Human Genome Project
Human Genome Project
The goals of the Human Genome Project
The United States Human Genome Project (HGP) is an initiative that was formally launched in 1990 by the National Institutes of Health (NIH) and the U.S. Department of Energy (DOE) to better understand all aspects related to human genetic material, or deoxyribonucleic acid (DNA). In 2001, the sequence of the human genome was published. Since then, work has focused on studying the sequence in more detail to identify regions of interest among the 30,000 genes that were determined to comprise the genome (a genome is the total DNA in an organism).
Around the time that the HGP was formally introduced, it was an issue of debate whether it would be more important to know the complete sequence of the genome, or whether known sequences should be better understood and their functions determined before further sequences were determined. The scientific approach to identifying and defining the function of genes and to determine how genes interact is a field of genetics called functional genomics. Structural genomics is a field of genetics focused on determining the location of a gene by an approach called genetic mapping, or the localization of genes with respect to each other. In the end, functional genomics became secondary to sequencing the human genome; it was felt that functional genomics would best follow the determination of the genome sequence. After the publication of the human genome sequence in 2001, the genomic research entered what has been termed the post-genomic era. Put another way, functional genomics has now become paramount.
The goals of the Human Genome Project
At its inception, the HGP had several targeted goals that were intended to better assist scientists in understanding the human genome. One goal, which is still in progress as of 2006, is to identify the estimated 30,000 genes. Secondly, because it is estimated that there are almost four billion nucleotides (the building blocks of DNA) that makeup the human genome, identifying ways to store this information on publicly accessible databases was an important HGP goal and a challenge to computational biologists. Another goal was to improve analytical tools related to data acquisition so that sequences of the human genome could be compared to sequences from a database that includes gene sequence information from many different organisms. Genes that encode similar proteins can be identified this way, which can provide information on the evolution of organisms and the differences and similarities between organisms. Another goal, which is also ongoing as of 2006, is to better understand the complete structure and functioning of the human genome; only a small percentage of the human genome is actually comprised of genes, with much more of the genome occupied by noncoding regions of DNA. Whether these regions are really functionless or, as is becoming increasingly clear, play a role in the regulation of gene expression, could be best addressed when the complete human genome sequence was known. Finally, the last objective was to address the inevitable ethical, legal, and social implications of having access to an individual’s genetic information. This component of the HGP was strongly urged due to the nature of the information that would become available and the potential for negative impacts related to using this information inappropriately.
DNA sequencing methodology
DNA is packaged into structures called chromosomes that unwind when genes are given the appropriate cues to produce protein. Chromosomes are important structures for organizing the long stretches of DNA and provide a platform for which this material can be replicated and separated so that as the cell divides, both of the two new cells will have the appropriate amount of genetic material. Chromosomes can range in size between 50 to 250 million nucleotide bases. In order to sequence these bases, they must first be broken into fragments. Each fragment is used to produce a collection of smaller sized fragments that differ in length by only a single base and are amplified. The amplified set is separated by a gel matrix, and an electrical field is created that separates the DNA fragments in the matrix based on size and charge. These fragments are used as a template for the DNA sequencing reaction. Since DNA is double stranded where A binds to T and C binds to G (and vice versa), a single-stranded template can be used for adding fluorescent-labeled nucleotides of complementary sequence. Using current technology, up to 700 bases can be sequenced.
The timeline
The first decade
In as early as 1983, scientists at Los Alamos National Laboratory (LANL), a Department of Energy Laboratory, and Lawrence Berkeley National Laboratory (LBNL) were working to begin the production of what are called DNA libraries. DNA libraries allow scientists to categorize different DNA sequences so that they can piece together the continuous sequence for each chromosome. Only two years later, the feasibility of the Human Genome Initiative was carefully being considered. In 1986, the Department of Energy and the Office of Health and Environmental Research announced a $5.3 million pilot project to begin the Human Genome Initiative in order to develop resources and technologies that would improve this effort. In 1987, the Health and Environmental Research Advisory Committee recommended a 15-year goal to map and sequence the entire human genome, the first undertaking ever to be made.
In 1988, the Human Genome Organization was founded in order to provide international collaborative opportunities for scientists. In 1989, the ELSI Task Force was created. An official and formal, five year joint agreement between NIH and DOE was presented to Congress in 1990 along with a 15-year goal to sequence the entire human genome. Already artificial chromosomes were being created that would give scientists the ability to insert large DNA sequences into these constructs. In particular, bacterial artificial chromosomes (BACs) were being produced that allowed larger fragments to be inserted, accelerating sequencing efforts. Inserts of human DNA into BACs represent a type of DNA library. In 1991, a repository called the Genome Database was created, marking the first major computational effort to begin teasing out the complex genetic material that separates humans from other organisms. In 1992, only two years after the HGP formally began, the first crude map of the human genome was published using sequence data acquired by linking various genes together based on known locations (or markers) along a chromosome. This gave the research community a glimpse into the human genome map.
The next ten years: Public and private contributions
In 1993, an international consortium was established to sort out sequences derived from expressed genes and efforts to map theses sequences ensued. This consortium was called the Integrated Molecular Analysis of Gene Expression (IMAGE) Consortium and it paved the way for structural and functional genomics. Novel sequencing methodology was being developed almost as rapidly as the DNA sequences were elucidated. A new artificial chromosome vector called YAC (yeast artificial chromosome) was introduced providing a construct with an even larger DNA insert capacity.
In 1994, the HGP announced the completion of the five year goal of producing the genetic map of the human genome one year earlier than proposed. Each chromosome had an expanding DNA library resource. In the same year, the first legislation to be passed initiated by the U.S. HGP and called the Genetic Privacy Act was designed to control how DNA is collected, analyzed, stored, and used.
