The open session of the National Advisory Council for Human Genome Research was convened for its thirty-eighth meeting at 8:40 a.m. on September 13, 2004 at the Natcher Conference Center, National Institutes of Health, Bethesda, MD. Francis Collins, Director of the National Human Genome Research Institute, called the meeting to order.
The meeting was open to the public from 8:40 a.m. until 12:30 p.m. on September 13, 2004. In accordance with the provisions of Public Law 92-463, the meeting was closed to the public from 12:30 p.m. on September 13, 2004 until adjournment for the review, discussion, and evaluation of grant applications.
Marilyn Coors, ad hoc
Geoff Duyk, ad hoc
Sean Eddy, ad hoc
Beverly Gaines, by teleconference
Jeffrey Murray, ad hoc
Vicki Yates Brown
Chris Austin, OD
Joy Boyer, DER
Lisa Brooks, DER
Brian Campbell, DER
Cheryl Chick, DER
Francis Collins, OD
Karen Deleon, OD
Tanya Dougans, DER
Elise Feingold, DER
Adam Felsenfeld, DER
Phyllis Frosst, OD
Barbara Fuller, OD
Peter Good, DER
Bettie Graham, DER
Alan Guttmacher, OD
Mark Guyer, DER
Linda Hall, DER
John Hodges, DER
Joanie Hussey, DER
Shira Katseff, DER
Rebecca Kolberg, OD
Tim Leshan, OD
Laura Liefer, DER
Jean McEwen, DER
James McWilliams, DER
Jessica Melone, DER
Patrick Nailer, DER
Ken Nakamura, DER
Vivan Ota Wang, DER
Brad Ozenberger, DER
Allison Peck, DER
Jane Peterson, DER
Matthew Portnoy, DIR
Rudy Pozzatti, DER
Nathaniel Rhodes, DER
Eddie Rivera, OD
Laura Rodriguez, OD
Jeff Schloss, DER
Michael Shi, DER
Shundel Stephenson, DER
Gary Temple, DER
Elizabeth Thomson, DER
Susan Vasquez, OD
Fred Walker, OD
Kris Wetterstrand, DER
Jonathan Witonsky, DER
Lynn Zacharia, DER
Jennifer Couzin, Science
Rachel Diaz, Families of Untreated Mentally Ill Persons
Sarah Gaia, Association of Independent Research Institutions
Andrew Hawkins, The Blue Sheet
Edward Kloza, National Society of Genetic Counselors
Sharon Olsen, International Society of Nurses in Genetics
Aristides Patrinos, U.S. Department of Energy
Michelle Russell-Einhorn, J. Craig Venter Science Foundation
Mark Guyer introduced four recently approved council members currently serving in the capacity of ad hoc council members: Marilyn Coors from the University of Colorado Health Sciences Center, Geoff Duyk from TPG Ventures, Sean Eddy from the Howard Hughes Medical Institute, Washington University School of Medicine and Jeff Murray from the University of Iowa.
Dr. Guyer introduced new NHGRI staff: Gary Temple, Program Director for the Mammalian Gene Collection; Brian Campbell, Grants Management Specialist; Michael Stebbins, ASHG Fellow; Phyllis Frosst, Science Policy Analyst; Shira Katseff, Jessica Melone, Patrick Nailer and Laura Liefer, Scientific Program Analysts.
Dr. Guyer welcomed members of the press and liaisons from professional societies: Sharon Olsen of the International Society of Nurses in Genetics, Edward Kloza of the National Society of Genetic Counselors, Jennifer Couzin of Science and Andrew Hawkins of The Blue Sheet.
Dr. Collins presented certificates of appreciation and thanked Ron Davis, Kim Nickerson, Janet Rowley and Rick Lifton, who have all completed their terms as council members.
The minutes from the May 2004 Council meeting were approved as submitted.
The following dates were proposed for future meetings: February 7-8, 2005, May 23-24, 2005, September 12-13, 2005, February 12-14, 2005, May 22-23, 2006 and September 11-12, 2006.
