- Microbial genomics—the use of bacteria to create new energy sources such as biofuels and safe, efficient toxic waste cleanup; enhanced understanding of
FIGURE 7.6
Selected landmarks of the human genome project [CONTINUED] how microbes cause disease; and protection from threats of biological and chemical terrorism and warfare (see Figure 7.7) - Risk assessment—measuring the risks and health problems caused by exposure to radiation, carcinogens (cancer-causing agents), and mutagenic chemicals; and reduction of the probability of heritable mutations
- Archaeology, anthropology, evolution, and human migration—comparing the genomes of humans and other organisms such as mice already has identified similar genes associated with diseases and traits; improving the understanding of germline (cells that give rise to eggs or sperm) mutations; studying migration based on female genetic inheritance; examining mutations on the Y chromosome to trace lineage and migration of males; and comparing the DNA sequences of entire genomes of different microbes to enhance the understanding of the relationships among the three domains of life: archae-bacteria (cells that do not contain nuclei), eukaryotes (cells that contain nuclei), and prokaryotes (single-celled organisms without nuclei)
- DNA forensics—identifying crime victims, potential suspects, and catastrophe victims through examination of DNA; confirm paternity and other family relationships; clear people wrongly accused of crimes; identify and protect endangered species; detect bacterial and other environmental pollutants; match organ donors and recipients for transplant programs; and determine pedigrees for animals and plants
- Agriculture and livestock breeding—develop healthier, stronger crops and farm animals able to resist insects, disease, and drought; create safer pesticides; grow more nutritious produce; incorporate vaccines into food products; and redeploy plants such as tobacco for use in environmental cleanup programs
FIGURE 7.6
Selected landmarks of the human genome project [CONTINUED]
Molecular Medicine
The HGP and the technological advances it has produced have moved the field of molecular medicine forward with extraordinary speed. In "Genomes, Transcriptomes, and Proteomes: Molecular Medicine and Its Impact on Medical Practice" (Archives of Internal Medicine, vol. 163, no. 2, January 27, 2003), Ivan Gerling et al. asserted that the HGP will not only influence the way science is conducted, but will also advance the clinical practice of medicine. Gerling and his fellow researchers credited the HGP for the technological advances that enable preclinical detection—recognition of disease before its earliest biochemical or visible expression. They foresaw increasing accuracy and ease of preclinical detection, as well as the ability to predict disease based on three fundamental levels of biologic determination:
- The genomic DNA constitution of the individual (the genome), which is unchanged from the moment of conception, with the exception of some isolated, local mutations
FIGURE 7.7
Toxic waste site cleanup
SOURCE: "Toxic Waste Site Cleanup," in "Genomics: GTL Images," Genomics Image Gallery, U.S. Department of Energy, Office of Science, Office of Biological and Environmental Research, Human Genome Project, http://www.ornl.gov/sci/techresources/Human_Genome/graphics/slides/images/01-0414a.jpg (accessed February 21, 2005) - The transcribed messenger RNA complement (the transcriptome)
- The full range of translated proteins (the proteome)
Gerling and his colleagues posited that the environment influences gene expression and modifies gene products in ways that initiate, accelerate, or slow progress of disease-causing processes. This does not change the genome, but it does change the transcriptome and the proteome. Recent technological breakthroughs have provided the tools to perform the comprehensive molecular analyses needed to examine not only the genome, but also the transcriptome and proteome. Using new technologies will dramatically increase understanding at the molecular level of the mechanisms of disease development.
Along with molecular diagnosis of diseases even before they are clinically apparent, Gerling et al. predicted increasingly effective therapies as genetic information enables physicians to individualize treatment in response to the availability of comprehensive genetic and molecular profiles. Although there are many promises and potential benefits of molecular medicine—improved diagnostic ease, speed, and accuracy; earlier detection of genetic predisposition or susceptibility to disease; gene therapy; and pharmaceutical drug development, specifically pharmacogenetics to produce "customized drugs"—Gerling and his coauthors also concluded that the increased knowledge must be used responsibly. They cautioned that society must take steps to ensure that this improved understanding of genetics is not deployed to exclude people from obtaining insurance or employment.
The Haplotype Mapping Project
In October 2002 an international effort to develop a haplotype map of the human genome was launched. A haplotype is a set of alleles or markers on one of a pair of homologous chromosomes, and a haplotype map will show human genetic variation. The premise of the International HapMap Project is that within the human genome different genetic variants within a chromosomal region—haplotypes—occur together far more frequently than others. Based on common haplotype patterns—combinations of DNA sequence variants that are usually found together—the haplotype map aims to simplify the search for medically important DNA sequence variations and to offer new understanding of human population structure and history.
Because any two people are 99.9% identical genetically, understanding the one-tenth of 1% difference is important because it helps explain why one person may be more susceptible to a certain disease than another. Researchers can use the HapMap to compare the genetic variation patterns of a group of people known to have a specific disease with a group of people without the
FIGURE 7.8
Most single nucleotide polymorphism (SNP) variation occurs
within all groups
Since investigators hypothesize that differences between haplotypes may be associated with varying susceptibility to disease, mapping the haplotype structure of the human genome may be the key to identifying the genetic basis of many common disorders. The HapMap project also aims to serve as a resource for studying the genetic factors that contribute to variation in response to environmental factors, in susceptibility to infection, and in the identification of genetic variants associated with the effectiveness of, and adverse responses to, drugs and vaccines.
