The Human Genome Project (HGP) is one of the greatest scientific feats in history. The project was a voyage of biological discovery led by an international group of researchers looking to comprehensively study all of the DNA (known as a genome) of a select set of organisms. Launched in October 1990 and completed in April 2003, the Human Genome Project’s signature accomplishment – generating the first sequence of the human genome – provided fundamental information about the human blueprint, which has since accelerated the study of human biology and improved the practice of medicine.

Did you know that your genome contains about six billion individual building blocks - and that we can now read the order of all those building blocks in about a day and for about $1000? Leaps in technology since the Human Genome Project have enabled remarkable genomics-based advances in medicine, agriculture, forensics, and our understanding of evolution.

Our genome (that is, our DNA "blueprint") - and in fact the genomes of all life forms on earth - are made of four chemical "bases" strung together in varying orders. To study the exact order (or sequence) of someone's DNA, researchers follow three major steps: (1) purify and copy the DNA; (2) read the sequence; and (3) compare to other sequences.

First they use chemical methods to purify, then, for some menthods, "amplify" the DNA in the sample - that means they copy small parts of the sample to reach high enough levels for measuring. The amplification step makes it possible to do DNA testing from very small starting amounts, like those in forensic samples or ancient bones. Then, different methods can be used to determine the order of each base in the DNA sample. Finally, they use computers to compare the sequence of the DNA to a reference sequence (for example, of the human genome), in order to see if there are any differences in the order of the bases.

Technology Advances Since the Human Genome Project

The Human Genome Project opened the door to vast improvements in three major areas:

• The methods used to amplify and sequence DNA, including a million-fold reduction in the cost for sequencing a human genome.
• Continually improving the accuracy of the reference "human genome sequences" that everyone can use for comparing newly generated human genome sequences.
• Powerful new computer-based methods for analyzing and comparing many human genome sequences.

As a result, we now have multiple methods for sequencing DNA quickly and inexpensively, and we have the computational ability to compare thousands of genomes at once.

DNA Sequencing Has Gone Mobile and Into Space

When the Human Genome Project officially started in 1990, no one knew that it would lead to the generation of over $1 trillion in economic return and the creation of hundreds of thousands of jobs. It brought together scientists from all over the world. In 2016, genomics went beyond this world! Dr. Kathleen "Kate" Rubins became the first person to sequence DNA in space. She used a hand-held instrument to sequence a DNA sample sent from earth, showing that DNA sequencing can be performed in space. In December 2017, fellow astronaut Dr. Peggy Whitson became the first person to sequence microbes brought from earth to the International Space Station itself. Adding this technology to the space station can bring the same advances in medicine and science to space exploration.

The Human Genome Project was a large, well-organized, and highly collaborative international effort that generated the first sequence of the human genome and that of several additional well-studied organisms. Carried out from 1990–2003, it was one of the most ambitious and important scientific endeavors in human history.

What were the goals of the Human Genome Project?

A special committee of the U.S. National Academy of Sciences outlined the original goals for the Human Genome Project in 1988, which included sequencing the entire human genome in addition to the genomes of several carefully selected non-human organisms.

Eventually the list of organisms came to include the bacterium E. coli, baker’s yeast, fruit fly, nematode and mouse. The project’s architects and participants hoped the resulting information would usher in a new era for biomedical research, and its goals and related strategic plans were updated periodically throughout the project.

In part due to a deliberate focus on technology development, the Human Genome Project ultimately exceeded its initial set of goals, doing so by 2003, two years ahead of its originally projected 2005 completion. Many of the project’s achievements were beyond what scientists thought possible in 1988.

President Bill Clinton and Francis Collins, M.D., Ph.D., (NHGRI Director) at a June 2000 event at the White House celebrating the draft human genome sequence generated by the Human Genome Project. Dr. Collins served as the de facto leader of the International Human Genome Sequencing Consortium, the group that sequenced the human genome during the Human Genome Project. (NHGRI Photo Archive)

What is DNA sequencing? How was it performed during the Human Genome Project?

DNA sequencing involves determining the exact order of the bases in DNA — the As, Cs, Gs and Ts that make up segments of DNA. Because the Human Genome Project aimed to sequence all of the DNA (i.e., the genome) of a set of organisms, significant effort was made to improve the methods for DNA sequencing.

Ultimately, the project used one particular method for DNA sequencing, called Sanger DNA sequencing, but first greatly advanced this basic method through a series of major technical innovations.

Whose DNA was sequenced by the Human Genome Project? How was it collected?

The sequence of the human genome generated by the Human Genome Project was not from a single person. Rather, it reflects a patchwork from multiple people whose identities were intentionally made anonymous to protect their privacy.

