California
Association
for
Medical Laboratory Technology
Distance Learning Program
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Human Genome
Project: Second in a Series Course
Number: DL-971 © California Association
for Medical Laboratory Technology. CAMLT is approved by the California Department
of Health Services 1895 Mowry Ave, Suite 112 Notification of Distance Learning Deadline This is a reminder that all the continuing education units required to renew your license must be earned no later than the expiration date printed on your license. If some of your units are made up of Distance Learning courses, please allow yourself enough time to retake the testin the event you do not pass on the first attempt. CAMLT urges you to earn your CE units early! |
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Human Genome Project: Second in a Series
Abstract:
This course provides a discussion and overview of the Human Genome Project.
From conception to completion, the project moved forward at a rate paced by
technological advances and the competitive drive of researchers around the world.
Much has been learned about the human genome as well as the genomes of other
organisms due to the Human Genome Project. Much work is left in deciphering
the data and putting it to useful applications. As stated by the U.S. Department
of Energy (DOE), “Available to researchers worldwide, the human genome
reference sequence provides a magnificent and unprecedented biological resource
that will serve throughout the century as a basis for research and discovery
and, ultimately, myriad practical applications”. Rapid progress in genome
science and a glimpse into its potential applications have spurred observers
to predict that biology will be the foremost science of the 21st century. Technology
and resources generated by the Human Genome Project and other genomics research
are already having a major impact on research across the life sciences as well
as human diagnostics.
Objectives:
At the end of this exercise, participants will be able to:
- 1. Define the
Human Genome Project and its promise for future research.
2. Discuss the changing goals of the project as it progressed.
3. List several information points gathered during the Human Genome Project.
4. Compare the genome size and estimated number of genes of humans and several other species.
5. Describe the value of the Internet to sharing and accessing genomic databases and tools that can be used to investigate genetic disorders, chromosomes, genome maps, genes, sequence data, genetic variants and molecular structures.
Introduction:
The Human Genome Project (HGP) refers to the international 13-year effort to
discover all the estimated 20,000-25,000 human genes and make them accessible
for further biological study. Another project goal was to determine the complete
sequence of the 3 billion DNA subunits (bases) in the human genome. As part
of the HGP, parallel studies were carried out on selected model organisms such
as the bacterium, Escherichia coli, and the mouse, Mus musculus, to help develop
the technology and interpret human gene function. The DOE Human Genome Program
and the National Institutes of Health (NIH) National Human Genome Research Institute
(NHGRI) together sponsored the U.S. Human Genome Project.
Conceived in 1986, the U.S. Human Genome Project formally began in 1990 and
ended in 2003. Interestingly, the project began as an initiative in the U.S.
Department of Energy. The project originally was planned to last 15 years, but
rapid technological advances accelerated the completion date to 2003. The DOE
and the NIH brought a proposal entitled, “Understanding Our Genetic Inheritance,
The U.S. Human Genome Project: The First Five Years (FY 1991-1995)” to
members of congress in February of 1990. The approval they sought needed the
funding of 200 million dollars per year for the next 15 years. The document
outlined the current state of genome science at that time, proposed joint roles
for DOE and NIH in administering research agendas, set the stage for international
collaboration and provided goals for the project.
The completion in the spring of 2003 of the human DNA sequence project proposed
by the DOE and NIH coincided with the 50th anniversary of Watson and Crick’s
description of the fundamental structure of DNA. Some 18 countries participated
in the worldwide effort producing an amazing database of genomic information
that continues to grow. The analytical power arising from the reference DNA
sequences of the entire human genome and other model organisms determined during
the Human Genome Project has created genomics resources that have jump-started
what some call the “biology century.”