Dr. Collins reflected upon the life of Francis Crick who passed away July 28, 2004, at the age of 88, following a prolonged battle with colon cancer. He was trained as a physicist but was widely regarded as one of the twentieth century's most significant figures in biology. John Fletcher, former ELSI grantee and the first Chief Ethics Officer of the NIH Clinical Center, passed away on May 27, 2004. Dr. Fletcher was professor emeritus of biomedical ethics in internal medicine at the University of Virginia medical school.
NHGRI Grantee Michael Eisen from Lawrence Berkeley National Laboratory received the Presidential Early Career Award for Scientists and Engineers (PECASE) on September 9, 2004, for his pioneering work in developing novel computational methods and tools to identify patterns in genomic data.
NIH released a notice regarding the NIH Policy on Sharing of Model Organisms for Biomedical Research on May 7, 2004, reaffirming support for the concept of timely sharing and distribution of biomedical resources. Beginning October 1, 2004, all investigators submitting an application or contract proposal are expected to include a specific plan for data sharing, or a justification of why they cannot abide by this policy.
An RFA for Intellectual Property Rights in Genetics and Genomics was released June 2, 2004, to encourage the study of the role of laws and policies regarding intellectual property rights in genetics and genomics research and development.
NHGRI is involved in two recently released NIH roadmap RFAs. An RFA for Molecular Libraries Screening Instrumentation was released July 13, 2004, to develop innovative instrumentation to accelerate the pace and maximize the efficiency of molecular library high throughput screening. An RFA for the Molecular Libraries Screening Center Network (MLSCN) was released April 18, 2004. The NIH Chemical Genomics Center, which will be housed within the NHGRI Division of Intramural Research, is the first of the screening centers in this network. Additional information about the NIH Roadmap can be found at nihroadmap.nih.gov. More information regarding the NIH Roadmap effort will also be presented at the February council session.
On June 25, 2004, NHGRI's extramural division officially relocated from the main NIH campus in Bethesda, MD to Rockville, MD near the Twinbrook metro station. In addition, the NIH Intramural Sequencing Center (NISC) and several other NHGRI intramural laboratories are also expected to relocate to Twinbrook offices on September 30, 2004.
The sequencing program has been very active since the last council session, generating sequence from a number of organisms. In addition, a number of press advisories have been released. On August 4, 2004, NHGRI announced that the Large-Scale Sequencing Research Network could begin sequencing 18 selected organisms. On June 8, 2004, NHGRI announced a partnership with the Melbourne-based Australian Genome Research Facility Ltd. to sequence the Tammar wallaby (Macropus eugenii), a small member of the kangaroo family. In addition, on July 14, 2004, NHGRI announced the first draft of the dog (boxer) genome sequence. The team of researchers from the Broad Institute of MIT and Agencourt Bioscience Corporation assembled the genome based on seven-fold genome sequence coverage.
A "Workshop on Characterizing Human Genetic Variation" was held on August 3-4, 2004 to examine potential NHGRI human resequencing efforts and technology development needs in this area. A number of groups presented data regarding the status of different technologies. The workshop participants debated the merits of whole genome shotgun approaches and targeted resequencing of conserved regions, concluding that a balance of the two should be included in the NHGRI portfolio. Bob Waterston and David Altshuler co-chaired the meeting.
June 28, 2004, NHGRI announced the award of two new Centers of Excellence in Genomic Science (CEGS) grants, one at Harvard Medical School in Boston led by George Church and the other at Johns Hopkins School of Medicine in Baltimore led by Andrew Feinberg. Council will hear a full review of the CEGS program at the February 2005 council session.
On August 31, 2004, NHGRI announced the launch of the Centers for Excellence in ELSI Research (CEER) initiative, led by NHGRI with additional funding from DOE and NICHD that will establish interdisciplinary research centers to address ELSI. The first four Centers will be established at Case Western Reserve University, led by Eric Juengst; Duke University, led by Robert Cook-Deegan; Stanford University, led by Mildred Cho; and the University of Washington, led by Wylie Burke. In addition, NHGRI has awarded three exploratory grants to Alexandra Shield at Georgetown University, Charmaine Royal at Howard University, and Donald Bailey at the University of North Carolina, Charlotte.