The project researchers used a thoughtful process to recruit volunteers, acquire their informed consent, and collect their blood samples. Most of the human genome sequence generated by the Human Genome Project came from blood donors in Buffalo, New York; specifically, 93% from 11 donors, and 70% from one donor.

Photo: Researcher at Washington University in St. Louis handling frozen clones containing human DNA being studied by Human Genome Project researchers. (NHGRI Photo Archive)

Who carried out the Human Genome Project?

The Human Genome Project could not have been completed as quickly and effectively without the dedicated participation of an international consortium of thousands of researchers. In the United States, the researchers were funded by the Department of Energy and the National Institutes of Health, which created the Office for Human Genome Research in 1988 (later renamed the National Center for Human Genome Research in 1990 and then the National Human Genome Research Institute in 1997).

The sequencing of the human genome involved researchers from 20 separate universities and research centers across the United States, United Kingdom, France, Germany, Japan and China. The groups in these countries became known as the International Human Genome Sequencing Consortium.

How much did the Human Genome Project cost?

The initially projected cost for the Human Genome Project was $3 billion, based on its envisioned length of 15 years. While precise cost-accounting was difficult to carry out, especially across the set of international funders, most agree that this rough amount is close to the accurate number.

The cost of the Human Genome Project, while in the billions of dollars, has been greatly offset by the positive economic benefits that genomics has yielded in the ensuing decades. Such economic gains reflect direct links between resulting products and advances in the pharmaceutical and biotechnology industries, among others.

Photo: A Human Genome Project researcher pipetting a DNA sample into an agarose gel to perform gel electrophoresis. (NHGRI Photo Archive)

Did the Human Genome Project produce a perfectly complete genome sequence?

No. Throughout the Human Genome Project, researchers continually improved the methods for DNA sequencing. However, they were limited in their abilities to determine the sequence of some stretches of human DNA (e.g., particularly complex or highly repetitive DNA).

In June 2000, the International Human Genome Sequencing Consortium announced that it had produced a draft human genome sequence that accounted for 90% of the human genome. The draft sequence contained more than 150,000 areas where the DNA sequence was unknown because it could not be determined accurately (known as gaps).

In April 2003, the consortium announced that it had generated an essentially complete human genome sequence, which was significantly improved from the draft sequence. Specifically, it accounted for 92% of the human genome and less than 400 gaps; it was also more accurate.

On March 31, 2022, the Telomere-to-Telomere (T2T) consortium announced that had filled in the remaining gaps and produced the first truly complete human genome sequence.

How did the Human Genome Project change practices around data sharing in the scientific research community?

Human Genome Project scientists made every part of the draft human genome sequence publicly available shortly after production.

This routine came from two meetings in Bermuda in which project researchers agreed to the “Bermuda Principles,” which set out the rules for the rapid release of sequence data. This landmark agreement has been credited with establishing a greater awareness and openness to the sharing of data in biomedical research, making it one of the most important legacies of the Human Genome Project.

How did the Human Genome Project foster ethics in biological research?

The leaders of the Human Genome Project recognized the need to be proactive in addressing a wide range of ethical and social issues related to the acquisition and use of genomic information. They were especially aware of the potential risks and benefits of incorporating new genomic knowledge into research and medicine. Similarly, they were aware of the potential misuse of genomic information when it came to insurance and employment, among others.

To help understand and address these issues, NHGRI established the Ethical, Legal, and Social Implications (ELSI) Research Program in 1990.

The early appreciation of the value of this program later led the U.S. Congress to mandate that NHGRI dedicate at least 5% of its research budget to studying the ethical, legal and social implications of genomic advances. The NHGRI ELSI Research Program has become a model for bioethics research worldwide.

How did the Human Genome Project affect biological research in general?

The Human Genome Project demonstrated that production-oriented, discovery-driven scientific inquiry—which did not involve the investigation of a specific hypothesis or the direct answering of preformed questions—could be remarkably valuable and beneficial to the broader scientific community.

The project was also a successful example of “big science” in biomedical research. The magnitude of the technological challenges prompted the Human Genome Project to assemble interdisciplinary groups from across the world, involving experts in engineering, biology, and computer science, among other areas. It also required the work to be concentrated in a modest number of major centers to maximize economies of scale.

Before the Human Genome Project, the biomedical research community viewed projects of such scale with deep skepticism. These kinds of massive scientific undertakings have become more commonplace and well-accepted based in part on the success of the Human Genome Project.

Advances in the field of genomics over the past quarter-century have led to substantial reductions in the cost of genome sequencing. The underlying costs associated with different methods and strategies for sequencing genomes are of great interest because they influence the scope and scale of almost all genomics research projects.