A genome is the entire DNA in an organism, including its genes. Genes carry information for making all the proteins required by all organisms. These proteins determine, among other things, how the organism looks, how well its body metabolizes food or fights infection, and sometimes even how it behaves. DNA is made up of four similar chemicals, adenine, thymine, guanine and cytosine, called bases and abbreviated A, T, C, and G. These are repeated millions or billions of times throughout a genome. The human genome, for example, has 3 billion pairs of bases. The particular order of As, Ts, Cs, and Gs is extremely important. The order underlies all of life’s diversity, dictating whether an organism is human or another species such as yeast, rice, or fruit fly, all of which have their own genomes and are themselves the focus of genome projects. Because all organisms are related through similarities in DNA sequences, insights gained from nonhuman genomes often lead to new knowledge about human biology. Knowledge about the effects of DNA variations among individuals can lead to revolutionary new ways to diagnose, treat, and someday prevent the thousands of disorders that affect us. Besides providing clues to understanding human biology, learning about nonhuman organisms’ DNA sequences can lead to an understanding of their natural capabilities that can be applied toward solving challenges in health care, agriculture, energy production, environmental remediation, and carbon sequestration.
Goals of the Human Genome Project were set forth from the beginning to help guide the process. The initial proposal set forth the following five-year goals for the human genome project:
- Mapping and Sequencing the Human Genome
o Genetic Mapping – Complete a fully connected human genetic map with markers spaced an average of 2 to 5 cM (centimorgans, about 1 million base pairs) apart. Identify each marker by a sequence tagged site (STS).
o Physical Mapping – Assemble STS maps of all human chromosomes with the goal of having markers spaced at approximately 100,000-bp (base pair) intervals. Generate overlapping sets of cloned DNA or closely spaced unambiguously ordered markers with continuity over lengths of 2 Mb (Megabase = 1 million nucleotides, roughly equal to 1 centimorgan) for large parts of the human genome.
o DNA Sequencing – Improve current and develop new methods for DNA sequencing that will allow large-scale sequencing of DNA at a cost of $0.50 per base pair. Determine the sequence of an aggregate of 10 Mb of human DNA in large continuous stretches in the course of technology development and validation.
- Mapping and Sequencing the Genomes of Model Organisms
o Prepare a mouse genome genetic map based on DNA markers. Start physical mapping on one or two chromosomes.
o Sequence an aggregate of about 20 Mb of DNA from a variety of model organisms, focusing on stretches that are 1 Mb long, in the course of developing and validating new and improved DNA sequencing technology.
- Data Collection and Distribution
o Develop effective software and database designs to support large-scale mapping and sequencing projects.
o Create database tools that provide easy access to up-to-date physical mapping, genetic mapping, chromosome mapping, and sequencing information and allow ready comparison of the data in these several data sets.
o Develop algorithms and analytical tools that can be used in the interpretation of genomic information.
- Ethical, Legal, and Social Considerations
o Develop programs directed toward understanding the ethical, legal, and social implications of the Human Genome Project data. Identify and define the major issues and develop initial policy options to address them.
- Research Training
o Support research training of pre- and post-doctoral fellows starting in FY 1990. Increase the number of trainees supported until a steady state of about 600 per year is reached by the fifth year.
o Examine the need for other types of research training in the next year (FY 1991).
- Technology Development
o Support automated instrumentation and innovative and high-risk technological developments as well as improvements in current technology to meet the needs of the genome project as a whole.
- Technology Transfer
o Enhance the already close working relationships with industry.
o Encourage and facilitate the transfer of technologies and of medically important information to the medical community.
The third, and final, five-year plan with goals was developed during a series of DOE and NIH workshops attended by project personnel, researchers and interested parties.
Third five-year plan and goals:
- Human DNA Sequence
o Finish the complete human genome sequence by the end of 2003.
o Finish one-third of the human DNA sequence by the end of 2001.
o Achieve coverage of at least 90% of the genome in a working draft based on mapped clones by the end of 2001.
o Make the sequence totally and freely accessible
- Sequencing Technology
o Continue to increase the throughput and reduce the cost of current sequencing technology.
o Support research on novel technologies that can lead to significant improvements in sequencing technology.
o Develop effective methods for the advanced development and introduction of new sequencing technologies into the sequencing process.
- Human Genome Sequence Variation
o Develop technologies for rapid, large-scale identification and/or scoring of single nucleotide polymorphisms and other DNA sequence variants.
o Identify common variants in the coding regions of the majority of identified genes during this five-year period.
o Create a SNP map of at least 100,000 markers.
o Develop the intellectual foundations for studies of sequence variation.
o Create public resources of DNA samples and cell lines.
