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THE HUMAN GENOME PROJECT:
Its History, Status, and Ongoing Research
Prior columns have examined the Human Genome Project from various angles. Links to those columns are provided at the end of this column.
This month our focus is upon these aspects:
- What prompted the creation of the project?
- What were its goals?
- How was it funded?
- Who was involved?
- What does the HGP mean to us as family researchers?
This project may well be the most important scientific
undertaking in human history. Not only has it sought to unravel the
mystery of life itself, with research into the genetic makeup of
insects, plants, and animals (human and non-human), but has also shown
the efficacy of cooperative international effort directed toward a
common goal. All the findings of each scientific laboratory or group has
been added to the publicly available database so that each advance by
any one scientist or group can immediately aid the efforts of all.
The HGP encompassed many areas of research, the
identification and mapping of the human genetic structure (based on gene
mapping and DNA sequencing of the 23 chromosomes common to all humans);
methods to be used in naming sequences as well as methods and processes
best employed to speed up and ensure quality and accuracy of the data
obtained; means of translating "by hand" processing to computerized
processing; studies addressing the ethical, legal and societal issues
arising; advances in treatment and potential cures of diseases shown to
have genetic causes (such as chromosomal abnormalities), often related
to various types of cancer; improvements in crops to ensure a growing
world population will continue to be adequately nourished even as
climate changes impact farming and livestock husbandry; as well as
numerous additional areas of new or related uses such as DNA testing has
provided. The future seems to show no boundaries for the utilization of
the scientific findings evolving from this project.
It is interesting to note the original proposals for a
comprehensive mapping of the human genome were opposed by a number of
scientists. The opposition to such a study appears to have been based on
the fear such a monumental and overarching scientific effort would
drain the coffers by its sheer expense and redirect funding for smaller
but interrelated studies. Arguments opposing were varied, one prominent
grant recipient expounding on his view the actual work of identifying
chromosomal sequences would be "so boring no competent researcher would agree to do the work." Obviously that argument has been shown to have no merit.
WHAT PROMPTED THE CREATION OF THE PROJECT?
Three separate proposals arose almost simultaneously in 1985:
"May 1985, Robert Sinsheimer organized a workshop at the University of California, Santa Cruz, to discuss the feasibility of building a gene sequencing capability. In March, the Santa Fe Workshop was organized by Charles DeLisi and David Smith of the Department of Energy's Office of Health and Environmental Research (OHER). At the same time Renato Dulbecco, President of the Salk Institute for Biological Studies, proposed whole genome sequencing in an essay in Science. The published work titled, "A Turning Point in Cancer Research: Sequencing the Human Genome" was shortened from the original proposal using the sequence to understand breast cancer genes. James Watson followed two months later with a workshop held at the Cold Spring Harbor Laboratory. Thus the idea for obtaining a reference sequence had three independent origins: Sinsheimer, Dulbecco and DeLisi. Ultimately it was the actions by DeLisi that launched the project." (Source: Wikipedia)
As noted in Wikipedia, it was DeLisi's standing with a federally
funded agency (the DOE) and his excellent relationship with Senator Pete
Domenici of New Mexico that proved to be key in obtaining Congressional
approval for the HGP's funding:
"Of particular importance in congressional approval was the advocacy of New Mexico Senator Pete Domenici, whom DeLisi had befriended. Domenici chaired the Senate Committee on Energy and Natural Resources, as well as the Budget Committee, both of which were key in the DOE budget process. Congress added a comparable amount to the NIH budget, thereby beginning official funding by both agencies."
WHAT WERE THE PROJECT'S GOALS
(Source: Wikipedia)
The Human Genome Project (HGP) was an international scientific research project with the goal of determining the base pairs that make up human DNA, and of identifying, mapping and sequencing all of the genes of the human genome from both a physical and a functional standpoint. It remains the world's largest collaborative biological project. Planning started after the idea was picked up in 1984 by the US government, the project formally launched in 1990, and was declared complete on April 14, 2003. Level "complete genome" was achieved in May 2021. Y chromosome was not part of v1.1 and was added in January 2022 in v2.0.The Human Genome Project originally aimed to map the nucleotides contained in a human haploid reference genome (more than three billion). The "genome" of any given individual is unique; mapping the "human genome" involved sequencing a small number of individuals and then assembling to get a complete sequence for each chromosome. Therefore, the finished human genome is a mosaic, not representing any one individual. The utility of the project comes from the fact that the vast majority of the human genome is the same in all humans.
