May 2000 NACHGR Meeting Summary

National Human Genome Research Institute

National Institutes of Health
U.S. Department of Health and Human Services


National Advisory Council for Human Genome Research
Summary of Meeting

Bethesda, Md.

May 22, 2000

The National Advisory Council for Human Genome Research (NACHGR) was convened for its twenty-ninth meeting at 8:30 a.m. on May 22, 2000, at the Natcher Conference Center at the National Institutes of Health (NIH). Dr. Francis Collins, director of the National Human Genome Research Institute (NHGRI), called the meeting to order.

The meeting was open to the public from 8:30 a.m. until 11:30 a.m. on May 22. In accordance with the provisions of Public Law 92-463, the meeting was closed to the public from 12:30 p.m. on May 22 until adjournment for the review, discussion and evaluation of grant applications.

Council members present:

Wylie Burke
Ronald Davis
Raju Kucherlapati
Jeanne Lawrence
Richard Lifton
Joseph Nadeau
Kim Nickerson
Maynard Olson
Janet Rowley
Robert Waterston
Alan Williamson
Barbara Wold, ad hoc participant

Ex officio members:

Gerard Schellenberg

Council members absent:

Allen Buchanan
Aravinda Chakravarti
H. Robert Horvitz
Colleen Scanlon
William Nelson, Ex officio member

Staff from the National Human Genome Research Institute:

Jane Ades, OD
Mike Bournique, OD
Joy Boyer, DER
Lisa Brooks, DER
Jean Cahill, DER
Monika Christman, DER
Francis Collins, OD
Yasmin Cypel, DER
Adam Felsenfeld, DER
Elise Feingold, DER
Bettie Graham, DER
Mary Glynn, OD
Alan Guttmacher, OD
Mark Guyer, DER
Linda Hall, DER
Karen Hajos, OD
Nicole Haynes, OD
Craig Higgins, OD
Kathy Hudson, OD
Linda Jacobson, OD
Elke Jordan, OD
Charles Leasure, OD
Emily Linde, DER
Jean McEwen, DER
Monique Mansoura, OD
Susan Mix, DER
Ken Nakamura, DER
Khang Nguyen, DER
Diane Patterson, DER
Rudy Pozzatti, DER
Jane Peterson, DER
Jerry Roberts, DER
Jeff Schloss, DER
Erin Shannon, OD
Sandra Taubenkibel, OD
April Thompson, DER
Elizabeth Thomson, DER
Kris Wetterstrand, DER
Cathy Yarbrough, OD

Others present for all or a portion of the meeting:

Sally Amero, CSR
Diane Baker, University of Michigan
Robert Boyd, Knight Ridder
Genny Cardin, Genome Canada
Cheryl Corsaro, CSR
Machi Dilworth, National Science Foundation
Dianne Flescher, Epilespy Foundation
Rosalie Goldberg, National Society of Genetic Counselors
Lauren Hafner, The Blue Sheet
Kurt Hirschhorn, American College of Medical Genetics
P.C. Huang, CSR
Angela Kopack, PhRMA
Marc LePage, Medical Research Council-Canada
Steve Mockrin, NHLBI
Bernice Morrow, Albert Einstein College of Medicine
Susan Old, NHLBI
Ari Patrinos, DOE
Nancy Pearson, CSR
Liz Pennisi, Science
Marie Persinos, Washington Insight
Clifton Poodry, NIGMS
Michael Robinson-Chavez, Washington Post
Angela Sharpe, Consortium/Social Sciences Association

Introduction of New Council Members

Dr. Jordan introduced Dr. Ronald Davis, Department of Biochemistry at Stanford University who had joined council in February but was unable to attend.

Introduction of Liaisons and New Staff

Dr. Jordan welcomed liaisons to the council from the professional societies: Ms. Rosalie Goldberg representing the National Society of Genetic Counselors; Dr. Kurt Hirschhorn representing the American College of Medical Genetics; and Dr. Bernice Morrow representing the American Society for Human Genetics.