- Functional Genomics Technology
o Generate sets of full-length cDNA clones and sequences that represent human genes and model organisms.
o Support research on methods for studying functions of nonprotein-coding sequences.
o Develop technology for comprehensive analysis of gene expression.
o Improve methods for genome-wide mutagenesis.
o Develop technology for large-scale protein analyses.
- Comparative Genomics
o Complete the sequence of the roundworm Caenorhabitis elegans genome by 1998.
o Complete the sequence of the fruit fly Drosophila genome by 2002.
o Develop an integrated physical and genetic map for the mouse, generate additional mouse cDNA resources, and complete the sequence of the mouse genome by 2008.
o Identify other useful model organisms and support appropriate genomic studies.
- Ethical, Legal, and Social Issues (ELSI)
o Examine issues surrounding the completion of the human DNA sequence and the study of human genetic variation.
o Examine issues raised by the integration of genetic technologies and information into healthcare and public health activities.
o Examine issues raised by the integration of knowledge about genomics and gene-environment interactions in non-clinical settings.
o Explore how new genetic knowledge may interact with a variety of philosophical, theological, and ethical perspectives.
o Explore how racial, ethnic, and socioeconomic factors affect the use, understanding, and interpretation of genetic information; the use of genetic services; and the development of policy.
- Bioinformatics and Computational Biology
o Improve content and utility of databases.
o Develop better tools for data generation, capture, and annotation.
o Develop and improve tools and databases for comprehensive functional studies.
o Develop and improve tools for representing and analyzing sequence similarity and variation.
o Create mechanisms to support effective approaches for producing robust, exportable software that can be widely shared.
- Training and Manpower
o Nurture the training of scientists in genomics research.
o Encourage the establishment of academic career paths for genomic scientists.
o Increase the number of scholars who are knowledgeable in both genomic and genetic sciences and in ethics, law, or the social sciences.
Timeline: The timeline that follows comes from the U.S. Department of Energy’s
Department of Science. It is a sparse detailing of significant achievements
related to the Human Genome Project.
• 1990: W. French Anderson applies gene therapy for the first time. The
recipient is a young girl with ADA deficiency, an immune system disorder.
The Department of Energy and the National Institutes of Health formally launch
the Human Genome Project, a 15-year international effort to locate all of the
genes in the human genome and make them accessible for further biological study.
Another goal of the project is to determine and complete sequence of the genome’s
3 billion DNA nucleotide base pairs.
• 1992: Researchers at Lawrence Livermore National Laboratory and Lawrence Berkeley
National Laboratory in California discover a gene present in 25 to 30 percent
of the population that predisposes individuals to increased heart attack risk.
Discovery of this marker for heart disease on chromosome 19 may make possible
the development of a simple test to screen humans for susceptibility to heart
disease.
England’s Wellcome Trust joins the Human Genome Project.
• 1994: The Department of Energy launches its Microbial Genome Program.
• 1995: Craig Venter and colleagues at The Institute for Genomic Research in Maryland
decode the first whole genome of a free-living single-cell organism, the influenza
microbe, using the whole-genome shotgun sequencing method.
• 1996: Ian Wilmut and other researchers at Scotland’s
Roslin Institute clone a sheep from the cell of an adult ewe. This non-sexually
produced animal is named “Dolly.”
The complete genome of the E.
coli bacterium is sequenced.
• 1998: The first complete genome sequence of a multicellular
organism, the roundworm C. elegans, is published.
• 1999: The DOE Joint Genome Institute, a genome-sequencing center formed by Lawrence
Berkeley, Lawrence Livermore, and Los Alamos national laboratories, dedicates
its new production sequencing facility in Walnut Creek, California.
The complete genome of the Drosophila fruit fly is sequenced.
• 2000: Working drafts of the human genome are completed by the public International
Human Genome Project and by Craig Venter’s Celera Genomics, a private
company.
• 2001: The draft human genome sequence is published in the journals Nature and
Science. Twenty sequencing centers in six countries – China, France, Germany,
England, Japan, and the United States – contribute to the project. Most
of the sequencing is done by five major centers: the Wellcome Trust’s
Sanger Center in England, the DOE Joint Genome Institute in California, and
three NIH-funded centers at Baylor College of Medicine in Texas, Washington
University School of Medicine in Missouri, and the Whitehead Institute in Massachusetts.
