V

Skip to Main content



Human Genome Project

Related terms:

Bioinformatics

Genome Research

High Throughput

View all Topics

Human Genome Project: German Perspective

J. Maurer, H. Lehrach, in International Encyclopedia of the Social & Behavioral Sciences, 2001

1 The Human Genome Project

The Human Genome Project differs from any previous biological or medical project in size and cost. Its ambitious goal is the deciphering (sequencing) of all 3 billion building blocks of our genetic make-up—the so-called DNA—by 2005, the identification of all genes encoded in that DNA, and the understanding of the role of these genes in health and disease. The knowledge of these genes and their function is crucial for basic biological research as well as for the improvement of prevention, diagnostics, and therapy of disease. It is the prerequisite for a targeted design of pharmaceuticals and for novel approaches like gene therapy. This knowledge poses hope to millions of affected people and contains also an immense economic potential.

The Human Genome Project was started in the USA in 1990, James Watson, the codiscoverer of the DNA structure being its first co-ordinator. It was clear from the beginning, due to the estimated cost of US $ 3 billion and the immense amount of work involved, that the Human Genome Project had to include many countries. The Human Genome Organization (HUGO), an independent international organization of genome scientists, was established to co-ordinate the duties. The US Human Genome Project started off with considerable public funding (US $ 87 million in 1990) and was soon followed by the UK and France. Between 1991 and 1996 France contributed a comprehensive genetic map of the human genome. It is noteworthy that this work was predominantly financed by private money from a patients' association. The British Wellcome Trust for its part set up the world's largest sequencing facility, the Sanger Centre. Smaller initiatives later emerged, for instance in Japan and Canada. No such activity, however, was seen in Germany until 1995. By 2001 a nearly complete 'working draft' of the human genome has been presented by the publicly funded Human Genome Project, including a significant German contribution. The complete sequence will be available in public databases some time ahead of schedule, probably by 2003. In 1998 an emerging competition to the Human Genome Project by private companies, namely by Craig Venter's Celera, had speeded up the deciphering of the human genetic code tremendously. But the knowledge of our comprehensive genetic make-up is not considered as a benefit for mankind by everybody. Profound ethical issues are raised by the possibilities inherent in this knowledge. This had been realized by the founders of the project and therefore, about 3 percent of the budget was dedicated to exploring the ethical, legal, and social implications of the Human Genome Project. In most countries participating in the Human Genome Project, an extensive discussion took place about the opportunities and risks attached to these novel technologies. In Germany a parliamentary committee was established to elucidate the topic. But the discussion was much more polarized in Germany than in other countries.

View chapterPurchase book

Human Genome Project: Japanese Perspective

T. Gojobori, in International Encyclopedia of the Social & Behavioral Sciences, 2001

The Japanese human genome project began in 1988 as a response to the progress in the corresponding activities in the United States and Europe. At the outset the human genome project in Japan was confronted by criticism from various sources. There was a strong belief amongst certain group that this kind of project was not true research but rather mere routine work. Moreover, difficulties were experienced in relation to the scarcity of technicians skillful in this area who could support the genome researchers and also in the reluctance of government and private institutions to invest large grants in a single project. Japan overcame these difficulties by redefining the human genome project in the following way. In Japan, the aim of the human genome project was redirected not only to sequence the genome but also to include functional analysis of genes and elucidation of tertiary protein structures. Although this redefinition of the human genome project has successfully eased various criticisms, the main focus of the project has been diffused to a considerable extent, leading to an ambiguity of the Japanese contribution to the international effort of human genome sequencing. A successful outlook for the Japanese human genome project will be in placing more emphasis on the promotion of functional genomics, comparative genomics, analysis of genomic diversity, and the development of DNA chips or microarrays.

View chapterPurchase book

Measurement

Jules J. Berman Ph.D., M.D., in Principles of Big Data, 2013

Gene Counting

The Human Genome Project is a massive bioinformatics project in which multiple laboratories helped to sequence the 3 billion base pair haploid human genome (see Glossary item, Human Genome Project). The project began its work in 1990, a draft human genome was prepared in 2000, and a completed genome was finished in 2003, marking the start of the so-called postgenomics era. There are about 2 million species of proteins synthesized by human cells. If every protein had its own private gene containing its specific genetic code, then there would be about 2 million protein-coding genes contained in the human genome. As it turns out, this estimate is completely erroneous. Analysis of the human genome indicates that there are somewhere between 20,000 and 150,000 protein-coding genes. The majority of estimates come in at the low end (about 25,000 genes). Why are the current estimates so much lower than the number of proteins and why is there such a large variation in the lower and upper estimates (20,000 to 150,000)?