April Thompson, public affairs specialist was introduced to council. Ms. Thompson will be working with Ms. Cathy Yarbrough, chief, Public Information and Communications Branch in the Office of Policy and Public Affairs.

Approval of Minutes

The minutes from the February 28-29, 2000, NACHGR meeting were approved as submitted.

Future Meeting Dates

The following dates were proposed for future meetings: September 11-12, 2000; February 12-13, 2001; May 21-22, 2001; September 10-11, 2001 and February 11-12, 2002.

Dr. Jordan extended a welcome to visitors attending council and introduced two visitors from Genome Canada that Dr. Collins invited while visiting Vancouver last month.

Director's Report

General Announcements

On Tuesday, May 2, 2000, Council member Dr. Robert Waterston was elected to the National Academy of Sciences. This election is considered one of the highest honors for an American scientist and is well deserved.

On March 14, 2000, President Bill Clinton and Prime Minister Tony Blair issued a joint statement concerning the release of, and access to, raw fundamental human sequence information. They commended the decision of scientists within the Human Genome Project (HGP) to release raw fundamental data into the public domain. Dr. Henry Yang, Beijing China, who is part of the International Consortium, brought this same issue to the United Nations Education, Scientific and Cultural Organizations (UNESCO). On May 9, 2000, General Koichiro Matsuura, UNESCO director issued a statement urging the G-8 to uphold the principle of free availability of human genome data.

The Department of Health and Human Services (DHHS) has announced that they will not go forward with recommending a candidate for nomination as the NIH Director at this time. Dr. Kirschstein will continue to serve as the acting director until the next President nominates and the Senate confirms a new Director, presumably several months after the November election.

Recent Scientific Accomplishments

The finished sequence of chromosome 21 was achieved as an international collaboration by three German and two Japanese groups and was published in the May 18, 2000, issue of Nature. The development of Down syndrome is caused by having an extra copy of the chromosome. The results from chromosomes 21 and 22 suggest that the number of genes in the human genome may be lower than previously estimated.

"GeneSweep", organized by Ewan Birney of the European Bioinformatics Institute (EBI), is a Gene Sweepstake that was formed at the May 2000 Cold Spring Harbor Genome conference over the debated topic of the number of human genes. The number of genes has been estimated by the participants in this Sweepstake to be anywhere between 35,000 to 150,000. The Gene Sweepstake will run between 2000 and 2003.

Dr. Collins referred to a graph found under Tab "J" that shows the production of human DNA sequence over the past five years. 1.7 billion kilobases of total genome sequence was reported to council in February. As of May 15, 2000, 2.67 kilobases of total genome sequence was reported in GenBank. Over 80 percent of the human genome is in GenBank with 20 percent in finished form and the remainder in draft. Dr. Waterston will present to council in detail on the status of human sequencing.

The five largest sequencing centers, known as the G-5, met April 13, 2000, at the Baylor College of Medicine in Houston, Texas and meet every Friday by conference call. The International sequencing consortium, known as the G-16, met the Wednesday before the Cold Spring Harbor Genome conference on May 10, 2000 with intense discussion about progress. It is anticipated that a working draft of 90 percent of the genome will be completed in the near future. The intent is then to freeze the data collected, analyze it, and submit the results and findings in manuscript form through peer review. Publications are expected in the fall. In addition to the publication of the working draft, NHGRI is putting together educational materials including a CD Rom and video to be distributed to high school biology teachers.

The NHGRI and The SNP Consortium have done a great job on increasing the throughput of SNP production. 26,391 SNPs was reported to council in February. As of May 9, 2000, 129,000 SNPs were deposited in dbSNP. It is predicted that a half million SNPs will be in dbSNP as early as January 2001. NHGRI co-sponsored a meeting with the TSC on applications of SNPs on March 7-8, 2000, to discuss how many SNPs are needed for various types of research.

