Human Genome Project

The Human Genome Project (HGP) endeavoured to map the human genome down to the nucleotide (or base pair) level and to identify all the genes present in it.

History
The Project was launched in 1986 by Charles DeLisi, who was then Director of the US Department of Energy's Health and Environmental Research Programs. The goals and general strategy of the Project were outlined in a two-page memo to the Assistant Secretary in April 1986, which helped garner support from the DOE, the OMB and Congress, especially Senator Pete Domenici. A series of Scientific Advisory meetings, and complex negotiations with senior Federal officials resulted in a line item for the Project in the 1987 Presidential budget submission to the Congress.

Initiation of the Project was the culmination of several years of work supported by the US Department of Energy, in particular a feasibility workshop in 1986 and a subsequent detailed description of the Human Genome Initiative in a report that led to the formal sanctioning of the initiative by the Department of Energy. This 1987 report stated boldly, "The ultimate goal of this initiative is to understand the human genome" and "Knowledge of the human genome is as necessary to the continuing progress of medicine and other health sciences as knowledge of human anatomy has been for the present state of medicine." Candidate technologies were already being considered for the proposed undertaking at least as early as 1985.

James Watson was Head of the National Center for Human Genome Research at the NIH starting from 1988. Largely due to his disagreement with his boss, Bernradine Healy, over the issue of patenting genes, he was forced to resign in 1992. He was replaced by Francis Collins in April 1993 and the name of the Center was changed to the National Human Genome Research Institute (NHGRI) in 1997.

The $3-billion project was formally founded in 1990 by the United States Department of Energy and the U.S. National Institutes of Health, and was expected to take 15 years.

In addition to the United States, the international consortium comprised geneticists in China, France, Germany, Japan, and the United Kingdom.

Due to widespread international cooperation and advances in the field of genomics (especially in sequence analysis), as well as huge advances in computing technology, a rough draft of the genome was finished in 2000 (announced jointly by US president Bill Clinton and British Prime Minister Tony Blair on June 26, 2000), two years earlier than planned.

President Clinton had already awarded the Citizen's medal to DeLisi for his seminal role in the Project, in January 2000, before the completion of the Project was announced.

The Role of Celera Genomics
In 1998, an identical, privately funded quest was launched by researcher Craig Venter and his firm Celera Genomics. The $300 million Celera effort was intended to proceed at a faster pace and at a fraction of the cost of the roughly $3 billion taxpayer-funded project.

Celera used a newer, riskier technique called whole genome shotgun sequencing, which had been used to sequence bacterial genomes.

Celera initially announced that it would seek patent protection on "only 200-300" genes, but later amended this to seeking "intellectual property protection" on "fully-characterized important structures" amounting to 100-300 targets. The firm eventually filed patent applications on 6,500 whole or partial genes.

Celera also promised to publish their findings in accordance with the terms of the 1996 "Bermuda Statement," by releasing new data quarterly (the HGP released its new data daily), although, unlike the publicly-funded project, they would not permit free redistribution or commercial use of the data.

In March 2000, President Clinton announced that the genome sequence could not be patented, and should be made freely available to all researchers. The statement sent Celera's stock plummeting and dragged down the biotech-heavy Nasdaq. The biotech sector lost about $50 billion in market capitalization in two days.

Although the working draft was announced in June 2000, it was not until February 2001 that Celera and the HGP scientists published details of their drafts. Special issues of Nature (which published the publicly-funded project's scientific paper) and Science (which published Celera's paper) described the methods used to produce the draft sequence and offered analysis of the sequence. These drafts are hoped to comprise a 'scaffold' of 90 % of the genome, with gaps to be filled later.

The competition proved to be very good for the project. The rivals agreed to pool their data, but the agreement fell apart when Celera refused to deposit its data in the unrestricted public database Genbank. Celera had incorporated the public data into their genome, but forbade the public effort to use Celera data.

On 14 April 2003, a joint press release announced that the project had been completed by both groups, with 99 % of the genome sequenced with 99.99 % accuracy.

Each draft sequence has been checked at least four to five times to increase 'depth of coverage' or accuracy. About 47 % of the draft were high-quality sequences. The final version will have been checked eight to nine times giving an error rate of 1 in 10,000 bases.

HGP is one of several international genome projects aimed at sequencing the DNA of a specific organism. While the human DNA sequence offers the most tangible benefits, important developments in biology and medicine are predicted as a result of the sequencing of model organisms, including mice, fruitflies, zebrafish, yeast, nematodes and many microbial organisms and parasites.

In October 2004, researchers of the HGP announced a new estimate of 20,000 to 25,000 genes in the human genome. Previously 30,000 to 40,000 had been predicted, while estimates at the start of the project reached up to as high as 100,000.

Goals
The goals of the original HGP were not only to determine all 3 billion base pairs in the human genome with a minimal error rate, but also to identify all the genes in this vast amount of data. This part of the project is still ongoing although a preliminary count indicates about 30,000 genes in the human genome, which is far fewer than predicted by most scientists.