The genome published by the HGP does not represent the sequence of every individual's genome. It is the combined mosaic of a small number of anonymous donors, of African, European and east Asian ancestry. The HGP genome is a scaffold for future work in identifying differences among individuals. Subsequent projects sequenced the genomes of multiple distinct ethnic groups, though as of 2019 there is still only one "reference genome."
HOW WAS IT FUNDED?
The Human Genome Project: A Bit of History
Although most references to The Human Genome Project will
indicate funding and authorization for this massive undertaking occurred
in the 1980 to 1990 timeframe, it is interesting to note that nothing
may have come of the project without the Cold War and the international
competition to develop nuclear weapons focused on both attack primacy
and deterrent capability. Initial funding of a program to further
scientific study of "fissionable and radioactive" materials established
the base monies:
(Source for following initial bulleted timeline events: https://web.ornl.gov/sci/techresources/Human_Genome/project/timeline.shtml )
1946 Genome Project–Enabling Legislation
Atomic Energy Act of 1946 (P.L. 79-585) provided the initial charter for a comprehensive program of research and development related to the utilization of fissionable and radioactive materials for medical, biological, and health purposes. [1946]
This initial funding legislation was augmented by legislation to
create an agency tasked with research into the "biologic effects" of
atomic or nuclear warfare. This agency was established as fear grew of
atomic bombs and radioactive elements unleashed thereby. What would
happen if America became the target and American citizens were exposed?
What might the effects be on humans? Our animals? Our crops? Could we
survive?
1954 Genome Project–Enabling Legislation
Atomic Energy Act of 1954 (P.L. 83-706) authorized the Atomic Energy Commission (AEC, predecessor agency to ERDA and DOE) "to conduct research on the biologic effects of ionizing radiation." [1954]
Twenty years later additional funding was authorized to expand
the research and development into related practical, procedural, and
societal applications directed toward expansion of nuclear power as an
energy source, among other goals:
1974 Genome Project–Enabling Legislation
Federal Non-Nuclear Energy Research and Development Act of 1974 (P.L. 93-577) authorized the Energy Research and Development Agency (ERDA, predecessor agency to DOE) to conduct a comprehensive non-nuclear energy research, development, and demonstration program to include the environmental and social consequences of the various related technologies. [1974])
Federal Energy Reorganization Act of 1974 (P.L. 93-438) provided that responsibilities of the Energy Research and Development Administration (ERDA, predecessor agency to DOE) shall include "engaging in and supporting environmental, biomedical, physical, and safety research related to the development of energy resources and utilization technologies." (1974)
Three years later, Congress authorized ERDA to become the Department of Energy (DOE) with a three-fold mandate:
1977 Genome Project–Enabling Legislation
DOE Organization Act of 1977 (P.L. 95-91) mandated the Department of Energy to "assure incorporation of national environmental protection goals in the formulation and implementation of energy programs"; "advance the goal of restoring, protecting, and enhancing environmental quality and assuring public health and safety"; and to conduct "a comprehensive program of research and development on the environmental effects of energy technology and program." [1977]
Baby steps began under the direction of scientists employed by the DOE at two primary labs:
- LANL - Los Alamos National Laboratory, a Department of Energy Laboratory
LANL and LLNL began production of DNA clone (cosmid) libraries representing single chromosomes. [1983]
Interest in the HGP gained momentum as more and more scientific
researchers not only saw the astounding possibilities in "cracking the
code" of creation, but also began seeing what they might contribute to
the effort. Various memoranda, workshops, and scientific publications
circulated, generating more and more interest in the project and
inspiring excitement in the biochemistry and related fields. The initial
DNA clone libraries produced by the DOE Labs were being accessed and
utilized as more and more scientific and technological disciplines lent
thought to what would be required in order to pull off this incredible
task.
By 1988, sufficient interest had been generated and
Congressional and scientific support garnered for launching the Project
that President Ronald Reagan included in his official Budget the seed
funding to implement what was initially planned as a fifteen year
undertaking to accomplish the stated goals. The Human Genome Project was
officially a "GO."
(The official government site breaks down the annual budget
for the Human Genome Project at the link provided below. Their narrative
is referenced hereafter.)