A Mouse workshop is scheduled to be held Friday, May 26, 2000, as the second follow-up to the March 98 "priority setting" meeting. A review process is in place for investigators who want to obtain the sequence of a specific region of the mouse genome which has been identified in the Bacterial Artificial Chromosome (BAC) library. Drs. Bettie Graham and Jerry Roberts are coordinating this effort.

The genome sequence of Drosophila melanogaster was published in the March 24, 2000, issue of Science magazine. This was a collaborative effort between NHGRI grantee Dr. Gerald Rubin of the Berkeley Drosophila Genome Project, and Dr. J. Craig Venter of Celera Genomics. The sequence is available in GenBank without restriction as agreed to in the collaboration. About one year of finishing work through Dr. Rubin's laboratory, with assistance from Dr. Richard Gibbs, Baylor College of Medicine, is needed to close gaps.

Progress in annotation of genome sequence has moved aggressively since Dr. David Lipman, Director, National Center for Biotechnology Information (NCBI), addressed council in February. NCBI-, EBI- and the Department of Energy (DOE)-supported groups at the Oak Ridge National Laboratory are moving on a fast timetable. Some of the work was demonstrated at the Cold Spring Harbor Genome conference. There is a great deal of activity on developing systems for annotating and displaying sequence annotation information.

Policy

The NIH FY 2001 budget has gone through the Appropriations process. The NHGRI Appropriations Hearings were held March 1, 2000, before the House Subcommittee led by Congressman John Porter and on March 30, 2000, before the Senate led by Senator Arlen Specter. The House Bill is scheduled for Full Committee consideration on Wednesday, May 24, and the Senate Bill is awaiting consideration by the full Senate. It is still hoped that NIH will receive a 15 percent increase. A table explaining the NHGRI budget can be found under Tab "X." The House and Senate Conferees are still wrestling to merge the Patients' Bill of Rights legislation and have not gotten to the genetics portion yet.

The Secretary's Advisory Committee on Genetic Testing (SACGT) is chaired by Edward McCabe, M.D., Ph.D. of UCLA with Dr. Collins as the NIH liaison and council member Dr. Wylie Burke as a member of the committee. The SACGT is seeking public comment through May 22, 2000, on the preliminary conclusions and draft recommendations on the adequacy of oversight of genetic testing. A final report to the Secretary will be developed at the next SACGT meeting to be held June 5-7, 2000, in Washington D.C.

A public dialogue on gene patenting was held March 2, 2000, to discuss the Patent and Trademark Office's (PTO) revised utility guidelines to patent examiners concerning patents on DNA sequence. The PTO public comment period closed on March 22, 2000. Dr. Collins complimented council on their letter to the PTO and thought it was very useful. All public comments are available for view on the PTO Web site at http://www.uspto.gov/web/offices/com/speeches/00-25.htm. It is not known what the PTO's response will be to the public comments. Drs. Collins, Baxevanis and Guyer are scheduled to visit the PTO on May 24, 2000.

Education and Outreach

The effort to generate an educational packet, to include a CD-ROM and video for distribution to high school biology teachers, is being led by Dr. Kathy Hudson, director for policy and public affairs at NHGRI. The project is on a very fast timetable and NHGRI is thankful for the support from DOE.

The National Coalition for Health Professional Education in Genetics (NCHPEG), with support from the Robert Wood Johnson Foundation, is recruiting for an executive director to be in place by August 2000, which will enable NCHPEG to become more aggressive in achieving literacy amongst health care professionals.

The Genetics Resources on the Web (GROW) project is led by Dr. Alan Guttmacher, clinical advisor to the director, NHGRI. A second meeting of the GROW was held March 27-28, 2000, at the NIH with a goal to tie things together by: generating a search engine that is able to look at the Web pages of all of the participants in the effort; making sure quality is being attended to; and looking at the issue of assessment. The third GROW conference is scheduled for November 30 through December 1, 2000.

Dr. Collins invited questions about the director's report.

Dr. Lawrence wanted clarification on the publication of the human sequence working draft that is anticipated in the fall. Her understanding was that the data is available in GenBank. Dr. Collins replied that 86 percent of the working draft is currently in GenBank and that the publications will explain how the sequencing was accomplished and what was learned from it.