Counting is difficult when you do not fully understand the object that you are counting. The reason that you are counting objects is to learn more about the object, but you cannot always count an object accurately until you have already learned a great deal about the object. Perceived this way, counting is a bootstrapping problem. In the case of proteins, a small number of genes can account for a much larger number of protein species, because proteins can be assembled from combinations of genes, and the final form of a unique protein can be modified by so-called post-translational events (folding variations, chemical modifications, sequence shortening, clustering by fragments, etc.). The methods used to count protein-coding genes can vary.80 One technique might look for sequences that mark the beginning and the end of a coding sequence, whereas another method might look for segments containing base triplets that correspond to amino acid codons. The former method might count genes that code for cellular components other than proteins, and the latter might miss fragments whose triplet sequences do not match known protein sequences.81 Improved counting methods are being developed to replace the older methods, but a final number evades our grasp.

The take-home lesson is that the most sophisticated and successful Big Data projects can be stumped by the simple act of counting.

View chapterPurchase book

Alcoholism: Genetic Aspects

K.E. Browman, J.C. Crabbe, in International Encyclopedia of the Social & Behavioral Sciences, 2001

2.2 Quantitative Trait Loci (QTL) mapping strategies

The Human Genome Project has also led to genome mapping and DNA sequencing in a variety of other organisms including the laboratory mouse. Late twentieth-century developments in the physical mapping of the mouse make positional cloning of genes involved in various behaviors more likely. However, most behaviors (including responses to alcohol) are influenced by multiple genes. Behaviors, or complex traits, influenced by a number of genes are often termed quantitative traits. Within a population, a quantitative trait is not all-or-none, but differs in the degree to which individuals possess it. A section of DNA thought to harbor a gene that contributes to a quantitative trait is termed a quantitative trait locus (QTL). QTL mapping identifies the regions of the genome that contain genes affecting the quantitative trait, such as an alcohol response. Once a QTL has been located, the gene can eventually be isolated and its function studied in more detail. Thus, QTL analysis provides a means of locating and measuring the effects of a single gene on alcohol sensitivity.

In tests of sensitivity to convulsions following alcohol withdrawal, QTLs have been found on mouse chromosomes 1, 2, and 11. The QTL on chromosome 11 is near a cluster of GABAA receptor subunit genes. A number of subunits are needed to make a GABAA receptor, and the ability of a drug to act on the receptor seems to be subunit dependent. A polymorphism in the protein-coding sequence for Gabrg2 (coding for the γ2 subunit of the GABAA receptor) has been identified. This polymorphism is genetically correlated with duration of loss of righting reflex and a measure of motor incoordination following alcohol administration.

The use of QTL analysis has allowed us to begin the process of identifying the specific genes involved in alcohol related traits. Because each QTL initially includes dozens of genes, not all of which have yet been identified, it will require much more work before each QTL can be reduced to a single responsible gene. For the time being, one important aspect of QTL mapping in mice is that identification of a QTL in mice points directly to a specific location on a human chromosome in about 80 percent of cases. Thus, the animal mapping work can be directly linked to the human work in studies such as the COGA described in Sect. 1.1, which is in essence a human QTL mapping project. By using transgenic animal models (mice in which there has been a deliberate modification of the genome), such as null mutants, QTLs can be further investigated.

