A Vision for the Future of Genomics Research: A Blueprint for the Genomic Era
By Francis S. Collins, Eric D. Green, Alan E. Guttmacher, and Mark S. Guyer on behalf of the US National Human Genome Research Institute
Part VI
Implementation: The NHGRI's Role
The vision for the future of genomics presented here is broad and deep, and its realization will require the efforts of many. Continuation of the extensive collaboration between scientists and between funding sources that characterized the HGP will be essential. Although the NHGRI intends to participate in all the research areas discussed here, it will need to focus its efforts to use its finite resources as effectively as possible. Thus, it will take a major role in some areas, actively collaborate in others, and have only a supporting role in yet others. The NHGRI's priorities and areas of emphasis will also evolve as milestones are met and new opportunities arise.
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The approach that has characterized genomics and led to the success of the HGP — an initial focus on technology development and feasibility studies, followed by pilot efforts to learn how to apply new strategies and technologies efficiently on a larger scale, and then implementation of full-scale production efforts – will continue to be at the heart of the NHGRI’s priority-setting process. The following are areas of high interest, not listed in priority order.Large-Scale Production of Genomic Data Sets
The NHGRI will continue to support genomic sequencing, focusing on the genomes of mammals, vertebrates, chordates, and invertebrates; other funders will support the determination of additional genome sequences from microbes and plants. With current technology, the NHGRI could support the determination of as much as 45 — 60 gigabases of genomic DNA sequence, or the equivalent of 15 — 20 human genomes, over the next five years. But as the cost of sequencing continues to decrease, the cost/benefit ratio of sequence generation will improve, so that the actual amount of sequencing done will be greatly affected by the development of improved sequencing technology.
The decisions about which genomes to sequence next will be based on the results of comparative analyses that reveal the ability of genomic sequences from unexplored phylogenetic positions to inform the interpretation of the human sequence and to provide other insights. Finally, the degree to which any new genomic sequence is completed — finished, taken to an advanced draft stage, or lightly sampled — will be determined by the use for which the sequence is generated. And, of course, the NHGRI’s sequencing programme will maintain close contact with, and take account of the plans and output of, other sequencing programmes, as has happened throughout the HGP.
A second data set ready for production level effort is the human haplotype map (HapMap). This project, a collaboration between the NHGRI, many other NIH institutes, and four international partners, is scheduled for completion within three years. The outcome of the International HapMap Project will significantly shape the future direction of the NHGRI’s research efforts in the area of genetic variation.
Pilot-Scale Efforts
The NHGRI has initiated the ENCODE Project to begin the development of the human genome “parts list.” The first phase will address the application and improvement of existing technologies for the large-scale identification of coding sequences, transcription units, and other functional elements for which technology is currently available. When the results of the ENCODE Project show evidence of efficacy and affordability at the pilot scale, consideration will be given to implementing the appropriate technologies across the entire human genome.
Technology Development
Many areas of critical importance to the realization of the genomics-based vision for biomedical research require new technological and methodological developments before pilots and then large-scale approaches can be attempted. Recognizing that technology development is an expensive and high-risk undertaking, the NHGRI is nevertheless committed to supporting and fostering technology development in many of these crucial areas, including the following.
DNA Sequencing. There is still great opportunity to reduce the cost and increase the throughput of DNA sequencing, and to make rapid, cheap sequencing available more broadly. Radical reduction of sequencing costs would lead to very different approaches to biomedical research.
Genetic variation. Improved genotyping methods and better mathematical methods are necessary to make effective use of information about the structure of variation in the human genome for identifying the genetic contributions to human diseases and other complex traits.
The genome '''parts list.'' Beyond coding sequences and transcriptional units, new computational and experimental approaches are needed to allow the comprehensive determination of all sequence-encoded functional elements in genomes.
Proteomics. In the short term, the NHGRI expects to focus on the development of appropriate, scalable technologies for the comprehensive analysis of proteins and protein machines in human health and in both rare and complex diseases.
Pathways and networks. As a complement to the development of the genome ''parts list'' and increasingly effective approaches to proteome analysis, the NHGRI will encourage the development of new technologies that generate a synthetic view of genetic regulatory networks and interacting protein pathways.
Genetic contributions to health, disease, and drug response. The NHGRI will place a high priority on creating and applying new crosscutting genomics tools, technologies, and strategies needed to identify the genetic bases of medically relevant phenotypes. Research on the genetic contributions to rare and common diseases, and to drug response, will typically involve biological systems and diseases of primary interest to other NIH institutes and other funding organizations. Accordingly, the NHGRI expects that its involvement in this area of research will often be implemented through partnerships and collaborations. The NHGRI is particularly interested in stimulating research approaches to the identification of gene variants that confer disease resistance and other manifestations of ''good health.''
Molecular probes, including small molecules and RNA-mediated interference, for exploring basic biology and disease. Exploration of the feasibility of expanding chemical genomics in the academic and public sectors, particularly with regard to the establishment of one or more centralized facilities, will be pursued by the NHGRI in partnership with others.
Databases
Another type of community resource for the biological and biomedical research communities is represented by databases (Box 3). But their support represents a potentially significant problem. Funding agencies, reflecting the interest of the research community, tend to prefer to use their research funds to support the generation of new data, and the ongoing need for continued and increasing support for the data archives and robust access to them is often given less attention. Both the scientific community and the funding agencies must recognize that investment in the creation and maintenance of effective databases is as important a component of research funding as data generation. The NHGRI has been a major source of support for several major genetics/genomics-oriented databases, including the Mouse Genome Database (www.informatics.jax.org/mgihome/MGD/aboutMGD.shtml), the Saccharomyces Genome Database (genome-www.stanford.edu/Saccharomyces), FlyBase (flybase.bio.indiana.edu), WormBase (www.wormbase.org), and Online Mendelian Inheritance in Man (www.ncbi.nlm.nih.gov/omim). The NHGRI will continue to be a leader in exploring effective solutions to the issues of integrating, displaying, and providing access to genomic information.
Courtesy: National Human Genome Research Institute
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