Dr. Rowley expressed concern about the SACGT recommendation to have the Food and Drug Administration (FDA) involved in the review of genetic tests and believes that the FDA is not well informed to looking at the implications of genetic tests. Dr. Burke responded that her point was well taken and that this issue received a lot of discussion at the February meeting. The SACGT is looking into developing a scheme to identify genetic tests with the greatest need for scrutiny.

Report from the Department of Energy (DOE)

Dr. Ari Patrinos, associate director for Biological and Environmental Research, Office of Science at the Department of Energy reported to council on genome related activities. Currently Dr. James Decker is serving as the acting director, Office of Science Policy. Dr. Mildred Dresselhaus, an Institute Professor at the Massachusetts Institute of Technology (MIT) was nominated by President Clinton to serve as the permanent director and a confirmation hearing was held last week.

The Office of Science has asked for a significant increase in their budget, with the increase including microbial genomics.

Secretary Bill Richardson announced at the 25th Annual American Association for the Advancement of Science Colloquium on Science and Technology Policy that researchers at the Joint Genome Institute (JGI) decoded in draft the genetic information on human chromosomes 5, 16, and 19. It is anticipated that all three chromosomes will have 7-fold coverage by next month. The finishing work on chromosomes 5 and 19 will be done at the Stanford Genome Center and chromosome 16 at the Los Alamos National Laboratory.

The Biological and Environmental Research Advisory Committee (BERAC) will meet in June to discuss the future target of sequence production capacity at the Joint Genome Institute and the appropriate role of DOE's bioremediation program. The Office of Science is interested in sequencing organisms relevant to bioremediation.

The Office of Science followed the advice of the BERAC to connect what has been done with ELSI and the genome project to the program known as Bioremediation Associated Issues and Concerns (BASIC). BASIC is a counterpart to ELSI in the bioremediation arena and has many similarities in terms of ELSI issues. A subcommittee of BERAC will be announced soon to oversee both programs. This subcommittee will look at the quality of ELSI work, review RFAs, and give advice about the future.

The BERAC met several weeks ago and addressed the future of the Biological and Environmental Research program in the post human genome project era. There was a lot of discussion on the role DOE will play in the next stage of the biotechnology revolution in structural genomics. It is anticipated that the BERAC report will be available next week.

Council members expressed concern that communication and interaction between the DOE and NIH ELSI programs be maintained in the future. DOE's participation will focus on areas that deal with the protection of workers and issues that are dealt with by institutional review boards.

ELSI Research Advisors (ERA) Mission and Structure

Ms. Elizabeth Thomson, Ethical Legal and Social Issues (ELSI) Team Leader, reported to council on the plans for establishing the ERA and its mission and structure. After the review of the ELSI research grants programs at NHGRI and DOE, the ELSI Research Planning and Evaluation Group (ERPEG) recommended that NHGRI and DOE either establish an ongoing joint planning and evaluation group or establish other mechanisms to ensure continued interaction. Because of structural and administrative differences between the agencies, NHGRI and DOE have decided to establish independent groups. NHGRI will establish the ELSI Research Advisors (ERA), which will have some overlap in membership with DOE's ELSI advisory group.

The ERA mission will be to: carry out continuing review of the ELSI portfolio; assess the progress of the ELSI program toward accomplishing the goals stated in the HGP Five Year Plan and the recommendations contained in ERPEG's Final Report; identify new issues and priority areas; identify overlap and opportunities for collaboration with the DOE ELSI program; and participate in the development of future strategic plans and goals for the ELSI program.

The ERA will meet twice a year, provide an annual verbal report to council describing the activities, and a written report to council every three years. The membership will consist of 10 to 12 individuals with expertise in a wide range of fields and representatives from diverse communities and will include: at least one former member of the ERPEG, at least one council member, and a member of the DOE ELSI advisory group. A timeline of the proposed ERA activities was provided.