The ENCODE project is an effort to bring together experimental and computational research methods to identify all functional sequence elements in 1% of the human genome sequence. A Consortium meeting was held June 28-30, 2004. A second set of technology development grants will be discussed in closed session. An analysis working group, to be chaired by Ewan Birney, has been established to help guide Consortium analyses on specific topics and on an analysis of the overall progress of the Consortium. A manuscript describing the ENCODE project has been submitted for publication. The next Consortium meeting is scheduled for November 10 - 11, 2004, immediately preceding the Cold Spring Harbor meeting on the Identification of Functional Elements in Mammalian Genomes.
Gary Temple has been hired by NHGRI to be the full-time leader of the Mammalian Gene Collection (MGC) project. Rat full-length cDNAs have recently been added to the MGC effort. As of August 24, 2004, 32,505 full-ORF sequences have been submitted to GenBank. These comprise a non-redundant set of 23,834 total clones. A manuscript in Genome Research describing the current status of the MGC is in press.
With the goal of profiling ninety mouse tissues in depth by Massively Parallel Signature Sequencing (MPSS) technology, the Mouse Transcriptome Project was funded by eleven NIH institutes in October 2003 and is led by NHGRI. The data from this effort will be immediately deposited in GEO (the NCBI Gene Expression Omnibus), and will be available in searchable form from GEO as well as the Lynx Technologies website. A press release will notify the community of the project, once the data are available.
A Commentary in the September issue of Nature Genetics discusses the consensus reached at a Banbury meeting on genome-wide mouse mutagenesis (Knockout Mouse Project) held in October 2003. The consensus, which has been refined since the meeting, aims to produce and phenotype knockouts for all mouse genes and place the resources in the public domain.
The ELSI Genetic Variation Consortium (GVC) continues to meet regularly. The last meeting was held July 12-14, 2004. The meeting provided the opportunity for Principal Investigators and other key personnel funded for projects to continue to examine the ethical, legal, and social implications (ELSI) of research on human genetic variation, learn about other relevant NIH supported research, and discuss research approaches and findings.
June 9, 2004, NIH announced the establishment of the NIH Chemical Genomics Center, based in NHGRI's Division of Intramural Research, under the leadership of Chris Austin. The Center is expected to be up and running by February 2005.
A consortium of researchers at twelve research institutes, including Joan Bailey-Wilson at NHGRI, and NCI has discovered a possible inherited component for lung cancer. The researchers found strong evidence that a lung cancer susceptibility gene or genes is co-inherited with a genetic marker on human chromosome 6.
NHGRI held the 2004 annual Current Topics in Genomics Short Course for faculty and students at minority serving institutions July 26-30, at the NIH campus. The Course hosted 31 participants from 15 different colleges and universities across the country and included new components such as interactive sessions, student lab shadowing, new sessions with OD and DER staff, and curricula development for the faculty participants in partnership with National Coalition for Health Professional Education in Genetics (NCHPEG).
The NHGRI website, genome.gov, has been completely redesigned. The new site,
launched June 18, 2004, features improvements in navigation and content organization.
The American Academy of Family Physicians has chosen genomics as the topic for their 2005 Annual Clinical Focus for their 93,000 members. The official launch of the ACF 2005 Genomics will be held at the combined 2004 Annual Scientific Assembly/World Organization of Family Doctors meeting in Orlando, FL, October 13-17, 2004. Dr. Collins will give the keynote address at that event.
NHGRI has been working with the Surgeon General, Richard Carmona, and other agencies to increase the American public's awareness of the importance of family history. An effort is underway to develop a user-friendly, web-based tool for the public to collect family medical history information.
July 19, 2004, NHGRI launched a new web-based legislative and policy database that will enable researchers, health professionals and the general public to more easily locate information on laws and policies related to genetic issues, such as: genetic testing and counseling, insurance and employment discrimination, newborn screening, privacy of genetic information and confidentiality, informed consent, and commercialization and patenting.