View chapterPurchase book

Nucleic Acid Synthesis

Sankar Mitra, ... Tadahide Izumi, in Encyclopedia of Physical Science and Technology (Third Edition), 2003

I.F DNA Sequence and Chromosome Organization

The massive human genome project should achieve its goal of determining the complete sequence of human and mouse genomes in the near future; a "rough draft" has already been obtained. Furthermore, this genome initiative, pursued by both government and private enterprises in the United States and other countries, has already culminated in elucidating the complete sequence of E. coli and other bacteria, as well as yeast, a nematode, and the fruitfly Drosophila melanogaste. Significant progress has been made in elucidating the nucleotide sequences of both human and mouse genomes by using a two-pronged approach. On one hand, the sequences of transcribed regions of the genomes are being deduced from sequences of randomly isolated mRNA segments reverse transcribed into DNAs. At the same time, complete DNA sequences of fragments of whole chromosomes are being directly determined. This has opened up a huge scientific challenge of deciphering the genetic information, identifying unknown genes and their encoded proteins, and the variability of gene sequences with corresponding changes in the protein sequences in individuals. Functional genomics is a newly created discipline which deals with the deterministic prediction of protein functions from the primary sequences. One extension of such analysis is to ascertain the consequences of allelic polymorphisms in the human genome, i.e., minor changes in the sequences of cellular proteins which do not cause an explicit pathological phenotype and yet may affect survival and predisposition to specific diseases in the long term.

View chapterPurchase book

Y-chromosomes and Evolution

A. Ruiz-Linares, in International Encyclopedia of the Social & Behavioral Sciences, 2001

6 Conclusion

Developments resulting from the Human Genome Project have recently catapulted the use of Y-chromosome markers into the forefront of the study of human population origins and diversification. The large number of markers currently available together with novel highly efficient technologies enable analyses of an unprecedented resolution and scale. Evolutionary analyses are facilitated by the fact that slowly evolving markers allow the unambiguous assessment of the evolutionary relationship between Y-chromosomes. Rapidly evolving markers can refine analyses within specific lineages or populations. These studies illuminate not only questions related to the origin of our species and its early diversification but also allow the probing of more recent demographic events. The synthesis of genetic data with information obtained from sources including geology, paleoanthropology, archaeology, and historical demography is allowing a refined reconstruction of human evolution stretching from our origins as a species all the way to the exploration of quite recent historical events.

View chapterPurchase book

Cytomics: From Cell States to Predictive Medicine

G. Valet, ... A. Kriete, in Computational Systems Biology, 2006

A Single-cell image analysis

One of the most important outcomes of the Human Genome Project is the realization that there is considerably more biocomplexity in the genome and the proteome than previously appreciated (Herbert 2004). Not only are there many splice variants of each gene system, but some proteins can function in entirely different ways (in different cells and in different locations of the same cell), lending additional importance to the single-cell analysis of laser scanning cytometry and confocal microscopy. These differences would be lost in the mass spectroscopy of heterogeneous cell populations. Hence, cytomics approaches may be critical to the understanding of cellular and tissue functions.

Fluorescence microscopy represents a powerful technology for stoichiometric single-cell-based analysis in smears or tissue sections. Whereas in the past the major goal of microscopy and imaging was to produce high-quality images of cells, in recent years an increasing demand for quantitative and reproducible microscopic analysis has arisen. This demand came largely from the drug discovery companies, but also from clinical laboratories. Slide-based cytometry is an appropriate approach for fulfilling this demand (Tarnok and Gerstner 2002). Laser scanning cytometry (Gerstner et al. 2002; Tarnok and Gerstner 2002; Megason et al. 2003) was the first of this type of instrument to become commercially available, but today several different instruments are on the market (Jager et al. 2003; Molnar et al. 2003; Schilb et al. 2004).

These types of instruments are built around scanning fluorescence microscopes that are equipped with either a laser (Tarnok and Gerstner 2002; Schilb et al. 2004) or a mercury arc lamp as the light source (Bajaj et al. 2000; Molnar et al. 2003). The generated images are processed by appropriate software algorithms to produce data similar to flow cytometry. Slide-based cytometry systems are intended to be high-throughput instruments, although at present they have a lower throughput than flow cytometers. These instruments allow multicolor measurements of high complexity (Gerstner et al. 2002; Ecker and Steiner 2004) comparable to or exceeding that of flow cytometers.

A substantial advantage over flow cytometry is that cells in adherent cell cultures and tissues can be analyzed without prior disintegration (Smolle et al. 2002; Kriete et al. 2003; Ecker et al. 2004; Gerstner et al. 2004). In addition, due to the fixed position of the cells on the slide or in the culture chamber cells can be relocated several times and reanalyzed. Even restaining and subsequent reanalysis of each individual cell is feasible. Because a high information density on the morphological and molecular pattern of single cells can be acquired by slide-based cytometry, it is an ideal technology for cytomics.

