June 26, 2000 The Human Genome Project public consortium today announced that it has assembled a working draft of the sequence of the human genome — the genetic blueprint for a human being. This major milestone involved two tasks: placing large fragments of DNA in the proper order to cover all of the human chromosomes, and determining the DNA sequence of these fragments.
The assembly reported today consists of overlapping fragments covering 97 percent of the human genome, of which sequence has already been assembled for approximately 85 percent of the genome. The sequence has been threaded together into a string of As, Ts, Cs, and Gs arrayed along the length of the human chromosomes.
Production of genome sequence has skyrocketed over the past year, with more than 60 percent of the sequence having been produced in the past six months alone. During this time, the consortium has been producing 1000 bases a second of raw sequence — 7 days a week, 24 hours a day.
The average quality of the “working draft” sequence far exceeds the consortium’s original expectations for this intermediate product.
Consortium centers have produced far more sequence data than expected (over 22.1 billion bases of raw sequence data, comprising overlapping fragments totaling 3.9 billion bases and providing 7-fold sequence coverage of the human genome).
As a result, the “working draft” is substantially closer to the ultimate “finished” form than the consortium expected at this stage. Approximately 50 percent of the genome sequence is in near-“finished” form or better, and 24 percent of it is in completely “finished” form. Across the genome, the average DNA segment resides in a continuous gapless sequence “contig” of 200,000 bases. The average accuracy of all of the DNA sequence in this assembly is 99.9 percent.
The sequence information from the public project has been continuously, immediately and freely released to the world, with no restrictions on its use or redistribution. The information is scanned daily by scientists in academia and industry, as well as by commercial database companies providing information services to biotechnologists.
Already, many tens of thousands of genes have been identified from the genome sequence. Analysis of the current sequence shows 38,000 predicted genes confirmed by experimental evidence. There are many thousands of additional gene predictions to be tested experimentally. Dozens of disease genes have been pinpointed by access to the working draft.
Consortium goals. The consortium's goal for the spring of 2000 was to produce a “working draft” version of the human sequence, an assembly containing overlapping fragments that cover approximately 90 percent of the genome and that are sequenced in “working draft” form, i.e.- with some gaps and ambiguities. The consortium’s ultimate goal is to produce a completely “finished” sequence, i.e. one with no gaps and 99.99 percent accuracy. The target date for this ultimate goal had been 2003, but today’s results mean that the final, stand-the-test-of-time sequence will likely be produced considerably ahead of that schedule.
Complementary approaches. In a related announcement, Celera Genomics announced today that it has completed its own first assembly of the human genome DNA sequence.
The public and private projects use similar automation and sequencing technology, but different approaches to sequencing the human genome. The public project uses a ‘hierarchical shotgun’ approach in which individual large DNA fragments of known position are subjected to shotgun sequencing (i.e., shredded into small fragments that are sequenced, and then reassembled on the basis of sequence overlaps).
The Celera project uses a “whole genome shotgun” approach, in which the entire genome is shredded into small fragments that are sequenced and put back together on the basis of sequence overlaps.
The hierarchical shotgun method has the advantage that the global location of each individual sequence is known with certainty, but it requires constructing a map of large fragments covering the genome. The whole shotgun method does not require this step, but presents other challenges in the assembly phase.
Both approaches align the sequence along the human chromosomes by using landmarks contained in the physical map produced by the Human Genome Project.
"The two approaches are quite complementary. The public project and Celera plan to discuss the relative scientific merits of the methods employed by the two projects. In the end, the best approach may well be to use a combination of the methods for sequencing future genomes," said Francis Collins, M.D., Ph.D., director of the National Human Genome Research Institute of the National Institutes of Health. In fact, current plans by the public project to sequence the genome of the laboratory mouse involve this hybrid strategy.
Next phase. The Human Genome Project will now focus on converting the “working draft” and near-“finished” sequences to a “finished” form. This will be done by filling the gaps in the “working draft” sequence and by increasing the overall sequence accuracy to 99.99 percent. Although the “working draft” version is useful for most biomedical research, a highly accurate sequence that is as close to perfect as possible is critical for obtaining all the information there is to get from human sequence data. This has already been achieved for chromosomes 21 and 22, as well as for 24% of the entire genome.
