Human Genome Project

What was the Human Genome Project?

The Human Genome Project (HGP) was the international, collaborative research program whose goal was the complete mapping and understanding of all the genes of human beings. All our genes together are known as our "genome."
The HGP was the natural culmination of the history of genetics research. In 1911, Alfred Sturtevant, then an undergraduate researcher in the laboratory of Thomas Hunt Morgan, realized that he could - and had to, in order to manage his data - map the locations of the fruit fly (Drosophila melanogaster) genes whose mutations the Morgan laboratory was tracking over generations. Sturtevant's very first gene map can be likened to the Wright brothers' first flight at Kitty Hawk. In turn, the Human Genome Project can be compared to the Apollo program bringing humanity to the moon.
The hereditary material of all multi-cellular organisms is the famous double helix of deoxyribonucleic acid (DNA), which contains all of our genes. DNA, in turn, is made up of four chemical bases, pairs of which form the "rungs" of the twisted, ladder-shaped DNA molecules. All genes are made up of stretches of these four bases, arranged in different ways and in different lengths. HGP researchers have 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, complex versions of the type originated in early Drosophila research, through which inherited traits (such as those for genetic disease) can be tracked over generations.
The HGP has revealed that there are probably about 20,500 human genes. The completed human sequence can now identify their locations. This ultimate product of the HGP has given the world a resource of detailed information about the structure, organization and function of the complete set of human genes. This information can be thought of as the basic set of inheritable "instructions" for the development and function of a human being.
The International Human Genome Sequencing Consortium published the first draft of the human genome in the journal Nature in February 2001 with the sequence of the entire genome's three billion base pairs some 90 percent complete. A startling finding of this first draft was that the number of human genes appeared to be significantly fewer than previous estimates, which ranged from 50,000 genes to as many as 140,000.The full sequence was completed and published in April 2003.
Upon publication of the majority of the genome in February 2001, Francis Collins, the director of NHGRI, noted that the genome could be thought of in terms of a book with multiple uses: "It's a history book - a narrative of the journey of our species through time. It's a shop manual, with an incredibly detailed blueprint for building every human cell. And it's a transformative textbook of medicine, with insights that will give health care providers immense new powers to treat, prevent and cure disease."
The tools created through the HGP also continue to inform efforts to characterize the entire genomes of several other organisms used extensively in biological research, such as mice, fruit flies and flatworms. These efforts support each other, because most organisms have many similar, or "homologous," genes with similar functions. Therefore, the identification of the sequence or function of a gene in a model organism, for example, the roundworm C. elegans, has the potential to explain a homologous gene in human beings, or in one of the other model organisms. These ambitious goals required and will continue to demand a variety of new technologies that have made it possible to relatively rapidly construct a first draft of the human genome and to continue to refine that draft. These techniques include:

• DNA Sequencing
  
  
• The Employment of Restriction Fragment-Length Polymorphisms (RFLP)
  
  
• Yeast Artificial Chromosomes (YAC)
  
  
• Bacterial Artificial Chromosomes (BAC)
  
  
• The Polymerase Chain Reaction (PCR)
  
  
• Electrophoresis

Of course, information is only as good as the ability to use it. Therefore, advanced methods for widely disseminating the information generated by the HGP to scientists, physicians and others, is necessary in order to ensure the most rapid application of research results for the benefit of humanity. Biomedical technology and research are particular beneficiaries of the HGP.
However, the momentous implications for individuals and society for possessing the detailed genetic information made possible by the HGP were recognized from the outset. Another major component of the HGP - and an ongoing component of NHGRI - is therefore devoted to the analysis of the ethical, legal and social implications (ELSI) of our newfound genetic knowledge, and the subsequent development of policy options for public consideration.