The National Academy of Sciences Committee on Intellectual Property Rights in Genomic and Protein-Related Inventions, co-chaired by Shirley Tilghman and Rod McKelvie, held its second meeting June 4, 2004, and third meeting August 5, 2004. The committee will issue a report to document the types of patents that have been issued and to whom, differences in the criteria being applied by the U.S. and other major patent offices to the examination of such applications, and to the extent possible, the licensing arrangements for different types of patented materials. The study will also attempt to evaluate the consequences of genomic patents on the progress of research.
The House Labor, Health & Human Services, and Education Appropriations bill was passed in the House on September 9, 2004. The bill provides NIH with an increase of 2.8% over fiscal year 2004. This is equal to the President's fiscal year 2005 request. The NHGRI would receive a total of $492 million, which is $13 million above last year's level. The Senate has not yet taken up the bill. There were some disturbing amendments to the House bill. One included language stipulating that none of the budgeted funds may be used to pay for more than fifty federal employees to attend any conference or meeting outside the United States. This could make federal attendance at many important meetings problematic. The second amendment took funding away from two peer-reviewed NIMH grant applications involving the study of college student mental health because they were deemed not to be important research topics.
The Senate passed the Genetic Information Nondiscrimination Act of 2003 (S. 1053). However, it has languished in the House this year despite attempts to move it along. The Subcommittee on Employer and Employee Relations, of the Committee on Education and the Workforce, held a hearing on July 22, 2004, entitled "Genetic Non-Discrimination: Examining the Implications for Workers and Employers." The witnesses included Dr. Kathy Hudson, the director of the Genetics and Public Policy Center of Johns Hopkins University and former NHGRI staffer. After the hearing, Chairman Sam Johnson (R-TX) made it clear to the press that his committee would not pass such legislation this year. We have also seen action from the Secretary's Advisory Committee on Genetics Health and Society (SACGHS) on this issue. The SACGHS is also planning a hearing on this topic at their October meeting, to give those who may have been discriminated against a chance to go on record with their stories. This issue remains a priority for NHGRI and we will continue to work on it when the new Congress starts next year.
Aristides Patrinos reported on the budget situation at the U.S. Department of Energy (DOE), which continues to be grim. However, the DOE Joint Genome Institute sequencing production facility continues to increase its efficiency and is currently generating 2.4 Gigabases of raw sequence per month. In FY2005, 30 billion base pairs of sequence production is projected. An analysis of the human chromosome 5 sequence will be published soon in Nature. A paper describing the sequence of human chromosome 16 is currently under review. The poplar genome sequencing project has reached eight-fold genome sequence coverage, an assembly has been generated and annotated, and an annotation jamboree is scheduled. The Xenopus tropicalis genome is currently at seven-fold sequence coverage. Other sequencing projects include: Amphioxus, Daphnia pulex, Nematostella and 31 microbial projects.
The DOE's community sequencing project was launched earlier this year. This project involves the transformation of the sequencing facility at Walnut Creek to a community service facility. Of sixty proposals received from the community, twenty-four were funded. Ten of these are microbial projects, ten are basal organisms and four involve ESTs or targeted sequencing projects. A meeting of the advisory committee to the Genomes to Life program will take place soon. In addition, progress is being made regarding the DOE's effort to establish high-end biocomputing resources.
Barbara Fuller presented information regarding the role of council members as special government employees. As special government employees, council members are governed by the conflict of interest statutes. Under special circumstances, waivers to the statutes can be granted. Council members are encouraged to provide detailed information regarding situations requiring a waiver at the time that council members submit conflict of interest issues to NHGRI. Financial disclosure updates are required before each council session. It is also important to let NHGRI know of any relationships with foreign countries and institutions.
Peter Good presented a concept clearance for training institutional bioinformatics resource specialists - "training the trainers." Strong support for this initiative came from a meeting last year about HumanBase. That group recognized that many biological researchers in the community do not know how to use the many tools available to access genome informatics resources. This concept proposes to train instructors who can disseminate information at their home institutions. Career development awards would be made. Awardees would attend training sessions with NHGRI and receive curricula to take back to their institutions. NHGRI confirmed that they would appropriately evaluate the program. Institutional library resources are natural conduits for this program. Reaching out to high schools and learning from established similar programs are also options. The scale covered by this concept is probably not large enough to address this overall issue, and NHGRI should look to partner with other NIH institutes and societies such as ASHG. Council approved the concept.