Dr. Nickerson wanted to know what the extent of overlap between the NIH and DOE ELSI programs is. Ms. Thomson responded that historically the overlaps have been in the area of privacy and education, with NIH placing a greater emphasis on clinical integration of genetic technology and health professional education and DOE focusing on workplace issues and public education.

Dr. Lawrence asked if there would be any representation from other NIH Institutes on the ERA. Ms. Thomson explained that the group will focus on NHGRI's portfolio, however other institutes may want to participate by sending staff members as observers. Dr. Collins mentioned the Trans-NIH Bioethics Group has been trying to coordinate what the various institutes are doing regarding ELSI issues.

Status of Human Sequencing

Dr. Robert Waterston, Professor and Head, Department of Genetics, and Director, Genome Sequencing Center at the Washington University School of Medicine, updated Council on the status of the human sequencing effort. Dr. Waterston reported on the progress of the G-5 with the main focus on the efforts at Washington University.

Dr. Waterston explained in detail four aspects of the progress on the human sequence: 1) the effort to develop a BAC clone map; 2) sequencing production; 3) the integration of the sequence with the map to provide a contiguous overview of the sequence against the genome; and 4) the plans for completing the sequence.

A BAC map has been created from the RPCI-11 BAC clone library using the following steps: generating fingerprint data on each clone; automated binning of the clones based on the fingerprint data; manual editing of the clone order; and anchoring the contigs to chromosomes. There have been 283,287 clones assembled into 2245 contigs, 1,314 of which have more than 25 BACs. Most of the contigs have been assigned to chromosomes and ordered.

The question arose as to how much of the genome is represented in the clone contigs because these were the source of the sequence. A test using finished sequence from chromosomes 22 and 21 showed that 96 percent and 99.5 percent respectively of the finished sequence was in the BAC contigs.

Dr. Waterston elaborated on the challenges faced by the sequencers. The major challenges were: implementing capillary sequencers; increasing shotgun capacity by 10-fold over the last 14 to 15 months; and integrating the efforts of the G-5 and G-16. Dr. Waterston explained a monthly graph showing the summary of successful reads carried out by the G-5. The status as of May 15, 2000, shows 85 percent or more of the genome in GenBank, which is going up more than 2 percent a week. The definition of working draft for each center is: less than 1 percent error; no clones less than 3-fold redundant coverage; error estimates for every consensus base; the ends of inserts identified on every clone; and clones localized to chromosomal regions.

The next challenge was to integrate all of the sequences from the different sources and put them all together in a map. There are clones from libraries that are not fingerprinted and some misnamed clones. The approach was to use all of the information available to pull sequences into the map by using: in silico digests, BAC end sequences, or any other information that was available.

Dr. Waterston talked about the plans for completion of the human sequence. Chromosomes 21 and 22 have already been completed and there are more than 600 megabases of finished sequence in total. The centers have all projected that they will complete the full shotgun of their clones within the next year. The centers need to fill all clonable map gaps, complete all sequence gaps within the clones, and improve low quality regions.

Dr. Waterston stated that all of the data is available on the Web and has been used in a number of disease gene and homology hunts.

Dr. Lawrence wanted clarification of the statement that full shotgun would be completed within a year for all clones. Does that include clones that contain heterochromatic or centromeric sequence? Dr. Waterston stated they have not found any clones that look like they are all heterochromatin. Heterochromatic regions do not appear to be clonable in standard vectors.

Dr. Kucherlapati wanted to know whether there is an estimate of what kind of redundancy is required to get finished sequence. The view at Washington University is that shotgun is relatively cheap and scaleable and they can see getting 9 or 10X coverage in order to get as close to finished as possible before handing clones over to expert finishers.

Concept Clearance

Sequencing the Rat Genome

Dr. Jane Peterson presented a concept for a joint program between NHGRI and the National Heart, Lung and Blood Institute (NHLBI) to generate a working draft sequence of the rat genome. The rat genome is an important model for the study of a wide variety of complex diseases and is particularly important to the pharmaceutical industry.