Canada, China, Japan, Nigeria, the United States, and the United Kingdom have embarked on a three-year project to construct a haplotype map based on 200 to 400 genetic samples drawn from four geographically distinct populations. The populations were chosen based on their diverse population histories, which may result in differences in haplotype structure and frequencies, rather than to ensure diverse ethnic or racial representation. By 2005 the international consortium of researchers were studying 270 samples collected from four populations—the Yoruba in Ibadan, Nigeria; Japanese in Tokyo, Japan; Han Chinese in Beijing, China; and Utah residents with ancestry from northern and western Europe. Additional research will determine whether the common haplotypes identified in these populations are representative of those in other populations, or whether additional populations will need to be examined in order to identify the full range of haplotypes.
To create a haplotype map, researchers must have enough SNPs to be sure that regions containing disease alleles have been found and that regions not containing disease alleles can be excluded from further consideration. When the HapMap is completed, researchers will use it to study the genetic risk factors underlying a wide range of disorders. For any given disease, researchers could perform an association study by using the HapMap tag SNPs to compare the haplotype patterns of a group of people known to have the disease to a group of people without the disease. If the association study finds a specific haplotype more frequently in those with the disease, researchers could scrutinize the precise genomic region in their search for the specific genetic variant.
On February 7, 2005, the International HapMap consortium announced plans to create an even more powerful map of human genetic variation than the group had initially planned. The project was originally intended to complete the map of haplotypes by September 2005, but by mid-2005 a draft of the HapMap, consisting of one million markers of genetic variation, was released. The first draft of the HapMap has enabled researchers to analyze the human genome in ways that were not possible with the human DNA sequence alone. The second phase of the project, slated for completion by the end of 2005, will provide a denser map that will enable scientists to narrow gene discovery more precisely to specific regions of the genome.
The First Map of Common Human Genetic Variations
In February 2005 scientists working at Perlegen Sciences, Inc., in California produced the first map of common human genetic variations—differences in DNA that may assist in predicting disease risk and optimal disease treatment. To create the map, Perlegen investigators collaborated with researchers at the California Institute for Telecommunications and Information Technology at UC San Diego and the International Computer Science Institute at UC Berkeley. The map was unveiled at a meeting of the American Association for the Advancement of Science and described in the February 17, 2005, issue of Science.
Perlegen scientists looked at the DNA of seventy-one Americans of European, African, and Chinese ancestry and identified 1.58 million SNPs—single-letter genetic differences—most of them shared across the three populations. Although the 1.58 million SNPs are just about 10% of the ten million SNPs believed to exist, they appear to be among the most common. The Perlegen map does not pinpoint which SNPs are linked to disease risk, but future research will focus on identifying the SNP variations that trigger some people to develop diseases and others to resist or combat them.
The Future of Genomic Research
In "A Vision for the Future of Genomics Research," published in the April 24, 2003, issue of the journal Nature, the NHGRI described some of the research challenges of the postgenomic era. In addition to the HapMap project and the DOE's "Genomes to Life," the article detailed three other initiatives.
Directed by the NHGRI, the Encyclopedia of DNA Elements Project (ENCODE) aims to develop efficient ways to identify and locate all of the protein-coding genes, nonprotein-coding genes, and other sequence-based, functional elements contained in the human DNA sequence. This ambitious undertaking will produce an enormous resource for researchers seeking to use and apply the human sequence to predict disease risk and to develop new approaches to prevent and treat disease.
ENCODE entails three phases: a three-year pilot project phase; a second technology development phase that parallels phase 1; and a planned production phase. In the October 22, 2004, issue of Science, the ENCODE investigators described their plans to build a "parts list" of all sequence-based functional elements in the human DNA sequence. The researchers hope to identify as-yet-unrecognized functional elements. During the pilot phase they are developing and testing high-throughput ways to efficiently identify functional elements. They are focusing on forty-four DNA targets, which together cover about 1% of the human genome, or about thirty million base pairs. The target regions were strategically selected to provide a representative cross section of the entire human genome sequence. In the second phase other researchers will work to develop new technologies to apply to the ENCODE project. The results of the first two phases will determine how to begin the production phase and advance the ENCODE project to analyze the remaining 99% of the human genome.
Another NHGRI initiative is the creation of publicly available libraries of organic chemical compounds for scientists engaged in charting biological pathways. These chemical compounds have many promising applications in genomic research. For example, their ability to enter cells readily makes them natural vehicles for pharmaceutical drug development and drug delivery system design. An endeavor of this size and scope requires significant financial and human resources, and NHGRI is planning to use technologies such as robotic-enabled, high-output screening to create large libraries of 500,000 to 1,000,000 chemical compounds.
On June 4, 2004, the NIH announced the establishment of a Chemical Genomics Center based in the NHGRI Division of Intramural Research. It is an initiative that will establish a nationwide network to produce innovative chemical "tools" for use in biological research and drug development, and it will include a repository to acquire, maintain, and distribute a collection of up to one million chemical compounds. Like the HGP data, the chemical genomics network will be deposited in a central database, called PubChem, which will be freely available to the entire scientific community.
Finally, in April 2003 the United Kingdom's Wellcome Trust, along with Canadian funding organizations and the global pharmaceutical company GlaxoSmithKline, established a charitable organization, the Structural Genomics Consortium, to round out international efforts in structural genomics. Structural genomics is the systematic, high-volume generation of the three-dimensional structure of proteins. The goal of examining the structural genomics of any organism is the complete structural description of all proteins encoded by the genome of that organism. These descriptions are important for drug design, diagnosis, and treatment of disease. Like the HGP and Chemical Genomics Center, the Structural Genomics Consortium is placing all the protein structures in public databases where scientists throughout the world may access them.
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