The physical maps of chromosomes 16 and 19 were announced in 1995, followed by the publication of moderate-resolution maps of chromosomes 3, 11, 12 and 22. During this time, the HGP was not the only species that was being sequenced. Already, the genome from the bacteria that causes the flu (Haemophilusinfluenzae ) was completely sequenced, followed by the yeast genome (Saccharomyces cerevisiae ) a year later. Concerns over discrimination based on genetic information elicited a amendment to the Health Care Portability and Accountability Act that included a clause that prohibits healthcare insurance companies to use of genetic information in certain cases to determine eligibility. This was an important legislative initiative, helping to mitigate some of the immediate concerns related to genetic discrimination of the healthcare industry.
In January, 1997 the NIH declared that the National Human Genome Research Institute (NHGRI) would be a recognized collaborative institute. Following this decree, physical maps of chromosomes X and 7 were announced. GeneMap of 1998 was released allowing scientists the ability to use the mapped location of approximately 30,000 markers for genetic studies. It was also in 1998 that American geneticist Craig Ventor formed Celera Genomics, a company that would significantly contribute to the sequencing effort using many resources provided by the HGP. Celera Genomics, equipped with high-speed state of the art sequencing capabilities, became a leader in the race to sequence the human genome. Only nine years after the HGP was formally initiated, chromosome 22 was considered to be completely sequenced, meaning that although the 56 million bases that are estimated to makeup the entire sequence of chromosome 22, only 33.5 million bases were actually sequenced by the HGP. The remaining sequences, roughly 22.5 million bases, represent regions at the ends of chromosomes (called telomeres) and the center of chromosomes (centromeres) are comprised of repeated sequences that prevent them from being cloned into BACs or any other construct. There are few genes, if any, in most of these sequences. The sequenced portion of chromosome 22 represents 97% of regions that are rich in genes.
Using the sequencing data, a public database created by major pharmaceutical companies called the Single Nucleotide Polymorphism (SNP) Consortium was introduced in order to provide information about inherited variations in the human genome that might provide insight into health and disease. For example, inherited variations in genes that metabolize carcinogens might have inherited variations in some individuals that make them susceptible to developing cancer when they are exposed to environmental contaminants. People without these variations are therefore less likely to develop cancer. Identifying these individuals has important implications for reducing cases of cancer.
The human genome sequence published in 2001 was referred to as a draft sequence. Despite this
KEY TERMS
Clone —A cell or organism derived through asexual reproduction, and which contain the identical genetic information of the parent cell or organism.
Deoxyribonucleic acid (DNA) —The genetic material in a cell.
Eugenics —A social movement in which the population of a society, country, or the world is to be improved by controlling the passing on of hereditary information through selective breeding.
Gene —A discrete unit of inheritance, represented by a portion of DNA located on a chromosome. The gene is a code for the production of a specific kind of protein or RNA molecule, and therefore for a specific inherited characteristic.
Genome —The complete set of genes an organism carries.
Polymorphism —An variation in an individuals genetic material that is inherited in greater than 1% of the population and does not represent a spontaneous mutation.
designation, a great deal of effort had gone into producing the sequence and verifying its accuracy. Indeed, scientists sequenced each of the 52 chromosomes of the human genome four to five times to be certain of the accuracy of the sequence. The next step, which was completed in 2003, was to produce a higher quality sequence of approximately 95.8% of the human genome sequence. This version was very accurate, with an error rate of only one base per 10,000 bases. Final sequences are publicly available in databases such as GenBank.
A popular misconception about the published human genome sequence is that it is universal; that is, every human being has the exact same arrangement of nucleotides in his or her DNA. In fact, while there are highly conserved regions (regions that are the same between people) throughout the genome, which tend to be genes and regulatory regions important for controlling gene expression, there are also regions throughout the genome that vary from person to person. In fact, although 99% of the genome is conserved, 1% is variable. This means that roughly 3,000,000 bases differ between individuals. These differences are significant because there are nucleotides that are variable called polymorphisms and are found in greater then 1% of the population. These single nucleotide polymorphisms (SNPs) have become very useful in the field of pharmacogenomics, or the area of research that involves understanding how an individual’s genes affect the body’s response to drugs. For example, it is particularly significant if an SNP occurs in a gene that encodes a protein important for metabolizing a certain pharmaceutical agent. The protein, in this case an enzyme, might function at a reduced rate if the SNP causes an alteration in conformation of the protein. A reduction in function might lead to adverse drug reactions for this individual because the enzyme is capable of metabolizing only a small amount of the drug. Therefore, knowing if a person has the SNP is important for determining the appropriate drug to use.
Resources
BOOKS
Davies, Kevin. Cracking the Genome: Inside the Race to Unlock Human DNA. Baltimore: The Johns Hopkins University Press, 2002.
Palladino, Michael A. Understanding the Human Genome Project (2nd Edition). New York: Benjamin Cummings, 2005.
Thistlewaite, Susan B. Adam, Eve, and the Genome: The Human Genome Project and Theology. Minneapolis: Augsburg Fortress Publishers, 2003.
PERIODICALS
McElheny, Victor K. and Francis S. Collins. “The Human Genome Project +5.” The Scientist. 20 (2006): 42-48.
OTHER
National Institutes of Health. “The National Human Genome Research Institute: Advancing Human Health Through Genetic Research.” NHGRI. February, 2003. <http://www.genome.gov> (accessed October 31, 2006).
Bryan Cobb