Although at present not realized, the information density per cell can be increased further by implementing technologies such as spectral imaging (Ecker et al. 2004), confocal cytometry (Pawley 1995), fluorescence resonance energy transfer (FRET) (Jares-Erijman and Jovin 2003; Ecker et al. 2004; Peter and Ameer-Beg 2004), near-infrared Raman spectroscopy (Crow et al. 2004), fluorescence lifetime imaging (FLIM) (Murata et al. 2000; Peter and Ameer-Beg 2004), optical coherence tomography (Boppart et al. 1998), spectroscopic optical coherence tomography (Xu et al. 2004), and second harmonic imaging (Campagnola et al. 2003). All of these technologies mark the progress in optical bio-imaging.

In the future, developments in imaging resulting from a family of concepts that allows image acquisition far beyond the resolution limit (down to the nm range) are expected. These include multiphoton excitation (Manconi et al. 2003), ultrasensitive fluorescence microscopes (Hesse et al. 2004), stimulated emission depletion (STED) microscopy (Hell 2003), spectral distance microscopy (Esa et al. 2000), atomic force microscopy (AFM) and scanning near-field optical microscopy (SNOM) (Rieti et al. 2004), and image restoration techniques (Holmes and Liu 1992). Using laser ablation in combination with imaging, even thick tissue specimens can be analyzed on a cell-by-cell basis (Tsai et al. 2003).

View chapterPurchase book

Applications of Coordination Chemistry

M.T. Reetz, in Comprehensive Coordination Chemistry II, 2003

9.11.2.6. Annulation Reactions

Capillary array electrophoresis (CAE), used in the Human Genome Project,51,52 can be adapted to handle typical organic compounds in nonaqueous media in an automated and high-throughput manner, rapid separation of achiral or chiral (see Section 9.11.3) products being possible. In an illustrative investigation a previously discovered palladium-catalyzed annulation reaction of the indole derivative (19) yielding two isomeric products (20) and (21) (Equation (6)



Sign in to download full-size image

(6).

), was optimized in a combinatorial manner.53 Previous experience had shown that a number of parameters can affect the yield and product distribution, the optimum conditions being a matter of trial and error. In order to speed up discovery, various known palladium precursors, ligands, and bases were combined in parallel experiments, the yield and product ratio (20):(21) being detected by CAE. Although only 88 combinations were tested, several hits were identified. For example, the combination PdBr2/2PPh3/K2CO3 proved to be superior to the best reaction conditions originally reported in a traditional study, resulting in 96% conversion (but poor isomer selectivity). Other conditions led to some degree of isomer selectivity, but in this case conversion was poor.

Nevertheless, this study shows that CAE is a reliable detection system for rapid screening. It also suggests that larger libraries need to be prepared and screened.

View chapterPurchase book

Ethical Dilemmas: Research and Treatment Priorities

M. Betzler, in International Encyclopedia of the Social & Behavioral Sciences, 2001

2.2 Ethical Dilemmas in Biotechnology

The far-reaching potential advances in gene therapy and genetic engineering for humans (The Human Genome Project), and the implications for humans of cloning, have given rise to ethical dilemmas scientists have to face. The following examples can illustrate how progress in genetic engineering generates dilemmas between conflicting obligations and/or conflicts due to risk assessment (Chadwick 1992).

The identification of human genes, for example, can lead to the following conflict: on the one hand genetic knowledge enhances therapies for hereditary disease, on the other hand, it poses problems about the potentially exploitative use of resources and genetic information. The attempt to sequence the entire human genome raises ethical questions whether the risks of exploitation outweigh the benefits of knowledge.

Genetic alterations passed on to future generations through so-called germline therapy raise further problems regarding consent while, at the same time, 'improving' human genetic potential for future generations. Do we have an obligation to present generations to relieve suffering by seeking treatments for genetic disease or do future generations have a right to an unmodified genetic inheritance? Equally, the advantages of genetic screening can be outweighed by the costs of stigmatization on the basis of a person's genetic make-up. Such individuals might find themselves unemployable or uninsurable. There also arises the question whether the very existence of genetic screening can exert pressure on individuals with regard to their reproductive decisions, thus impairing their autonomy. How can genetic public health be fostered without practicing eugenics? Arguments about the moral urgency of relieving suffering also conflict with arguments about human dignity that discredit the production of 'designer babies' (Annas and Elias 1992).