Overview

Significant scrutiny and attention have been given to genome-sequencing costs and how they are calculated since the beginning of the field of genomics in the late 1980s. For example, NHGRI has carefully tracked costs per genome at its funded 'genome sequencing centers' for many years (see Figure 1). With the growing scale of human genetics studies and the increasing number of clinical applications for genome sequencing, even greater attention is being paid to understanding the underlying costs of generating a human genome sequence.

Accurately determining the cost for sequencing a given genome (e.g., a human genome) is not simple. There are many parameters to define and nuances to consider. In fact, it is difficult to cite precise genome-sequencing cost figures that mean the same thing to all people because, in reality, different researchers, research institutions, and companies typically track and account for such costs in different fashions

A Primer on Genome Sequencing

A genome consists of all of the DNA contained in a cell's nucleus. DNA is composed of four chemical building blocks or "bases" (for simplicity, abbreviated G, A, T, and C), with the biological information encoded within DNA determined by the order of those bases. Diploid organisms, like humans and all other mammals, contain duplicate copies of almost all of their DNA (i.e., pairs of chromosomes; with one chromosome of each pair inherited from each parent). The size of an organism's genome is generally considered to be the total number of bases in one representative copy of its nuclear DNA. In the case of diploid organisms (like humans), that corresponds to the sum of the sizes of one copy of each chromosome pair.

Organisms generally differ in their genome sizes. For example, the genome of E. coli (a bacterium that lives in your gut) is ~5 million bases (also called megabases), that of a fruit fly is ~123 million bases, and that of a human is ~3,000 million bases (or ~3 billion bases). There are also some surprising extremes, such as with the loblolly pine tree - its genome is ~23 billion bases in size, over seven times larger than ours. Obviously, the cost to sequence a genome depends on its size. The discussion below is focused on the human genome; keep in mind that a single 'representative' copy of the human genome is ~3 billion bases in size, whereas a given person's actual (diploid) genome is ~6 billion bases in size.

Genomes are large and, at least with today's methods, their bases cannot be 'read out' in order (i.e., sequenced) end-to-end in a single step. Rather, to sequence a genome, its DNA must first be broken down into smaller pieces, with each resulting piece then subjected to chemical reactions that allow the identity and order of its bases to be deduced. The established base order derived from each piece of DNA is often called a 'sequence read,' and the collection of the resulting set of sequence reads (often numbering in the billions) is then computationally assembled back together to deduce the sequence of the starting genome. Sequencing human genomes are nowadays aided by the availability of available 'reference' sequences of the human genome, which play an important role in the computational assembly process. Historically, the process of breaking down genomes, sequencing the individual pieces of DNA, and then reassembling the individual sequence reads to generate a sequence of the starting genome was called 'shotgun sequencing' (although this terminology is used less frequently today). When an entire genome is being sequenced, the process is called 'whole-genome sequencing.' See Figure 2 for a comparison of human genome sequencing methods during the time of the Human Genome Project and circa ~ 2016.

An alternative to whole-genome sequencing is the targeted sequencing of part of a genome. Most often, this involves just sequencing the protein-coding regions of a genome, which reside within DNA segments called 'exons' and reflect the currently 'best understood' part of most genomes. For example, all of the exons in the human genome (the human 'exome') correspond to ~1.5% of the total human genome. Methods are now readily available to experimentally 'capture' (or isolate) just the exons, which can then be sequenced to generate a 'whole-exome sequence' of a genome. Whole-exome sequencing does require extra laboratory manipulations, so a whole-exome sequence does not cost ~1.5% of a whole-genome sequence. But since much less DNA is sequenced, whole-exome sequencing is (at least currently) cheaper than whole-genome sequencing.

Another important driver of the costs associated with generating genome sequences relates to data quality. That quality is heavily dependent upon the average number of times each base in the genome is actually 'read' during the sequencing process. During the Human Genome Project (HGP), the typical levels of quality considered were: (1) 'draft sequence' (covering ~90% of the genome at ~99.9% accuracy); and (2) 'finished sequence' (covering >95% of the genome at ~99.99% accuracy). Producing truly high-quality 'finished' sequence by this definition is very expensive; of note, the process of 'sequence finishing' is very labor-intensive and is thus associated with high costs. In fact, most human genome sequences produced today are 'draft sequences' (sometimes above and sometimes below the accuracy defined above).

There are thus a number of factors to consider when calculating the costs associated with genome sequencing. There are multiple different types and quality levels of genome sequences, and there can be many steps and activities involved in the process itself. Understanding the true cost of a genome sequence therefore requires knowledge about what was and was not included in calculating that cost (e.g., sequence data generation, sequence finishing, upfront activities such as mapping, equipment amortization, overhead, utilities, salaries, data analyses, etc.). In reality, there are often differences in what gets included when estimating genome-sequencing costs in different situations.