Human DNA variation. The greater-than-expected sequence production has also yielded a bumper crop of human genetic variations - called single nucleotide polymorphisms or SNPs. The Human Genome Project had set a goal of discovering 100,000 SNPs by 2003. Already, with today’s assembled sequences and other data accumulated by The SNP Consortium, scientists have now found more than 300,000 SNPs and will likely have 1 million SNPs by year-end. These SNPs provide a powerful tool for studies of human disease and human history.
Sequencing, which is determining the exact order of DNA’s four chemical bases, commonly abbreviated A, T, C and G, has been expedited in the Human Genome Project by technological advances in deciphering DNA and the collaborative nature of the effort, which includes about 1,000 scientists worldwide working together effectively.
The Human Genome Sequencing Project aims to determine the sequence of the euchromatic portion of the human genome. The euchromatic portion excludes certain regions consisting of long stretches of highly repetitive DNA that encode little genetic information, and that are not recovered in the vector systems used by the genome project. Such regions account for about 10% of the genome, and are said to be heterochromatic. (For example, the center of chromosomes, called centromeres, consists of heterochromatic DNA.)
The international Human Genome Sequencing consortium includes scientists at 16 institutions in France, Germany, Japan, China, Great Britain and the United States. The five largest centers are located at: Baylor College of Medicine, Houston, Texas; Joint Genome Institute in Walnut Creek, CA; Sanger Centre near Cambridge, England; Washington University School of Medicine, St. Louis; and Whitehead Institute, Cambridge, Massachusetts. Together, these five centers have generated about 82% of the sequence. The following list provides more detail about the 16 centers and their individual contributions to the Human Genome Project.
The project has been tightly coordinated so that no region of the genome is left unattended to, and duplication is minimized. Participants in the international consortium have all adhered to the project’s quality standards and to the daily data release policy. The project is funded by grants from government agencies and public charities in the various countries. These include the National Human Genome Research Institute at the National Institutes of Health, the Wellcome Trust in England, and the US Department of Energy.
The total cost for the working draft is approximately $300 million worldwide, with roughly half ($150 million) being funded by the US National Institutes of Health. The cost of sequencing the human genome is sometimes reported as $3 billion. However, this figure refers to the original estimate of total funding for the Human Genome Project over a 15-year period (1990-2005) for a wide range of scientific activities related to genomics. These include studies of human diseases, experimental organisms (such as bacteria, yeast, worms, flies and mice), development of new technologies for biological and medical research, computational methods to analyze genomes, and ethical, legal and social issues related to genetics.
The sixteen institutions that form the Human Genome Sequencing Consortium include:
1. Baylor College of Medicine, Houston, Texas, USA
2. Beijing Human Genome Center, Institute of Genetics, Chinese Academy of Sciences, Beijing, China
3. Gesellschaft fur Biotechnologische Forschung mbH, Braunschweig, Germany
4. Genoscope, Evry, France
5. Genome Therapeutics Corporation, Waltham, MA, USA
6. Institute for Molecular Biotechnology, Jena, Germany
7. Joint Genome Institute, U.S. Department of Energy, Walnut Creek, CA, USA
8. Keio University, Tokyo, Japan
9. Max Planck Institute for Molecular Genetics, Berlin, Germany
10. RIKEN Genomic Sciences Center, Saitama, Japan
11. The Sanger Centre, Hinxton, U.K.
12. Stanford DNA Sequencing and Technology Development Center, Palo Alto, CA, USA
13. University of Washington Genome Center, Seattle, WA, USA
14. University of Washington Multimegabase Sequencing Center, Seattle, WA, USA
15. Whitehead Institute for Biomedical Research, MIT, Cambridge, MA, USA
16. Washington University Genome Sequencing Center, St. Louis, MO, USA
In addition, two institutions played a key role in providing computational support and analysis for the Human Genome Project over the course of the past eighteen months. These include:
The National Center for Biotechnology Information at NIH
The European Bioinformatics Institute in Cambridge, UK
Scientists at the University of California, Santa Cruz, and Neomorphic, Inc. also assisted the assembly of the genome sequence across chromosomes.
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