Beyond Genes: Scientists Venture Deeper into the Human Genome

In recent years, researchers have made tremendous progress in sequencing the genomes of humans and other organisms. Scientists use DNA sequence data to help find genes, which are the parts of the genome that code for proteins. However, the protein-encoding component of DNA comprises just a small fraction of the genome, accounting for roughly 1.5 percent of the genetic material of humans and other mammals. There is compelling evidence that other parts of the genome must have important functions, but at present there is only very limited information available about how these other parts work.

"The Human Genome Project has provided us with a wonderful foundation, but obviously having the human genomic sequence is not enough. We must keep on exploring this newfound wealth of knowledge if we are to realize the full potential of genome research to improve human health," said NHGRI Director Francis S. Collins, M.D., Ph.D., who led the public effort to sequence all 3 billion base pairs in human DNA.

"Our experimental and computational methods are still primitive when it comes to identifying functional elements that are not involved in protein coding. That has to change. So, with NHGRI's support, research teams around the world are embarking on a daunting mission: to build a comprehensive 'parts list' of the human genome by identifying and precisely locating all functional elements in our DNA sequence," Dr. Collins said.

The new effort, which is called the ENCyclopedia Of DNA Elements (ENCODE) project, will be carried out by an international consortium made up of scientists in government, industry and academia. A major aspect of this initiative is a three-year pilot project in which research groups will work cooperatively to test efficient, high-throughput methods for identifying, locating and fully analyzing all of the functional elements contained in a set of DNA target regions that covers approximately 30 megabases, or about 1 percent, of the human genome. If the pilot effort proves successful, the project will be expanded to cover the entire genome.

"The ultimate goal of the ENCODE project is to create a reference work that will help researchers fully utilize the human sequence to gain a deeper understanding of human biology, as well as to develop new strategies for preventing and treating disease," said Elise A. Feingold, Ph.D., the NHGRI program director in charge of the ENCODE project. "Following the model established by the Human Genome Project, data generated by ENCODE researchers will be collected and stored in databases, and will be rapidly and freely available to the entire scientific community.

The ENCODE pilot effort is being implemented by a consortium because the wide range of technologies that need to be tested and developed is well beyond the scope of any single scientific team. The DNA target regions were selected to provide a good cross section of different types of genome sequence and to encourage researchers to look for functional elements beyond genes, transcription-factor binding sites and others that are already fairly well characterized.

"Each member of the consortium will look at all the target regions. Researchers won't be able to come in and just focus on their favorite area of the genome," Dr. Feingold said. "By working together in a highly cooperative manner, we fully expect this consortium to lay the groundwork for a future, large-scale effort."

In addition to studying the human genome itself, another prominent component of the ENCODE project will be the comparison of genomic sequences from many different animals. "Multi-species comparisons enable us to zero in on DNA sequences that have been highly conserved throughout evolution, which is a strong indicator that these sequences reflect functionally important regions of the human genome," said NHGRI Scientific Director Eric D. Green, M.D., Ph.D., whose team recently published a pioneering study in the journal "Nature" that compared genomic sequences among 13 vertebrate species.

In this the first year of the ENCODE project, NHGRI has awarded approximately $10.5 million in funds to researchers who will study the large-scale application of existing technologies for determining functional elements. Ultimately, approximately $28 million is expected to be allocated to this part of the effort over three years.
Grant recipients in this category are:

RICHARD MYERS, PH.D., STANFORD UNIVERSITY, PALO ALTO, CALIF. -- "The Stanford ENCODE Project" -- First year funds, $2.7 million; total funds, $8 million.

GEORGE STAMATOYANNOPOULOS, M.D., DR. SCI., UNIVERSITY OF WASHINGTON, SEATTLE -- "Identification of Functional DNA Elements by HSqPCR" -- First year funds, $2.3 million; total funds, $6.9 million.

MICHAEL SNYDER, PH.D., YALE UNIVERSITY, NEW HAVEN, CONN. --"Transcription and Regulatory Elements in ENCODE Regions" -- First year funds, $1.7 million; total funds, $4.9 million.