A Brief History of the Human Genome Project

In February 2001, the Human Genome Project (HGP) published its results to that date: a 90 percent complete sequence of all three billion base pairs in the human genome. (The HGP consortium published its data in the February 15, 2001, issue of the journal Nature.
The project had its ideological origins in the mid-1980s, but its intellectual roots stretch back further. Alfred Sturtevant created the first Drosophila gene map in 1911.
The crucial first step in molecular genome analysis, and in much of the molecular biological research of the last half-century, was the discovery of the double helical structure of the DNA molecule in 1953 by Francis Crick and James Watson. The two researchers shared the 1962 Nobel Prize (along with Maurice Wilkins) in the category of "physiology or medicine."
In the mid-1970s, Frederick Sanger developed techniques to sequence DNA, for which he received his second Nobel Prize in chemistry in 1980. (His first, in 1958, was for studies of protein structure). With the automation of DNA sequencing in the 1980s, the idea of analyzing the entire human genome was first proposed by a few academic biologists.
The United States Department of Energy, seeking data on protecting the genome from the mutagenic (gene-mutating) effects of radiation, became involved in 1986, and established an early genome project in 1987.
In 1988, Congress funded both the NIH and the DOE to embark on further exploration of this concept, and the two government agencies formalized an agreement by signing a Memorandum of Understanding to "coordinate research and technical activities related to the human genome."
James Watson was appointed to lead the NIH component, which was dubbed the Office of Human Genome Research. The following year, the Office of Human Genome Research evolved into the National Center for Human Genome Research (NCHGR).
In 1990, the initial planning stage was completed with the publication of a joint research plan, "Understanding Our Genetic Inheritance: The Human Genome Project, The First Five Years, FY 1991-1995." This initial research plan set out specific goals for the first five years of what was then projected to be a 15-year research effort.
In 1992, Watson resigned, and Michael Gottesman was appointed acting director of the center. The following year, Francis S. Collins was named director.
The advent and employment of improved research techniques, including the use of restriction fragment-length polymorphisms, the polymerase chain reaction, bacterial and yeast artificial chromosomes and pulsed-field gel electrophoresis, enabled rapid early progress. Therefore, the 1990 plan was updated with a new five-year plan announced in 1993 in the journal Science (262: 43-46; 1993).
Indeed, a large part of the early work of the HGP was devoted to the development of improved technologies for accelerating the elucidation of the genome. In a 2001 article in the journal Genome Research, Collins wrote, "Building detailed genetic and physical maps, developing better, cheaper and faster technologies for handling DNA, and mapping and sequencing the more modest-sized genomes of model organisms were all critical stepping stones on the path to initiating the large-scale sequencing of the human genome."
Also in 1993, the NCHGR established a Division of Intramural Research (DIR), in which genome technology is developed and used to study specific diseases. By 1996, eight NIH institutes and centers had also collaborated to create the Center for Inherited Disease Research (CIDR), for study of the genetics of complex diseases.
In 1997, the NCHGR received full institute status at NIH, becoming the National Human Genome Research Institute in 1997, with Collins remaining as the director for the new institute. A third five-year plan was announced in 1998, again in Science, (282: 682-689; 1998).
In June 2000 came the announcement that the majority of the human genome had in fact been sequenced, which was followed by the publication of 90 percent of the sequence of the genome's three billion base-pairs in the journal Nature, in February 2001.
Surprises accompanying the sequence publication included: the relatively small number of human genes, perhaps as few as 30,000; the complex architecture of human proteins compared to their homologs - similar genes with the same functions - in, for example, roundworms and fruit flies; and the lessons to be taught by repeat sequences of DNA.

How NHGRI Managed the Human Genome Project

NHGRI was created in 1989 to manage the role of NIH in the HGP and funded research in a variety of areas related to the project.
The Division of Extramural Research (DER) for NHGRI supported and managed the role of NIH in the HGP, set the scientific priorities for HGP research and supervised the peer-reviewed research projects that addressed those research efforts. The extramural research community and the NHGRI National Advisory Council for Human Genome Research (NACHGR) advise the DER. Major areas of genome-related research overseen by the DER include: the development of technologies used in gene sequencing and mapping; the analysis of the functions of the genes and the proteins for which most genes code; computer technologies for managing and disseminating the enormous amounts of data generated by the HGP; determination of the crucial differences in the genetic makeup of individual human beings from each other; and examination of the ethical, legal and social implications of genetic research.

The Completion of the Sequence and Remaining Goals

In 2003, an accurate and complete human genome sequence was finished and made available to scientists and researchers two years ahead of the original HGP schedule and at a cost less than the original estimated budget. With the completion of the HGP, the mission of the NHGRI has expanded to include studies aimed at understanding how the human genome functions in the role of creating gene products, most notably the many proteins for which genes code.

NHGRI Mission and Goals

In late 2001 through 2002, NHGRI gathered the world's leading genome researchers to discuss and determine the direction of future research at two large "bookend" meetings called Beyond the Beginning: The Future of Genomics I and II (See: Long-Range Planning: Reports and Publications) and held workshops throughout 2002 to discuss specific areas of genomic research, policy, education and ethics.
The specific ideas and recommendations that arose from these sessions has informed the next stage of genomic research, resulting in a vision document authored by the leadership at NHGRI: A Vision for the Future of Genomics Research. The overarching mission of the HGP and the NHGRI, however, remains the same: the quest to understand the human genome and the role it plays in both health and disease.
Francis Collins called the publication in February 2001 of the majority of the human genome "the end of the beginning."With the completion of the HGP in April 2003, his words continue to ring true. Writing in a 2001 article for Genome Research titled: Contemplating the End of the Beginning [ncbi.nlm.nih.gov] Collins explained:

Critical understanding of gene expression, the connection between sequence variations and phenotype, large-scale protein-protein interactions, and a host of other global analyses of human biology can now get seriously underway. For me, as a physician, the true payoff from the HGP will be the ability to better diagnose, treat and prevent disease, and most of those benefits to humanity still lie ahead. With these immense data sets of sequence and variation now in hand, we are now empowered to pursue those goals in ways undreamed of a few years ago.