• 2001-2002: As rapid, highly accurate sequencing techniques become readily available,
the complete genomes of a wide variety of microbes and model organisms, including
the mouse, pufferfish, malaria mosquito, and sea squirt, are sequenced and analyzed.
Genome comparisons yield significant new insights into the causes and progress
of disease, biological evolution, and the relationship between organisms and
the environment.
DOE launches its “Genomes to Life” program.
• 2003: The finished human genome is published concurrent with the 50th Anniversary
of the discovery of the double helix.
Results:
The Human Genome Project was marked by accelerated progress. In June 2000, the
rough draft of the human genome was completed a year ahead of schedule. In February
2001, Science and Nature published special issues containing the working draft
sequence of the human genome and analysis of that sequence. By 2003, two full
years ahead of time, the sequencing of the human genome was complete. The rapid
completion was due to the enormous commitment to developing technology and changing
strategies that resulted in revised goals and plans as the project moved forward.
However, the sequencing is more a beginning than a final step. Knowing the sequence
is analogous to having a dictionary and needing to make an extraordinary proclamation.
The information is there but complete concept and interpretation have yet to
be put forward.
A unique aspect of the U.S. Human Genome Project is that it was the first large
scientific undertaking to address potential ELSI implications arising from project
data. Another important feature of the project was the federal government’s
long-standing dedication to the transfer of technology to the private sector.
By licensing technologies to private companies and awarding grants for innovative
research, the project catalyzed the multibillion-dollar U.S. biotechnology industry
and fostered the development of new medical applications.
Sequence and analysis of the human genome working draft was published in February
2001 and April 2003 issues of Nature and Science. The first panoramic views
of the human genetic landscape have revealed a wealth of information and some
early surprises. Much remains to be deciphered in this vast trove of information;
as the consortium of HGP scientists concluded in their seminal paper, “…
the more we learn about the human genome, the more there is to explore.”
A few highlights from the first publications analyzing the sequence follow:
The table that follows compares humans with other organisms in regards to genome size and the estimated number of genes.
| Organism | Genome Size (Bases) | Estimated Genes |
|---|---|---|
| Human (Homo sapiens) | 3 billion | 30,000 |
| Laboratory mouse (M. musculus) | 2.6 billion | 30,000 |
| Mustard weed (A. thaliana) | 100 million | 25,000 |
| Roundworm (C. elegans) | 97 million | 19,000 |
| Fruit fly (D. melanogaster) | 137 million | 13,000 |
| Yeast (S. cerevisiae) | 12.1 million | 6,000 |
| Bacterium (E. coli) | 4.6 million | 3,200 |
| Human immunodeficiency virus (HIV) | 9700 | 9 |
The estimated number of human genes is only one-third as great as previously
thought; although the numbers may be revised as more computational and experimental
analyses are performed. Scientists suggest that the genetic key to human complexity
lies not in gene number but in how gene parts are used to build different
products in a process called alternative splicing. Other underlying reasons
for greater complexity are the thousands of chemical modification made to
proteins and the repertoire of regulatory mechanisms controlling these processes.
Some current and potential applications of genome research include:
• Molecular medicine
• Energy sources and environmental applications
• Risk assessment
• Bioarchaeology, anthropology, evolution, and human migration
• DNA forensics (identification)
• Agriculture, livestock breeding, and bioprocessing
In addition to the genomic research, the Department of Energy and the National
Institutes of Health Genome Programs set aside 3% to 5% of their respective
annual HGP budgets for the study of the project’s ethical, legal, and
social issues. Nearly $1 million was spent on HGP ELSI research during the
Human Genome Project.