Rick Lifton reported on the NHGRI sequencing program. Five large centers are currently funded: Agencourt Bioscience Corporation, Baylor College of Medicine Human Genome Sequencing Center, Broad Institute/MIT Center for Genome Research, The Institute for Genome Research/J. Craig Venter Joint Technology Center and Washington University Genome Sequencing Center. The pipeline for sequencing is filled through a process involving advisory committees that consider the science behind choosing organisms, NHGRI staff and the Sequencing Advisory Panel (SAP). Members of the SAP include: Geoff Duyk, Bill Gelbart, Rick Lifton, David Valle, Alan Williamson and Barbara Wold.
The sequencing program started by funding numerous pilot projects to sequence the human genome. Since then a smaller number of centers were ramped up, reaching a peak of activity at the time of completing the human genome. Funds for the program have since decreased, while sequence capacity has continued to rise. Currently the five centers are able to sequence 90 Gigabases of raw sequence, which is equivalent to 30 single-pass coverages of a mammalian-sized genome. Further increases in efficiency are still to come. The centers are also involved in significant bioinformatics, technology development, mapping, outreach and community coordination efforts. These efforts make up about 20% of the overall sequencing budget. Production sequence costs have decreased over time. It cost about $10 in 1990 to produce a finished base compared with approximately six cents today.
To date, genome sequencing has been completed for a number of organisms. Finishing also remains a priority for the NHGRI sequencing program. The data for genomes are clearly being used by the community as evidenced by the hits to the various web browsers for human, mouse and rat genomes. There are a number of reasons for continued genome sequencing, including: generating reference sequences for important experimental organisms and annotating the human genome by comparative sequence analysis, the best approach for which is currently under debate. A number of mammals in the sequencing queue were chosen to provide a substantial amount of evolutionary branch length to enable informative comparative analyses. Primate species are also in the pipeline to provide comparative information at closer evolutionary distances. Non-mammalian vertebrates and invertebrates are also being sequenced for a number of reasons: particular biological interests, to fill niches of the evolutionary tree or to annotate model systems. Large-scale sequencing capacity could also include human resequencing.
Council discussed the amount of resources devoted to technology development at the centers and the resulting effect on sequence capacity and quality. Historically, if more funds had been spent on technology development, would sequence quality and production capacity currently be better and/or greater? Not necessarily; while the centers have not been the places for breakthrough technologies, they have made substantial improvements to their own pipelines. The funding system has been built in a way to allow the centers to try new technologies. The amount of pressure on the centers to reduce costs and increase efficiencies has been historically optimal. New technologies should be pushed just as hard.
It is very important to get a new technology in place in the next two to three years and to decrease its required infrastructure. The next generation of sequencing technology (~ten years) needs to have a further drop in reagent cost, an even smaller infrastructure and a drop in hardware cost. As technology improves and capacity increases, other aspects of sequencing, such as informatics, assembly and annotation may become rate-limiting.
Where possible, partnerships with private industry should be built. It was noted that the current NIH rules for SBIR grants tend to chase private money out of technology development, because of the limit to private ownership, which is currently 50%. In addition, the current sequencing pipeline is dependent on Applied Biosystems, who is not currently developing new sequencing machines.
When evaluating the sequencing centers, there is a tendency to stress cost figures and data generation. There are many additional important center activities including community interaction, accommodation of the needs of different organisms, project management and mapping. Finishing hasn't improved that much over time, but this is due to focus being put on the delivery of other levels of sequence data. Council agreed that the ability to finish is an ability that should not be lost. It was also noted that there is a portion of the genome, heterochromatin, that we are still unable to sequence.
