The Human Genome Project (HGP) is an international scientific research project with a primary goal of determining the sequence of chemical base pairs which make up DNA and to identify and map the approximately 20,000–25,000 genes of the human genome from both a physical and functional standpoint.
The project began in 1990 and was initially headed by head of the Office of Biological and Environmental Research in the U.S. Department of Energy’s Office of Science. A working draft of the genome was announced in 2000 and a complete one in 2003, with further, more detailed analysis still being published. The mapping of human genes is an important step in the development of medicines and other aspects of health care.
While the objective of the Human Genome Project is to understand the genetic makeup of the human species, the project has also focused on several other nonhuman organisms such as E. coli, the fruit fly, and the laboratory mouse. It remains one of the largest single investigative projects in modern science.
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 (except for identical twins and cloned organisms) is unique; mapping “the human genome” involves sequencing multiple variations of each gene.The project did not study the entire DNA found in human cells; some heterochromatic areas (about 8% of the total genome) remain un-sequenced.
The project began with the culmination of several years of work supported by the United States Department of Energy, in particular workshops in 1984 and 1986 and a subsequent initiative of the US 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 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.
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 the United Kingdom, France, Germany, Japan, China, and India.
Due to widespread international cooperation and advances in the field of genomics (especially in sequence analysis), as well as major advances in computing technology, a ‘rough draft’ of the genome was finished in 2000 (announced jointly by then US president Bill Clinton and the British Prime Minister Tony Blair on June 26, 2000). This first available rough draft assembly of the genome was completed by the UCSC Genome Bioinformatics Group, primarily led by then graduate student Jim Kent. Ongoing sequencing led to the announcement of the essentially complete genome in April 2003, 2 years earlier than planned. In May 2006, another milestone was passed on the way to completion of the project, when the sequence of the last chromosome was published in the journal Nature.
State of completion
There are multiple definitions of the “complete sequence of the human genome”. According to some of these definitions, the genome has already been completely sequenced, and according to other definitions, the genome has yet to be completely sequenced. There have been multiple popular press articles reporting that the genome was “complete.” The genome has been completely sequenced using the definition employed by the International Human Genome Project. A graphical history of the human genome project shows that most of the human genome was complete by the end of 2003. However, there are a number of regions of the human genome that can be considered unfinished:
- First, the central regions of each chromosome, known as centromeres, are highly repetitive DNA sequences that are difficult to sequence using current technology. The centromeres are millions (possibly tens of millions) of base pairs long, and for the most part these are entirely un-sequenced.
- Second, the ends of the chromosomes, called telomeres, are also highly repetitive, and for most of the 46 chromosome ends these too are incomplete. It is not known precisely how much sequence remains before the telomeres of each chromosome are reached, but as with the centromeres, current technological restraints are prohibitive.
- Third, there are several loci in each individual’s genome that contain members of multigene families that are difficult to disentangle with shotgun sequencing methods – these multigene families often encode proteins important for immune functions.
- Other than these regions, there remain a few dozen gaps scattered around the genome, some of them rather large, but there is hope that all these will be closed in the next couple of years.
In summary: the best estimates of total genome size indicate that about 92.3% of the genome has been completed and it is likely that the centromeres and telomeres will remain un-sequenced until new technology is developed that facilitates their sequencing. Most of the remaining DNA is highly repetitive and unlikely to contain genes, but it cannot be truly known until it is entirely sequenced. Understanding the functions of all the genes and their regulation is far from complete. The roles of junk DNA, the evolution of the genome, the differences between individuals, and many other questions are still the subject of intense interest by laboratories all over the world.
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. Computer programs have been developed to analyze the data, because the data itself is difficult to interpret without such programs.
The process of identifying the boundaries between genes and other features in a 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.
Another, often overlooked, goal of the HGP is the study of its ethical, legal, and social implications. It is important to research these issues and find the most appropriate solutions before they become large dilemmas whose effect will manifest in the form of major political concerns.
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 “reference genome” of a small number of anonymous donors. The HGP genome is a scaffold for future work in identifying differences among individuals. Most of the current effort in identifying differences among individuals involves single-nucleotide polymorphisms and the Hap Map.
Key findings of the draft (2001) and complete (2004) genome sequences include
1. There are approximately 20,500 genes in human beings, the same range as in mice and twice that of roundworms. Understanding how these genes express themselves will provide clues to how diseases are caused.
2. Between 1.1% to 1.4% of the genome’s sequence codes for proteins
3. The human genome has significantly more segmental duplications (nearly identical, repeated sections of DNA) than other mammalian genomes. These sections may underlie the creation of new primate-specific genes
4. At the time when the draft sequence was published less than 7% of protein families appeared to be vertebrate specific
5. The first printout of the human genome to be presented as a series of books, displayed at the Wellcome Collection, London
6. The Human Genome Project is considered a Mega Project because the human genome has approximately 3.3 billion base-pairs.