Funding: SOURCE: http://www.ornl.gov/hgmis
The Human Genome Project was sometimes reported to have cost $3 billion. However, this figure refers to the total projected funding over a 13-year period (1990–2003) 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. Human genome sequencing represents only a small fraction of the overall 13-year budget.The DOE and NIH genome programs set aside 3% to 5% of their respective total annual budgets for the study of the project's ELSI issues. For an in-depth look at the ELSI surrounding the project, see the ELSI Webpage.
See also a Table of major government and nonprofit genomics research funders, 1998-2000: http://www.stanford.edu/class/siw198q/websites/genomics/entry.htm -- compiled as part of the World Survey of Genomics Research . (http://www.stanford.edu/class/siw198q/websites/genomics/ ) of the Stanford-in-Washington Program.
What Were Its Goals:
The initial goals were:
- Identify all the approximately 20,000-25,000 genes in human DNA.
- Determine the sequences of the 3 billion chemical base pairs that make up human DNA.
- Store this information in databases;
- Improve tools for data analysis;
- Transfer related technologies to other sectors, such as industries;
- Address the ethical, legal, and social issues (ELSI) that may arise from the project.
It should also be noted the unofficial disclaimer could be
paraphrased as to "not permit a goal of perfection to deter progress"
and thereby interfere with reasonable completion of the tasks
undertaken.
The original project was scheduled to achieve the stated
goals within a fifteen year period. Following the initial disclaimer's
caution, it was determined all possible progress toward full project
completion had been achieved within thirteen years of official launch in
1990. Technology had to advance considerably for researchers to achieve
100% sequencing of the human genome. In the thirteen year span, a
phenomenal 92%+ of the human genome had been mapped, vetted, and the
Human Genome Project was proclaimed "complete in 2003.
HGP researchers deciphered the human genome in three major ways: determining the order, or "sequence," of all the bases in our genome's DNA; making maps that show the locations of genes for major sections of all our chromosomes; and producing what are called linkage maps, through which inherited traits (such as those for genetic disease) can be tracked over generations.
(SOURCE: https://www.genome.gov/human-genome-project/What)
A partial list of the possible areas currently utilizing findings
of the HGP and some potential future applications as listed by the
official government site
(https://web.ornl.gov/sci/techresources/Human_Genome/project/benefits.shtml ) are:
- Molecular medicine
- Energy sources and environmental applications
- Risk assessment
- Bioarchaeology, anthropology, evolution, and human migration
- DNA forensics (identification)
- Agriculture, livestock breeding, and bioprocessing
The website expands upon each listed area to delineate related applications.
http://www.ornl.gov/hgmis the official public website offering free access to all the Human Genome Project information, databases, and charts etc.
Who was involved?
The international project was funded and staffed by the
cooperative effort of six countries initially. The United States, the
United Kingdom, Japan, France, Germany, and China. Overall direction of
the HGP in America was placed in the capable hands of James Watson, who
along with Crick was deemed to have discovered the helical structure of
DNA. Watson was later replaced by Francis Collins. The second largest
bulk of funding and responsibility was shouldered by the United Kingdom,
headed by John Sulston director of the Wellcome Trust Sanger Institute.
The European Bioinformatics Institute in Cambridge, UK, and
the National Centre for Biotechnology Information at the US National
Institutes of Health also played a key role in providing computational
support and analysis for the Human Genome Project. Scientists at the
University of California, Santa Cruz, and Neomorphic, Inc. also assisted
the assembly of the genome sequence across chromosomes.
Twenty laboratories within the six countries were assigned
specific duties related to sequencing the 23 pairs of chromosomes so as
to even out the workload. Ultimately, five laboratories ended up
performing the bulk of the sequencing and became known as the G5.
Fully one-third of the sequencing was completed by scientists at
Wellcome ("sequenced one-third of the human genome, focusing on
chromosomes 1, 6, 9, 10, 11, 13, 20, 22 and X" although some were shared
with other centres).