Below is summary information about: (1) the estimated cost of sequencing the first human genome as part of the HGP; (2) the estimated cost of sequencing a human genome in 2006 (i.e., roughly a decade ago); and (3) the estimated cost of sequencing a human genome in 2016 (i.e., the present time).

Timeline of Costs

How much did it cost to generate the first human genome sequence as part of the Human Genome Project?

The HGP generated a 'reference' sequence of the human genome - specifically, it sequenced one representative version of all parts of each human chromosome (totaling ~3 billion bases). In the end, the quality of the 'finished' sequence was very high, with an estimated error rate of 1 in 100,000 bases; note this is much higher than a typical human genome sequence produced today. The generated sequence did not come from one person's genome, and, being a 'reference' sequence of ~3 billion bases, really reflects half of what is generated when an individual person's ~6-billion-base genome is sequenced (see below).

The HGP involved first mapping and then sequencing the human genome. The former was required at the time because there was otherwise no 'framework' for organizing the actual sequencing or the resulting sequence data. The maps of the human genome served as 'scaffolds' on which to connect individual segments of assembled DNA sequence. These genome-mapping efforts were quite expensive, but were essential at the time for generating an accurate genome sequence. It is difficult to estimate the costs associated with the 'human genome mapping phase' of the HGP, but it was certainly in the many tens of millions of dollars (and probably hundreds of millions of dollars).

Once significant human genome sequencing began for the HGP, a 'draft' human genome sequence (as described above) was produced over a 15-month period (from April 1999 to June 2000). The estimated cost for generating that initial 'draft' human genome sequence is ~$300 million worldwide, of which NIH provided roughly 50-60%.

The HGP then proceeded to refine the 'draft' and produce a 'finished' human genome sequence (as described above), which was achieved by 2003. The estimated cost for advancing the 'draft' human genome sequence to the 'finished' sequence is ~$150 million worldwide. Of note, generating the final human genome sequence by the HGP also relied on the sequences of small targeted regions of the human genome that were generated before the HGP's main production-sequencing phase; it is impossible to estimate the costs associated with these various other genome-sequencing efforts, but they likely total in the tens of millions of dollars.

The above explanation illustrates the difficulty in coming up with a single, accurate number for the cost of generating that first human genome sequence as part of the HGP. Such a calculation requires a clear delineation about what does and does not get 'counted' in the estimate; further, most of the cost estimates for individual components can only be given as ranges. At the lower bound, it would seem that this cost figure is at least $500 million; at the upper bound, this cost figure could be as high as $1 billion. The truth is likely somewhere in between.

The above estimated cost for generating the first human genome sequence by the HGP should not be confused with the total cost of the HGP. The originally projected cost for the U.S.'s contribution to the HGP was $3 billion; in actuality, the Project ended up taking less time (~13 years rather than ~15 years) and requiring less funding - ~$2.7 billion. But the latter number represents the total U.S. funding for a wide range of scientific activities under the HGP's umbrella beyond human genome sequencing, including technology development, physical and genetic mapping, model organism genome mapping and sequencing, bioethics research, and program management. Further, this amount does not reflect the additional funds for an overlapping set of activities pursued by other countries that participated in the HGP.

As the HGP was nearing completion, genome-sequencing pipelines had stabilized to the point that NHGRI was able to collect fairly reliable cost information from the major sequencing centers funded by the Institute. Based on these data, NHGRI estimated that the hypothetical 2003 cost to generate a 'second' reference human genome sequence using the then-available approaches and technologies was in the neighborhood of $50 million.

How much did it cost to sequence a human genome in 2006 (i.e., roughly a decade ago)?

Since the completion of the HGP and the generation of the first 'reference' human genome sequence, efforts have increasingly shifted to the generation of human genome sequences from individual people. Sequencing an individual's 'personal' genome actually involves establishing the identity and order of ~6 billion bases of DNA (rather than a ~3-billion-base 'reference' sequence; see above). Thus, the generation of a person's genome sequence is a notably different endeavor than what the HGP did.

Within a few years following the end of the HGP (e.g., in 2006), the landscape of genome sequencing was beginning to change. While revolutionary new DNA sequencing technologies, such as those in use today, were not quite implemented at that time, genomics groups continued to refine the basic methodologies used during the HGP and continued lowering the costs for genome sequencing. Considerable efforts were being made to the sequencing of nonhuman genomes (much more so than human genomes), but the cost-accounting data collected at that time can be used to estimate the approximate cost that would have been associated with human genome sequencing at that time.