If the sequence obtained was to be stored in book form, and if each page contained 1000 base-pairs recorded and each book contained 1000 pages, then 3300 such books would be needed in order to store the complete genome. However, if expressed in units of computer data storage, 3.3 billion base-pairs recorded at 2 bits per pair would equal 786 megabytes of raw data. This is comparable to a fully data loaded CD.
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 covered about 83% of the genome (90% of the euchromatic regions with 150,000 gaps and the order and orientation of many segments not yet established). In February 2001, at the time of the joint publications, press releases announced that the project had been completed by both groups. Improved drafts were announced in 2003 and 2005, filling in to ≈92% of the sequence currently.
The competition proved to be very good for the project, spurring the public groups to modify their strategy in order to accelerate progress. The rivals at UC Santa Cruz initially 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.
HGP is the most well known of many 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, fruit flies, zebrafish, yeast, nematodes, plants, and many microbial organisms and parasites.
In 2004, researchers from the International Human Genome Sequencing Consortium (IHGSC) 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 2,000,000. The number continues to fluctuate and it is now expected that it will take many years to agree on a precise value for the number of genes in the human genome.
This Mega Project is co-ordinated by the U.S. Department of Energy and the National Institute of Health. During the early years of the project, the Wellcome Trust (U.K.) became a major partner, other countries like Japan, Germany, China and France contributed significantly. Already the atlas has revealed some starting facts. The two factors that made this project a success are:
- Genetic Engineering Techniques, with which it is possible to isolate and clone any segment of DNA.
- Availability of simple and fast technologies, to determining the DNA sequences.
The IHGSC used pair-end sequencing plus whole-genome shotgun mapping of large (≈100 Kbp) plasmid clones and shotgun sequencing of smaller plasmid sub-clones plus a variety of other mapping data to orient and check the assembly of each human chromosome.
The Celera group emphasized the importance of the “whole-genome shotgun” sequencing method, relying on sequence information to orient and locate their fragments within the chromosome. However they used the publicly available data from HGP to assist in the assembly and orientation process, raising concerns that the Celera sequence was not independently derived.
The work on interpretation of genome data is still in its initial stages. It is anticipated that detailed knowledge of the human genome will provide new avenues for advances in medicine and biotechnology. 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 easy ways to administer genetic tests that can show predisposition to a variety of illnesses, including breast cancer, disorders of hemostasis, cystic fibrosis, liver diseases and many others. Also, the etiologies for cancers, Alzheimer’s disease and other areas of clinical interest are considered likely to benefit from genome information and possibly may lead in the long term to significant advances in their management.
There are also many tangible benefits for biological scientists. For example, a researcher investigating a certain form of cancer may have narrowed down his/her search to a particular gene. By visiting the human genome database on the World Wide Web, this researcher can examine what other scientists have written about this gene, including (potentially) the three-dimensional structure of its product, its function(s), its evolutionary relationships to other human genes, or to genes in mice or yeast or fruit flies, possible detrimental mutations, interactions with other genes, body tissues in which this gene is activated, diseases associated with this gene or other datatypes.
Further, deeper understanding of the disease processes at the level of molecular biology may determine new therapeutic procedures. Given the established importance of DNA in molecular biology and its central role in determining the fundamental operation of cellular processes, it is likely that expanded knowledge in this area will facilitate medical advances in numerous areas of clinical interest that may not have been possible without them.
The analysis of similarities between DNA sequences from different organisms is also opening new avenues in the study 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.
The Human Genome Diversity Project (HGDP), spin off research aimed at mapping the DNA that varies between human ethnic groups, which was rumored to have been halted, actually did continue and to date has yielded new conclusions. In the future, HGDP could possibly expose new data in disease surveillance, human development and anthropology. HGDP could unlock secrets behind and create new strategies for managing the vulnerability of ethnic groups to certain diseases (see race in biomedicine). It could also show how human populations have adapted to these vulnerabilities.
Advantages of Human Genome Project:
- Knowledge of the effects of variation of DNA among individuals can revolutionize the ways to diagnose, treat and even prevent a number of diseases that affects the human beings.
- It provides clues to the understanding of human biology.
Ethical, legal and social issues
The project’s goals included not only identifying all of the approximately 24,000 genes in the human genome, but also to address the ethical, legal, and social issues (ELSI) that might arise from the availability of genetic information. Five percent of the annual budget was allocated to address the ELSI arising from the project.
Debra Harry, Executive Director of the U.S group Indigenous Peoples Council on Biocolonialism (IPCB), says that despite a decade of ELSI funding, the burden of genetics education has fallen on the tribes themselves to understand the motives of Human genome project and its potential impacts on their lives. Meanwhile, the government has been busily funding projects studying indigenous groups without any meaningful consultation with the groups
The main criticism of ELSI is the failure to address the conditions raised by population-based research, especially with regard to unique processes for group decision-making and cultural worldviews. Genetic variation research such as HGP is group population research, but most ethical guidelines, according to Harry, focus on individual rights instead of group rights. She says the research represents a clash of culture: indigenous people’s life revolves around collectivity and group decision making whereas the Western culture promotes individuality. Harry suggests that one of the challenges of ethical research is to include respect for collective review and decision making, while also upholding the Western model of individual rights.