BING REN, PH.D., LUDWIG INSTITUTE FOR CANCER RESEARCH, UNIVERSITY OF CALIFORNIA, SAN DIEGO -- "Mapping Transcriptional Regulatory Elements in Human DNA" -- First year funds, $1.4 million; total funds, $3.1 million.

THOMAS GINGERAS, PH.D., AFFYMETRIX, INC., SANTA CLARA, CALIF. -- "Mapping Sites of Transcription and Regulation" -- First year funds, $990,000; total funds, $2 million.

RODERIC GUIGO, PH.D., MUNICIPAL INSTITUTE OF MEDICAL RESEARCH, BARCELONA, SPAIN -- "Encyclopedia of Genes and Gene Variants" -- First year funds, $570,000; total funds, $1.5 million.

ANINDYA DUTTA, PH.D., UNIVERSITY OF VIRGINIA, CHARLOTTESVILLE -- "Mapping Replication Elements on Human Chromosomes" -- First year funds, $380,000; total funds, $1.1 million.

IAN DUNHAM, PH.D., THE WELLCOME TRUST SANGER INSTITUTE, HINXTON, U.K. -- "Detecting Human Functional Sequences with Microarrays" -- First year funds, $490,000; total funds, $730,000.

In addition to the new grantees, a number of other groups will participate in the ENCODE consortium, including those headed by NHGRI's Dr. Green, who will spearhead the comparative sequencing efforts for this project; the University of California, Santa Cruz's David Haussler, Ph.D., who will coordinate the database for all sequence-related data; NHGRI's Andreas D. Baxevanis, Ph.D., who will coordinate the database for other data types; and Children's Hospital Oakland Research Institute's Pieter de Jong, Ph.D., who will lead the team that will create the clone resources needed to support the comparative sequencing.. Furthermore, the ENCODE project is open to other investigators willing to participate within the criteria and guidelines established for the consortium.

Simultaneously, NHGRI has awarded $2.6 million in first-year funding to researchers for a second component of the ENCODE project: to develop new or improved technologies for finding functional elements in genomic DNA. Further technology development is critical to the long-term goal of the project because scientists currently do not have all of the necessary tools to complete the encyclopedia for the entire human genome in a rapid, efficient and cost-effective manner. Approximately $7.8 million will be allocated to this part of the effort over three years.
Grant recipients in this category are:

ZHIPING WENG, PH.D., BOSTON UNIVERSITY -- "Alternative Promoter Usage in Tissue-Specific Gene Expression" -- First year funds, $530,000; total funds, $1.5 million.

XIANG-DONG FU, PH.D., UNIVERSITY OF CALIFORNIA, SAN DIEGO - -- "A Novel chIP-Chip Technology for ENCODE" -- First year funds, $460,000; total funds, $1.4 million.

ROBERT KINGSTON, PH.D., MASSACHUSETTS GENERAL HOSPITAL, BOSTON -- "Long-Range, High-Resolution Mapping of Chromatin" -- First year funds, $430,000; total funds, $1.3 million.

ROLAND GREEN, PH.D., NIMBLEGEN SYSTEMS, INC., MADISON, WISC. -- "Discovery of Binding Sites for Transcription Factors" -- First year funds, $400,000; total funds $1.3 million.

MARK MCCORMICK, PH.D., NIMBLEGEN SYSTEMS, INC., MADISON, WISC. -- "DNA Array-based Exon Detection and Linkage Mapping" -- First year funds, $400,000; total funds, $1.2 million.

JOB DEKKER, PH.D., UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL, WORCESTER -- "Structural Annotation of the Human Genome" -- First year funds, $370,000; total funds, $1.2 million.

NHGRI is one of 27 institutes and centers at the National Institutes of Heath, which is an agency of the Department of Health and Human Services. NHGRI's Division of Extramural Research supports grants for research, and for training and career development at sites nationwide.

For more information about NHGRI's ENCODE project, go to www.genome.gov/ENCODE/. Additional information about NHGRI can be found at its Web site, www.genome.gov.

Message posted by: Frank S. Zollmann