Based on data collected by NHGRI from the Institute's funded genome-sequencing groups, the cost to generate a high-quality 'draft' human genome sequence had dropped to ~$14 million by 2006. Hypothetically, it would have likely cost upwards of $20-25 million to generate a 'finished' human genome sequence - expensive, but still considerably less so than for generating the first reference human genome sequence.

How much does it cost to sequence a human genome in 2016 (i.e., today)?

The decade following the HGP brought revolutionary advances in DNA sequencing technologies that are fundamentally changing the nature of genomics. So-called 'next-generation' DNA sequencing methods arrived on the scene, and their effects quickly became evident in terms of lowering genome-sequencing costs; note that these NHGRI-collected data are 'retroactive' in nature, and do not always accurately reflect the 'projected' costs for genome sequencing going forward).

In 2015, the most common routine for sequencing an individual's human genome involves generating a 'draft' sequence and comparing it to a reference human genome sequence, so as to catalog all sequence variants in that genome; such a routine does not involve any sequence finishing. In short, nearly all human genome sequencing in 2015 yields high-quality 'draft' (but unfinished) sequence. That sequencing is typically targeted to all exons (whole-exome sequencing) or aimed at the entire ~6-billion-base genome (whole-genome sequencing), as discussed above. The quality of the resulting 'draft' sequences is heavily dependent on the amount of average base redundancy provided by the generated data (with higher redundancy costing more).

Adding to the complex landscape of genome sequencing in 2015 has been the emergence of commercial enterprises offering genome-sequencing services at competitive pricing. Direct comparisons between commercial versus academic genome-sequencing operations can be particularly challenging because of the many nuances about what each includes in any cost estimates (with such details often not revealed by private companies). The cost data that NHGRI collects from its funded genome-sequencing groups includes information about a wide range of activities and components, such as: reagents, consumables, DNA-sequencing instruments, certain computer equipment, other equipment, laboratory pipeline development, laboratory information management systems, initial data processing, submission of data to public databases, project management, utilities, other indirect costs, labor, and administration. Note that such cost-accounting does not typically include activities such as quality assurance/quality control (QA/QC), alignment of generated sequence to a reference human genome, sequence assembly, genomic variant calling, or annotation. Almost certainly, companies vary in terms of which of the items in the above lists get included in any cost estimates, making direct cost comparisons with academic genome-sequencing groups difficult. It is thus important to consider these variables - along with the distinction between retrospective versus projected costs - when comparing genome-sequencing costs claimed by different groups. Anyone comparing costs for genome sequencing should also be aware of the distinction between 'price' and 'cost' - a given price may be either higher or lower than the actual cost.

Based on the data collected from NHGRI-funded genome-sequencing groups, the cost to generate a high-quality 'draft' whole human genome sequence in mid-2015 was just above $4,000; by late in 2015, that figure had fallen below $1,500. The cost to generate a whole-exome sequence was generally below $1,000. Commercial prices for whole-genome and whole-exome sequences have often (but not always) been slightly below these numbers.

Looking Ahead

Innovation in genome-sequencing technologies and strategies does not appear to be slowing. As a result, one can readily expect continued reductions in the cost for human genome sequencing. The key factors to consider when assessing the 'value' associated with an estimated cost for generating a human genome sequence - in particular, the amount of the genome (whole versus exome), quality, and associated data analysis (if any) - will likely remain largely the same. With new DNA-sequencing platforms anticipated in the coming years, the nature of the generated sequence data and the associated costs will likely continue to be dynamic. As such, continued attention will need to be paid to the way in which the costs associated with genome sequencing are calculated.

In 2003, an accurate and complete human genome sequence was finished and made available to scientists and researchers two years ahead of the original Human Genome Project schedule and at a cost less than the original estimated budget.

The Finished Genome Sequence

This international effort to sequence the 3 billion DNA letters in the human genome is considered by many to be one of the most ambitious scientific undertakings of all time, even compared to splitting the atom or going to the moon.

The finished sequence produced by the Human Genome Project covers about 99 percent of the human genome's gene-containing regions, and it has been sequenced to an accuracy of 99.99 percent. In addition, to help researchers better understand the meaning of the human genetic instruction book, the project took on a wide range of other goals, from sequencing the genomes of model organisms to developing new technologies to study whole genomes.

Besides delivering on the stated goals below, the international network of researchers has produced an amazing array of advances that most scientists had not expected until much later. These "bonus" accomplishments include: an advanced draft of the mouse genome sequence, published in December 2002; an initial draft of the rat genome sequence, produced in November 2002; the identification of more than 3 million human genetic variations, called single nucleotide polymorphisms (SNPs); and the generation of full-length complementary DNAs (cDNAs) for more than 70 percent of known human and mouse genes.

