, polymorphism, etc. could affect the strategy, production pipeline, and costs. c. Informatics. In this section, four aspects of the overall informatics component of the center should be discussed: i. The center's informatics infrastructure. The applicant must include a description of the basic informatics infrastructure (including database management, laboratory information management, data handling, and data submission) of the sequencing center as part of the shotgun-sequencing component of the Research Plan. ii. Assembly. The applicant must describe how assemblies of all types will be done at different sequencing depths proposed and description of additional genome assembly software or capability, if proposed. iii. Automated annotation. The primary, automated annotation process should be described in detail, including what will be done, and where the point of completion and handoff to the community will occur. iv. The development of new informatics systems for the three components listed above should be discussed, if appropriate. Proposed informatics costs should be broken out of the total costs in the Projected Cost Format spreadsheet available at URL http://www.genome.gov/Pages/Grants/RFAHG-02-002-Format. B. Finished sequence production. The NHGRI considers the finishing component to include all of the activities that are required by the center to improve draft-quality sequence to the point at which the center will not work on the sequencing project any longer and will deposit the information as "finished" in a public database (current definition: "finished" sequence has a frequency of no more than one error in 10,000 bases and no gaps that can be closed by state-of- the-art technology.). 1. Data generation. The Research Plan must include a discussion of: a. How the finishing capacity of the center will be maintained, increased and made more efficient. b. The decision-making process that the center will use to determine the degree to which different projects will be finished; the proposed incremental cost per base of finishing a draft genome 2. Informatics. The informatics issues and requirements associated with the finishing process. Proposed finishing costs should be indicated in the Projected Cost Format spreadsheet available at URL http://www.genome.gov/Pages/Grants/RFAHG-03-002-Format. C. Additional informatics: Any informatics activities beyond those addressed in the shotgun sequence production and finished sequence production components should be described in a separate section of the Research Plan. D. Technology development. The Research Plan should include a separate section describing plans for technology development for the purpose of continuing to advance the state of the art by reducing costs and increasing throughput. Proposed technology development costs should be broken out of the total costs in the Projected Cost Format spreadsheet available at URL http://www.genome.gov/Pages/Grants/RFAHG-03-002-Format. III. Budget Request. The budget requested must be described clearly and be well justified. Applicants should submit the Detailed Budget for the Initial Budget Period (page 4 of PHS-398) and the Budget for Entire Proposed Period of Support (page 5 of PHS-398). Based on extensive experience with review of large-scale sequencing grant proposals, NHGRI believes it is very important that reviewers understand both requested overall costs on a per-read basis, and also the portions of those costs that are due to various typical components of a large-scale sequencing center. Therefore, NHGRI strongly suggests that applicants use the Projected Cost Format spreadsheet available at URL http://www.genome.gov/Pages/Grants/RFAHG-03-002-Format. This format is intended to provide a view of all-inclusive total production costs per read, and incremental finishing costs per base. The format also breaks out from those totals the amount requested for technology development and informatics activities.

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