NHGRI feels it is time to consider sequencing other organisms in parallel with the human and the mouse. The extensive knowledge of biology of the rat will complement the genetics in the mouse and enhance the understanding of the human sequence. The NHLBI has already collaboratively funded three initiatives for the rat: the Rat Genome Project with NHGRI in 1995, the Rat EST Program in 1997, and the Rat Genome Database. The proposal is to have the working draft of the rat sequence within 2 to 3 years with support from both institutes, depending on funding levels.

Dr. Collins mentioned that there is an interest at the Sanger Centre to sequence the zebrafish and that it would be beneficial to the scientific community to have all of these organisms sequenced at the same time (rat, mouse, zebrafish) within the next couple of years.

Dr. Kucherlapati was enthusiastic for a collaboration between NHGRI and NHLBI. He wanted to know the current thought on why we would not want to finish the sequence of the rat genome. Dr. Peterson replied that what is needed will become clearer as the mouse sequence comes out and we are able to compare it with the rat. Currently only the working draft is the goal.

Several council members expressed concern about how to prioritize sequencing of organisms. Dr. Collins explained a set of criteria that was used in the Five-Year Plan. We would like to choose an organism that: 1) has a community that wants to work on it; 2) has some genetics already developed; 3) has various possibilities to enable the use of sequence information to design downstream experiments; and 4) will fill out the evolutionary tree.

Dr. Jordan, as co-chair of the Trans-NIH Non-Mammalian Models Committee, spoke about a process the committee has developed on how NIH would go about deciding on funding for genomic resources for non-mammalian organisms. The applicant will be asked to submit a proposal for the committee to review. The committee will discuss the proposal and ascertain whether any institute or agency is interested in supporting the request. The committee includes members from, the National Science Foundation (NSF), Department of Energy (DOE), USDA and HHMI.

Dr. Kucherlapati thought it would be worthwhile for NHGRI to take a leadership role at NIH to develop a process for prioritizing the sequence of organisms and plan for the future. Dr. Collins believes this issue to be much broader than the NIH and that a plan should be established through an international consortium for large-scale sequencing. Dr. Rowley believes that this issue should be discussed within the G-16.

Dr. Olson shared his thoughts on taking a longer-range perspective on trying to find a balance between the budgetary issues and scientific issues in thinking about the future of sequencing.

Dr. Lawrence suggested developing a plan to evaluate the benefits of having completed finished sequence as opposed to working draft of an organism and how much added value the information has. Dr. Collins replied that the plan for the mouse genome is to produce finished sequencing and that we need to trade off the cost of finishing one organism versus completing the working draft of many organisms.

Council approved the concept paper for rat genome sequencing.

Announcements and Items of Interest

Dr. Jordan noted the items of interest in the council folders, and referred council to the material under Tab "P."

Council-Initiated Discussion

Dr. Jordan alerted council that the September meeting will have a full agenda. The following items will be discussed: annotation of the human sequence; finishing the human sequence; the status of training programs; and the NHGRI plan to evaluate health disparities.

Dr. Collins opened the floor to suggestions for future discussion items.

Dr. Burke would like to have a global look at the sequencing effort, where it is going, and what the priorities are.

Budget Table

Dr. Jordan referred to the budget table found under Tab "S."

Review of Applications

In closed session, the Council reviewed 113 applications, totaling $25,587,093. The applications included 25 regular research grants, three pilot projects, 23 ELSI grants, two in response to requests for application, one AREA grant, one center grant, four conference grants, two research career development awards, two training grants, two continuing education training programs, 29 SBIR Phase I, eight SBIR Phase II, eight fellowship grants, two S.T.T.R. - Phase I, and one "other." A total of 51 applications requesting $15,175,218 was commended.

I hereby certify that, to the best of my knowledge, the foregoing minutes are accurate and complete.



Date Elke Jordan, Ph.D.
Executive Secretary
National Advisory Council for Human Genome Research


Date Francis S. Collins, M.D., Ph.D.
Chairman
National Advisory Council for Human Genome Research

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Last Reviewed: March 2006