Achievements

Key Definitions

cDNA: cDNA stands for complementary DNA, a synthetic type of DNA generated from messenger RNA, or mRNA, the molecule in the cell that takes information from protein-coding DNA - the genes - to the protein-making machinery and instructs it to make a specific protein. By using mRNA as a template, scientists use enzymatic reactions to convert its information back into cDNA and then clone it, creating a collection of cDNAs, or a cDNA library. These libraries are important to scientists because they consist of clones of all protein-encoding DNA, or all of the genes, in the human genome.

cM: cM stands for centiMorgan, a unit of genetic distance. Generally, one centiMorgan equals about 1 million base pairs.

Eukaryotic: A eukaryote is a single-celled or multicellular organism whose cells contain a distinct membrane-bound nucleus. If something is described as "eukaryotic," it means that it has cells with membrane-bound nuclei.

Mb: Mb stands for megabase, a unit of length equal to 1 million base pairs and roughly equal to 1 cM.

Microarray: Microarrays are devices used in many types of large-scale genetic analysis. They can be used to study how large numbers of genes are expressed as messenger RNA in a particular tissue, and how a cell's regulatory networks control vast batteries of genes simultaneously. In microarray studies, a robot is used to precisely apply tiny droplets containing functional DNA to glass slides. Researchers then attach fluorescent labels to complementary DNA (cDNA) from the tissue they are studying. The labeled cDNA binds to its matched DNA sequence at a specific location on the slide. The slides are put into a scanning microscope that can measure the brightness of each fluorescent dot. The brightness reveals how much of a specific cDNA fragment is present, an indicator of how active a gene is.

Scientists use microarrays in many different ways. For example, microarrays can be used look at which genes in cells are actively making products under a specific set of conditions, as well as to detect and/or examine differences in gene activity between healthy and diseased cells.

Oligonucleotide: A short polymer of 10 to 70 nucleotides. A nucleotide is one of the structural components, or building blocks, of DNA and RNA. A nucleotide consists of a base chemical - either adenine (A), thymine (T), guanine (G) or cytosine (C) - plus a sugar-phosphate backbone. Oligonucleotides are often used as probes for detecting complementary DNA or RNA because they bind readily to their complements.

SNP: SNP stands for single nucleotide polymorphism. SNPs - pronounced "snips" - are common, but minute, variations that occur in the human genome at a frequency of one in every 300 bases. That means 10 million positions out of the 3 billion base-pair human genome have common variations. These variations can be used to track inheritance in families and susceptibility to disease, so scientists are working hard to develop a catalogue of SNPs as a tool to use in their efforts to uncover the causes of common illness like diabetes or heart disease.

STS: STS stands for sequence tagged site, a short DNA segment that occurs only once in a genome and whose exact location and order of bases is known. Because each is unique, STSs are helpful in chromosome placement of mapping and sequencing data from many different laboratories. STSs serve as landmarks on the physical map of a genome

Human Genome Project Timeline of Events

Completed in April 2003, the Human Genome Project gave us the ability to read nature's complete genetic blueprint for a human. This timeline lists key moments from the history of the project.

1984-86

In December 1984, the U.S. Department of Energy (DOE) and the International Commission for Protection against Environmental Mutagens and Carcinogens (ICPEMC) cosponsor "The Alta Summit," highlighting the growing role of recombinant DNA technologies. In May 1985, University of California, Santa Cruz Chancellor Robert Sinsheimer hold "The Santa Cruz Workshop" on human genome sequencing. In March 1986, the DOE Office of Health and Environmental Research hold the "Genome Sequencing Workshop" in Santa Fe, New Mexico, to assess the feasibility of pursuing a Human Genome Project.

1988

From Feb. 29 to March 1, 1988, NIH Director James Wyngaarden assembles scientists, administrators and science policy experts in Reston, Virginia, to lay out a plan for the Human Genome Project.

In April 1988, two published reports recommend creating an effort to sequence the human genome. The National Research Council Commission on Life Sciences, National Academy Press publishes "Mapping and Sequencing the Human Genome." The U.S. Congress Office of Technology Assessment publishes Mapping Our Genes—Genome Projects: How big? How fast?."

In October 1988, NIH and DOE sign a memorandum of understanding to "coordinate research and technical activities related to the human genome." Also, the Secretary of Health and Human Services (HHS) Otis R. Bowen creates the Office for Human Genome Research within the NIH Office of the Director James Wyngaarden.

1989

On Oct. 1, 1989, HHS creates the National Center for Human Genome Research (NCHGR) to carry out the NIH component of the United States Human Genome Project. The center's first director is James D. Watson, who co-discovered the double helical structure of DNA.