The G5:
·
- Broad Institute/Whitehead Institute for Biomedical Research (MIT) in Cambridge, USA
·
- Washington University in St. Louis, USA
·
- Baylor College of Medicine in Houston, USA
·
- Department of Energy's Joint Genome Institute in Walnut Creek, USA
·
- Wellcome Trust Sanger Institute (previously known as the Sanger Centre) in Cambridge, UK
Within each country the work was carried on by various laboratories, each with their own primary researchers, as listed below:
Members of the International Human Genome Sequencing Consortium
1. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK
2. Broad Institute/Whitehead Institute/MIT Center for Genome Research, Cambridge, Massachusetts, USA
3. Washington University School of Medicine Genome Sequencing Center, St. Louis, Missouri, USA
4. Joint Genome Institute, US Department of Energy, Walnut Creek, California, USA
5. Baylor College of Medicine Human Genome Sequencing Center, Department of Molecular and Human Genetics, Houston, Texas, USA
6. RIKEN Genomic Sciences Center, Yokohama-city, Japan
7. Genoscope and CNRS, UMR-8030, Evry Cedex, France
8. Genome Therapeutics Corporation (GTC) Sequencing Center, Genome Therapeutics Corporation, Waltham, Massachusetts, USA
9. Department of Genome Analysis, Institute of Molecular Biotechnology, Jena, Germany
10. Beijing Genomics Institute/Human Genome Center, Institute of Genetics, Chinese Academy of Sciences, Beijing, China
11. Multimegabase Sequencing Center, The Institute for Systems Biology, Seattle, Washington, USA
12. Stanford Genome Technology Center, Stanford, California, USA
13. Stanford Human Genome Center and Department of Genetics, Stanford University School of Medicine, Stanford, California, USA
14. University of Washington Genome Center, Seattle, Washington, USA
15. Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan
16. University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA*
17. University of Oklahoma's Advanced Center for Genome Technology, Department of Chemistry and Biochemistry, University of Oklahoma, Norman, Oklahoma, USA
18. Max Planck Institute for Molecular Genetics, Berlin, Germany
19. Cold Spring Harbor Laboratory, Lita Annenberg Hazen Genome Center, Cold Spring Harbor, New York, USA
20. Gesellschaft für Biotechnologische Forschung mbH (GBF) - German Research Centre for Biotechnology, Braunschweig, Germany.
Note *Sequencing centre is no longer in operation
SOURCE: https://www.yourgenome.org/stories/who-was-involved-in-the-human-genome-project
It was interesting to find these facts quoted on Wellcome's site:
"The human genome sequenced during the Human Genome Project was from randomly chosen anonymous donations given in the USA."
"The second-ever human genome to be sequenced was that of James Watson, the co-discoverer of the structure of DNA."
"The human genome sequenced during the Human Genome Project was from randomly chosen anonymous donations given in the USA."
"The second-ever human genome to be sequenced was that of James Watson, the co-discoverer of the structure of DNA."
Significant Findings:
Not only has the Human Genome Project accomplished the
sequencing of the elements of the 23 Chromosomes that determine the
human as a species and how SNPs create the traits that make each of us a
unique individual, but along the way amazing advances in technological
tools, methods, processes, and applications have been developed. Coincidentally, the Project determined 99% of all humans DNA is
identical. It is that One Percent that creates us as unique
individuals.
From deciphering "the first sequence of the 3 billion
letters making up the human genetic blueprint" to transforming how
today's and future pharmaceutical, medical, and related computerized
applications work, the Project has advanced human knowledge and
capability dramatically.
Generating the first human genome sequence required actively sequencing human DNA for 6-8 years; today, scientists can sequence a human genome in a day. Such fast human genome sequencing allows physicians to make quick diagnoses of rare genetic disorders in acute settings.
Another notable achievement since the end of the Human Genome Project is the reduced cost of sequencing a human genome. That price has dropped from a billion dollars to mere hundreds, thanks to federal investments used to develop new technologies for DNA sequencing.
"The Human Genome Project transformed the way we study our biology and medicine. From accessing a genome sequence at the click of a mouse, performing newborn genome sequencing in an intensive care unit or the group's revolutionary decision to share the data with all, the Project's intentions and goals have spilled into how we do science today," said Francis Collins, M.D., Ph.D., National Institutes of Health director.
SOURCE: https://www.genome.gov/news/news-release/the-Human-Genome-Project-turns-the-big-30#:~:text=The%20project%20showed%20that%20humans,choreography%20involved%20in%20gene%20expression.
What remains to be discovered?
As your author penned the narrative accompanying this
complex subject, a series of Notifications interrupted her
concentration. Low and behold!