The incorporation of foreign genes into the genome of an organism is commonly discussed in connection with animals and plants. One dilemmatic issue concerns the interests of the host organism (particularly in the case of animals), the consequences for human health and for other species, and the risks of releasing genetically engineered organisms into the environment.

A related issue has been the matter of justification of treatment. Animal experimentation poses the question whether animals have moral status to the detriment of life-enhancing research results for humans. As subjects of genetic engineering, for example, farm animals have suffered from unintended deleterious effects, while research animals have suffered the consequences of being intentionally bred for propensity to develop debilitating diseases. A further important issue is related to the question whether an agent who had moral status can cease to have that status. The human cases of the brain dead, anencephalic infants, and those in a permanently vegetative state are cases in point. If so, then the case of xenotransplantation or the transplanting of animal organs into humans is affected. The interlocking questions of moral standing, justification of treatment, and loss of moral considerability can thus cause conflicts as to which consideration should be given more weight. Ethical dilemmas in research are thus a challenge to those within and those outside research, to debate whether research practices and their effects are right and just. For further treatment see Animal Rights in Research and Research Application; Bioethics: Examples from the Life Sciences; Euthanasia; Genetic Counseling: Historical, Ethical, and Practical Aspects; Reproductive Medicine: Ethical Aspects; Research Subjects, Informed and Implied Consent of.

View chapterPurchase book

Introduction to Human Genome Computing Via the World Wide Web

Lincoln D. Stein, in Guide to Human Genome Computing (Second Edition), 1998

3.5 GDB

GDB, the Genome Database, is the main repository for all published mapping information generated by the Human Genome Project. It is a species-specific database: only Homo sapiens maps are represented. Among the information stored in GDB is:

▪

genetic maps

▪

physical maps (clone, STS and fluorescent in situ hybridization (FISH) based)

▪

cytogenetic maps

▪

physical mapping reagents (clones, STSs)

▪

polymorphism information

▪

citations

To access GDB, connect to its home page (Figure 1.15). GDB offers several different ways to search the maps:



Sign in to download full-size image

Figure 1.15. The GDB home page provides access to the main repository for human genome mapping information.

▪

A simple search. This search, accessible from GDB's home page, allows you to perform an unstructured search of the database by keyword or the ID of the record. For example, a keyword search for 'insulin' retrieves a list of clones and STSs that have something to do either with the insulin gene or with diabetes mellitus.

▪

Structured searches. A variety of structured searches available via the link labeled 'Other Search Options' allow you to search the database in a more deliberate manner. You may search for maps containing a particular region of interest (defined cytogenetically, by chromosome, or by proximity to a known marker) or for individual map markers based on a particular attribute (e.g. map position and marker type). GDB also offers a 'Find a gene' interface that searches through the various aliases to find the gene that you are searching for.

Searches that recover individual map markers and clones will display them in a list of hypertext links similar to those displayed by Entrez and PDB. When you select an entry you will be shown a page similar to Figure 1.16. Links on the page lead to citation information, information on maps this reagent has been assigned to, and cross-references to the GenBank sequence for the marker or clone. GDB holds no primary sequence information, but the Web's ability to interconnect databases makes this almost unnoticeable.



Sign in to download full-size image

Figure 1.16. GDB displays most entries using a text format like that shown here.

A more interesting interface appears when a search recovers a map. In this case, GDB launches a Java applet to display it. If multiple maps are retrieved by the search, the maps are aligned and displayed side by side (Figure 1.17). A variety of settings allows you to adjust the appearance of the map, as well as to turn certain maps on and off. Double clicking on any map element will display its GDB entry in a separate window.



Sign in to download full-size image

Figure 1.17. GDB maps are displayed using an interactive Java applet.

View chapterPurchase book

Recommended publications:

Current Opinion in Systems Biology

Journal

Computational Biology and Chemistry

Journal

Journal of Biomedical Informatics

Journal

Journal of Discrete Algorithms

Journal