1989-1990

At its January 1989 meeting, the Program Advisory Committee on the Human Genome establishes a working group to develop a plan for the ethical, legal, and social implications component of the human genome program. This working group, later named the NIH-DOE Joint Working Group on Ethical, Legal, and Social Implications of Human Genome Research (ELSI Working Group), holds its first meeting in September 1989. In January, 1990, the working group issue its first report. In it, the working group agrees that the ELSI program should anticipate and address the implications for individuals and society of mapping and sequencing the human genome.

1990

In April 1990, NIH and DOE publish a plan for the first five years of an expected 15-year project. The goals of the project include mapping the human genome and determining the sequence of all its 3.2 billion letters; mapping and sequencing the genomes of other organisms important to the study of biology; and developing technology to analyze DNA. On Oct. 1, 1990, the project officially begins. NIH allocates the first funds to research grants aimed at developing the scientific approaches, technologies, and resources needed to map and sequence the human genome.

1992

On April 10, James Watson resigns as first director of NCHGR. NIH Director Bernadine Healy appoints Michael Gottesman, chief of laboratory of cell biology at the National Cancer Institute (NCI) as acting NCHGR director.

1993

Due to the rapid progress toward the goals established in 1990, NIH and DOE establish a new set of goals for the Human Genome Project in 1993 — two years ahead of schedule. The goals include creating detailed genetic and physical maps, developing efficient strategies for sequencing, and encouraging technology research through September 1998.

1994

In September 1994, the Human Genome Project meets its first mapping goal — a comprehensive human genetic linkage map. Genetic linkage maps show the relative order of and approximate spacing between specific DNA patterns, called markers, positioned on chromosomes. This genetic linkage map met one of the project's scientific goals a full year ahead of schedule. Genetic linkage maps are the first tool that researchers use to find a disease-causing gene. These maps identify the general area of the chromosome that contains the gene.

1995

In December 1995, the project met one of the its goals is to complete a physical map that contains actual, physical locations of identifiable landmarks on chromosomes . A physical map uses sequence-tagged sites as the landmarks to help order large segments of DNA. The map in 1995 is a significant milestone toward that goal. The physical map serves as a backbone for ultimately assembling the full human genome DNA sequence.

1996

In February 1996, Human Genome Project leaders meet in Bermuda at the first International Strategy Meeting on Human Genome Sequencing. They decide that all human genomic sequence information should be made freely available and placed in the public domain within 24 hours of being generated by federally funded large-scale human sequencing centers. The "Bermuda Principles" are drafted to encourage research and development, and to maximize the Human Genome Project's benefits to society. This contrasts with the standard practice in scientific research of making experimental data available only after its publication. These principles reshape the practices of an entire industry and establish rapid prepublication data release as the norm in genomics and other fields. Project leaders reconvene in Bermuda the following year to affirm these principles at the second International Strategy Meeting on Human Genome Sequencing.

1998

On Oct. 23, 1998, Science publishes the new NIH-DOE five-year plan for the Human Genome Project. Because all of the major goals of the previous five-year plan have been met, the new five-year plan predicts completion of human sequencing in 2003 — two years ahead of schedule. The plan reflects a commitment to generate a "working draft" of the human genome by 2001. It also notes that “because this [draft] sequence will have gaps, it will not be as useful as finished sequence for studying DNA features that span large regions or require high sequence accuracy over long stretches. Availability of the human sequence will not end the need for large-scale sequencing."

1999

In March 1999, the international Human Genome Project successfully completes the pilot phase of sequencing the human genome and the launch of the full-scale effort to sequence all 3 billion letters that make up the complete genetic blueprint for a human.

In May 1999, following a meeting at Cold Spring Harbor Laboratory, leaders of the International Human Genome Sequencing Consortium, comprised of 20 sequencing centers in the U.S. and around the globe, reaffirm their commitment to providing free, immediate and unrestricted access to human sequencing data. They also define powerful new ways to coordinate the worldwide effort to sequence the human genome. The group reiterates its commitment to place all sequence data in the public domain immediately and denounces the trend towards treating human genome sequence as a commodity.

In December 1999, an international team of researchers achieves the scientific milestone of unraveling the genetic code of an entire human chromosome for the first time. Researchers decipher the sequence of the 33.5 million letters that make up the DNA of chromosome 22. Seeing the organization of a human chromosome for the first time at this level paves the way for the rest of the Human Genome Project.