BREAKING NEWS: The Human Genome has now been
FULLY SEQUENCED! The Project was deemed complete in 2003 with just over
92% of the entire genome sequenced. Research had outrun development of
technology. No further sequencing was possible until greater
understanding of centromeres (the segment of the chromosome that binds
the sections together during cell division) and telomeres (the complex
structure at each end of a chromosome, See Below) was achieved, along
with a technological advancement to make their analysis possible.
But no less than six major publications shared the
announcement today that the finding of a rare, possibly unique,
chromosome containing only male DNA made it possible to isolate those
sequences that were specific go male DNA. Further analysis will now make
it possible to then isolate those segments specific to female DNA.
From the Government site itself:
SOURCE: https://www.genome.gov/news/news-release/researchers-generate-the-first-complete-gapless-sequence-of-a-human-genome
The full sequencing builds upon the work of the Human Genome Project, which mapped about 92% of the genome, and research undertaken since then. Thousands of researchers have developed better laboratory tools, computational methods and strategic approaches to decipher the complex sequence. Six papers encompassing the completed sequence appear in Science, along with companion papers in several other journals.
That last 8% includes numerous genes and repetitive DNA and is comparable in size to an entire chromosome. Researchers generated the complete genome sequence using a human cell line with only one copy of each chromosome, unlike most human cells, which carry two copies of each chromosome. The researchers noted that most of the newly added DNA sequences were near the repetitive telomeres (long, trailing ends of each chromosome) and centromeres (dense middle sections of each chromosome).
(telomere is the end of a chromosome. Telomeres are made of repetitive sequences of non-coding DNA that protect the chromosome from damage. Each time a cell divides, the telomeres become shorter. Eventually, the telomeres become so short that the cell can no longer divide.)
Additional news sources announcing the completion of this goal:
- https://time.com/6163452/human-genome-fully-sequenced/
- https://www.nbcnews.com/science/science-news/human-genome-finally-fully-decoded-rcna22029
- https://www.genome.gov/news/news-release/researchers-generate-the-first-complete-gapless-sequence-of-a-human-genome
- https://www.scientificamerican.com/article/completing-the-human-genome-sequence-again/
How does the Human Genome Project affect us?
Beyond the obvious DNA testing that provides us with DNA
Matches (available from Ancestry, 23&Me, Family Tree and similar
companies) that serve to either prove our paper trail and family lore or
furnish clues to break down our brick walls, the work of the consortium
of international scientific and technological researchers has almost
immeasurable potential.
One amazing breakthrough is the ability to perform genetic
testing within a hospital environment for myriad potential health
issues. The testing is reasonably priced, generally covered by
insurance, and results can dictate treatment for identified risks or
alleviate fear.
One such circumstance hit close to home this past month. A
granddaughter chose to undergo genetic testing for cancer
predisposition. Ruby Smith, fearful as a result of the prevalence for
cancer in her lineage elected to test. In her own words, extracted from
her messages we can see the speed at which the results were provided and
the reaction:
"Baptist Medical Group, Hematology and Oncology
Thankful to be getting genetic testing today. This testing is so important for not only myself but also my sister and her children as well. 84 genes are being tested today and each gene will reveal if it has a mutation that will likely cause cancer in my lifetime giving me the chance to be proactive instead of reactive. If I test positive for any of the mutations then there is significant need for familial testing.
March 17, 2022.~~~~~~~~~~
Tested negative for BRCA 1 and BRCA 2, primary markers for breast cancer
Announced 30 March~~~~~~~~~~~
Out of 84 genes I’m negative for all!!!!!!!!
I do have a variant in my DNA, but it's insignificant.
Announced 31 March 2022."~~~~~~~~~~~~
As promised, here are links to columns published previously that augment the information in this month's publication:
- December 2021 DNA: Complex. Tantalizing. And Nothing Short of Miraculous
http://pencilstubs.com/magazine/MagPage.asp?NID=6383
- January 2022 DNA: Complex. Tantalizing. And Nothing Short of Miraculous, Part 2
http://pencilstubs.com/magazine/MagPage.asp?NID=6411
- February 2022 DNA Glossary in Logical Order
http://pencilstubs.com/magazine/MagPage.asp?NID=6436
- March 2022 The Human Genome Project - Historical Advances
http://pencilstubs.com/magazine/MagPage.asp?NID=6459
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