A tabular summary of some of the sequencing milestones from the Human Genome
Project follows:
| Area | HGP Goal | Standard Achieved | Date Achieved |
|---|---|---|---|
| Genetic Map | 2- to 5-cM resolution map (600 – 1,500 markers) | 1-cM resolution map (3,000 markers) | September 1994 |
| Physical Map | 30,000 STSs | 52,000 STSs | October 1998 |
| DNA Sequence | 95% of gene-containing part of human sequence finished to 99.99% accuracy | 99% of gene-containing part of human sequence finished to 99.99% accuracy | April 2003 |
| Capacity and Cost of Finished Sequence | Sequence 500 Mb/year at < $0.25 per finished base | Sequence > 1,400 Mb/year at <$0.09 per finished base | November 2002 |
| Human Sequence Variation | 100,000 mapped human SNPs | 3.7 million mapped human SNPs | February 2003 |
| Gene Identification | Full-length human cDNAs | 15,000 full-length human cDNAs | March 2003 |
| Model Organisms | Complete genome sequences of E. coli, S. cerevisiae, C. elegans, D. melanogaster | Finished genome sequences of E. coli, S. cerevisiae, C. elegans, D. melanogaster, plus whole-genome drafts of several others, including C. briggsae, D. pseudoobscura, mouse and rat | April 2003 |
| Functional Analysis | Develop genomic-scale technologies | High-throughput oligonucleotide synthesis | 1994 |
| DNA microarrays | 1996 | ||
| Eukaryotic, whole-genome knockouts (yeast) | 1999 | ||
| Scale-up of two-hybrid system for protein-protein interaction | 2002 |
Conclusion:
The Human Genome Project is completed but the door has merely been nudged open to the scientific research and discovery that lies ahead as science puts the information to further test and application. Medical science will benefit greatly from this process. An excellent source of information for those not current in genetic aspects and applications of disease analysis is the Gene Gateway a DOE website: http://doegenomes.org/ click on Gene Gateway.
-
References:
- Jasny BR, Roberts L. Building on the DNA revolution, Introduction. Science. 11 Apr 2003; 300:277.
- Collins FS, Morgan, M, Patrinos A. The human genome project: lessons from large-scale biology. Science. 11 Apr 2003;300:286-290.
- Frazier ME, Johnson GM, Thomassen CE, Patrinos A. Realizing the potential of the genome revolution: The genomes to life program. Science. 11 Apr 2003;300:290-293.
- Collins FE, Green ED, Guttmacher AE, Guyer MS. A vision for the future of genomics research. A blueprint for the genomic era. Nature. 24 Apr 2003;422:835.
- Carroll SB. Genetics and the making of Homo sapiens. Nature. 24 Apr 2003;422:849.
- Arnold A, Hilton N. Genome sequencing: revelations from a bread mould. Nature. 24 Apr 2003;422;821.
- Information compiled from the U.S. Department of Energy
Review Questions - Course #DL-971 - Choose the one best answer
for each question
Link to On-line REGISTRATION, PAYMENT and QUIZ
- An organism’s genome is:
a. a protein data base
b. an NIH project
c. the entire DNA content of the organism
d. the result of replication
- The Human Genome Project was initially conceived in:
a. 1986
b. 1990
c. 1998
d. 2003
- Genes in the human genome appear to be arranged:
a. at regular intervals along the chromosome
b. at random intervals along the chromosome
c. at the centromere of the chromosome
d. at every third juncture of the chromosome
- The human genome contains 3 billion bases. What portion of the bases code
for proteins?
a. less than 50%
b. 60%
c. 70%
d. more than 80%
- Which of the following organisms has the fewest genes?
a. mustard seed
b. yeast
c. mouse
d. fruit fly
- A goal of the original five-year plan was:
a. to minimize industry involvement in the project
b. to decrease the throughput of sequencing technology
c. to sidestep congressional involvement
d. to engage industry participation in the project
- STS is an abbreviation for
a. start the sequencer
b. standard test sequestering
c. sequence tagged site
d. separate technology steps
- Gene therapy had its first trial in a patient with
a. cardiovascular disease
b. type II diabetes
c. ADA deficiency
d. breast cancer
- The first organism sequenced was:
a. E. coli
b. C. elegans
c. Influenza
d. S. cerevisiae
- Human genetic complexity is dependent on:
a. nucleotide bases found only in humans
b. gene numbers
c. chemical modifications made to proteins
d. sequencing analysis