The sequencing centers recognize that NHGRI support for sequencing is decreasing. As other funding agencies are able to support sequencing, the sequencing centers are increasing and diversifying their portfolio of projects. Even though the sequencing pipeline is now high throughput and automated, there are aspects of the sequencing process such as assembly and annotation that remain difficult research problems. The centers are uniquely qualified to handle these difficulties. Also, even though there are many research entities interested in technology development, they will not be sites for data production. Therefore, data generation needs to be sustained at some level; at least until the next generation of sequencing technology is established.
NHGRI-supported sequencing comprises over half of the worldwide sequencing
NHGRI is the leader in maintaining sequencing capacity, driving technology development and coordinating sequencing efforts with other institutions and funding agencies. The International Sequencing Consortium meets annually and supports a website of sequencing projects in order to help coordinate international sequencing efforts. NHGRI maintains communication with DOE and the Wellcome Trust, as well as other entities. It was suggested that NHGRI consider collaborations with Singapore and India.
It was noted that dialogue regarding sequencing has evolved from 'simple' sequence generation to addressing scientific questions. The next round of sequencing recommendations will address the identification of conserved elements, informing other model organisms, human resequencing, additional primate sequencing and finishing of some genomes. The new plans will be presented to council in the February and May council sessions.
Lisa Brooks provided an update on the HapMap Project, an international effort to generate a haplotype map for the entire human genome. The genotyping on 270 samples from four populations currently proceeds in two phases. Phase I aims to produce a SNP every 5 kilobases. The second phase will increase the SNP coverage and involve a total of ~3 million SNPs, to improve the choice of tag SNPs. There are currently eight international groups participating in genotyping efforts. A quality assessment exercise has taken place, with a second currently in process and a third scheduled.
Most chromosomes are 60-80% complete in terms of SNP coverage in the "Hap-Mappable" genome for the 5 kb map. In order to define the rules for completing the map, deeper data are being generated for a small number of regions. Additional SNP discovery was done in ten of the ENCODE regions and all known SNPs will be genotyped in these regions. The third phase of the HapMap involves examining the ENCODE regions in additional populations and comparing the patterns between populations. Sample collection efforts are currently underway for these populations.
Council discussion included the extension of the numbers of individuals rather than the number of populations. This will be done in ten of the ENCODE regions, where an additional 270 samples from the four populations will be genotyped. It was also noted that a haplotype map does not answer all types of research questions. Additional work will be needed to identify all SNPs at a lower minor allele frequency threshold.
Cheryl Chick went over the Statement of Understanding that outlines the relationship between the NHGRI and the Council regarding the review of grant applications and staff administrative authorities. Council concurred with the statement as written. Given the size of some NHGRI grants, council expressed some concern with language giving authority to NHGRI to award administrative supplements of up to 25% of a grant's budget without Council approval. The statement will be presented again to February 2005 council for its regular annual approval. NHGRI will modify the MOU to reflect Council comments regarding the 25% supplement authority. In the interim, the Council approved the statement as written.
In February 2005, we will have a discussion of the CEGS program, a presentation about the NIH Roadmap and a presentation of the results of the sequencing center site visits. Mary Hendrix suggested a presentation regarding epigenetic analysis. It was noted that a recently awarded CEGS project deals with this issue. The PI, Andy Feinberg, could be invited to present at the May Council session. Rick Myers suggested a presentation regarding resequencing technologies.
Dr. Guyer noted one item of interest in the Council folders, a notice regarding supplements to promote reentry of scientists into biomedical and behavioral research centers.
Dr. Guyer read the Conflict of Interest policy to Council and asked them to sign the forms provided.
In closed session, the Council reviewed 179 applications, requesting $71,349,960. The applications included 48 regular research grants, 1 pilot project, 18 ELSI grants, 65 responses to RFAs, 1 area grant, 3 center grants, 1 conference grant, 24 SBIR Phase I grants, 5 SBIR Phase II grants, 2 fellowship grants, 3 STTR Phase I grants and 3 others. A total of 114 applications totaling $56,122,011 were recommended.
I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.
Date Mark Guyer, Ph.D.
National Advisory Council for Human Genome Research
Date Francis S. Collins, M.D., Ph.D.
National Advisory Council for Human Genome Research
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Last Reviewed: March 23, 2012