Another goal of the HGP was to develop faster, more efficient methods for DNA sequencing and sequence analysis and the transfer of these technologies to industry. The sequencing of the human genome was made possible, in part by the development of a new technology, termed Rolling Circle Amplification Technology, that amplified the number of copies of DNA in the samples being sequenced, thereby facilitating the analysis. Rolling Circle Amplification Technology was developed through the independent efforts of the research groups of Paul Lizardi (Yale University), Eric Kool (The University of Rochester), Jeffrey Auerbach (Replicon, Inc.) and David Zhang (Mount Sinai Medical Center).

The sequence of the human DNA is stored in databases available to anyone on the Internet. The U.S. National Center for Biotechnology Information (and sister organizations in Europe and Japan) house the gene sequence in a database known as Genbank, along with sequences of known and hypothetical genes and proteins. Other organizations such as the University of California, Santa Cruz, and ENSEMBL present additional data and annotation and powerful tools for visualizing and searching it. Computer programs have been developed to analyse the data, because the data itself is difficult to interpret without them.

The process of identifying the boundaries between genes and other features in raw DNA sequence is called genome annotation and is the domain of bioinformatics. While expert biologists make the best annotators, their work proceeds slowly, and computer programs are increasingly used to meet the high-throughput demands of genome sequencing projects. The best current technologies for annotation make use of statistical models that take advantage of parallels between DNA sequences and human language, using concepts from computer science such as formal grammars.

All humans have unique gene sequences, therefore the data published by the HGP does not represent the exact sequence of each and every individual's genome. It is the combined genome of a small number of anonymous donors. The HGP genome is a scaffold for future work in identifying differences between individuals. Most of the current effort in identifying differences between individuals involves single nucleotide polymorphisms and the HapMap.

Benefits
Clear practical results of the project emerged even before the work was finished. For example, a number of companies, such as Myriad Genetics started offering inexpensive and easy ways to administer genetic tests that can show predisposition to a variety of illnesses, including breast cancer, blood clotting, cystic fibrosis, liver diseases and many others.

There are also many tangible benefits for biological scientists. For example, a researcher investigating a certain form of cancer may have narrowed down his search to a particular gene. By visiting the human genome database on the worldwide web, this researcher can examine what other scientists have written about this gene, including (potentially) its three-dimensional structure, its function(s), its evolutionary relationships to other human genes, or to genes in mice or yeast or fruitflies, possible detrimental mutations, interactions with other genes, body tissues in which this gene is activated, diseases associated with this gene... The list of datatypes is long, one reason why bioinformatics is so challenging.

The work on interpretation of genome data is still in its initial stages. In the future the knowledge gained by the understanding of the genome will boost the fields of medicine and biotechnology, potentially leading to cures for cancer, Alzheimer's disease and other diseases.

On a more purely scientific level, the analysis of similarities between DNA sequences from different organisms is opening new avenues in the study of the theory of evolution. In many cases, evolutionary questions can now be framed in terms of molecular biology; indeed, many major evolutionary milestones (the emergence of the ribosome and organelles, the development of embryos with body plans, the vertebrate immune system) can be related to the molecular level. Many questions about the similarities and differences between humans and our closest relatives (the primates, and indeed the other mammals) are expected to be illuminated by the data from this project.

Whose genome was sequenced?
''This answer is posted as supplied by Dr. Marvin Stodolsky, U.S. DOE Office of Biological and Environmental Research, Office of Science. This statement is believed to be in the public domain since it is a work of the United States government''

"Whose genome was sequenced in the public (HGP) and private projects?"

"The human genome reference sequences do not represent any one person’s genome. Rather, they serve as a starting point for broad comparisons across humanity. The knowledge obtained is applicable to everyone because all humans share the same basic set of genes and genomic regulatory regions that control the development and maintenance of their biological structures and processes."

"In the international public-sector Human Genome Project (HGP), researchers collected blood (female) or sperm (male) samples from a large number of donors. Only a few of many collected samples were processed as DNA resources. Thus the donor identities were protected so neither donors nor scientists could know whose DNA was sequenced. DNA clones from many different libraries were used in the overall project."

"Technically, it is much easier to prepare DNA cleanly from sperm than from other cell types because of the much higher ratio of DNA to protein in sperm and the much smaller volume in which purifications can be done. Using sperm does provide all chromosomes for study, including equal numbers of sperm with the X (female) or Y (male) sex chromosomes. However, HGP scientists also used white cells from the blood of female donors so as to include female-originated samples."

"In the Celera Genomics private-sector project, DNAs from a few different genomes were mixed up and processed for sequencing. The DNA resources used for these studies came from anonymous donors of European, African, American (North, Central, South), and Asian ancestry. The lead scientist of Celera Genomics at that time, Craig Venter, has since acknowledged that his DNA was one of those in the pool."

"Many small regions of DNA that vary among individuals (called polymorphisms) also were identified during the HGP, mostly single nucleotide polymorphisms (SNPs). Most SNPs are without physiological effect, although a minority contribute to the delightful and beneficial diversity of humanity. A much smaller minority of polymorphisms affect an individual’s susceptibility to disease and response to medical treatments."

"Although the HGP has been completed, SNP studies continue in the International HapMap Project, whose goal is to identify patterns of SNP groups (called haplotypes, or “haps”). The DNA samples for the HapMap came from a total of 270 individuals: Yoruba people in Ibadan, Nigeria; Japanese in Tokyo; Han Chinese in Beijing; and the French Centre d’Etude du Polymorphisme Humain (CEPH) resource."