2000

On June 26, 2000, the International Human Genome Sequencing Consortium announces that it completed a working draft of the sequence of the human genome — the genetic blueprint for a human being. President Bill Clinton holds a ceremony at the White House to announce this achievement. The ceremony takes place in the East Room of the White House, where politicians, ambassadors, scientists, company executives, disease advocates and journalists gather to celebrate a major milestone for the project.

2001

On Feb. 12, 2001, the International Human Genome Sequencing Consortium announces the publication of a draft sequence and initial analysis of the human genome in the journal Nature. A wealth of information is obtained from the initial analysis of the human genome draft. For instance, the number of human genes is originally estimated to be about 35,000. (This is later revised to about 20,000.) Researchers also report that the DNA sequences of any two human individuals are 99.9% identical.

2003

On April 14, 2003, the International Human Genome Sequencing Consortium announces the successful completion of the Human Genome Project. This is more than two years ahead of schedule.

2004

On Oct. 20, 2004, the International Human Genome Sequencing Consortium publishes its scientific description of the finished human genome sequence.

Explore frequently asked questions and answers about the Human Genome Project and its impact on the field of genomics.

What is a genome?

A genome is an organism's complete set of deoxyribonucleic acid (DNA), a chemical compound that contains the genetic instructions needed to develop and direct the activities of every organism. DNA molecules are made of two twisting, paired strands. Each strand is made of four chemical units, called nucleotide bases. The bases are adenine (A), thymine (T), guanine (G) and cytosine (C). Bases on opposite strands pair specifically; an A always pairs with a T, and a C always with a G.

The human genome contains approximately 3 billion of these base pairs, which reside in the 23 pairs of chromosomes within the nucleus of all our cells. Each chromosome contains hundreds to thousands of genes, which carry the instructions for making proteins. Each of the estimated 30,000 genes in the human genome makes an average of three proteins.

What is DNA sequencing?

Sequencing means determining the exact order of the base pairs in a segment of DNA. Human chromosomes range in size from about 50,000,000 to 300,000,000 base pairs. Because the bases exist as pairs, and the identity of one of the bases in the pair determines the other member of the pair, scientists do not have to report both bases of the pair.

The primary method used by the HGP to produce the finished version of the human genetic code was map-based, or BAC-based, sequencing. BAC is the acronym for "bacterial artificial chromosome." Human DNA is fragmented into pieces that are relatively large but still manageable in size (between 150,000 and 200,000 base pairs). The fragments are cloned in bacteria, which store and replicate the human DNA so that it can be prepared in quantities large enough for sequencing. If carefully chosen to minimize overlap, it takes about 20,000 different BAC clones to contain the 3 billion pairs of bases of the human genome. A collection of BAC clones containing the entire human genome is called a "BAC library."

In the BAC-based method, each BAC clone is "mapped" to determine where the DNA in BAC clones comes from in the human genome. Using this approach ensures that scientists know both the precise location of the DNA letters that are sequenced from each clone and their spatial relation to sequenced human DNA in other BAC clones.

For sequencing, each BAC clone is cut into still smaller fragments that are about 2,000 bases in length. These pieces are called "subclones." A "sequencing reaction" is carried out on these subclones. The products of the sequencing reaction are then loaded into the sequencing machine (sequencer). The sequencer generates about 500 to 800 base pairs of A, T, C and G from each sequencing reaction, so that each base is sequenced about 10 times. A computer then assembles these short sequences into contiguous stretches of sequence representing the human DNA in the BAC clone.

Whose DNA was sequenced?

This was intentionally not known to protect the volunteers who provided DNA samples for sequencing. The sequence is derived from the DNA of several volunteers. To ensure that the identities of the volunteers cannot be revealed, a careful process was developed to recruit the volunteers and to collect and maintain the blood samples that were the source of the DNA.

The volunteers responded to local public advertisements near the laboratories where the DNA "libraries" were prepared. Candidates were recruited from a diverse population. The volunteers provided blood samples after being extensively counseled and then giving their informed consent. About 5 to 10 times as many volunteers donated blood as were eventually used, so that not even the volunteers would know whether their sample was used. All labels were removed before the actual samples were chosen.

What were the goals?

The main goals of the Human Genome Project were first articulated in 1988 by a special committee of the U.S. National Academy of Sciences, and later adopted through a detailed series of five-year plans jointly written by the National Institutes of Health and the Department of Energy. The principal goals laid out by the National Academy of Sciences were achieved, including the essential completion of a high-quality version of the human sequence. Other goals included the creation of physical and genetic maps of the human genome, which were accomplished in the mid-1990s, as well as the mapping and sequencing of a set of five model organisms, including the mouse. All of these goals were achieved within the time frame and budget first estimated by the NAS committee.

Notably, quite a number of additional goals not considered possible in 1988 have been added along the way and successfully achieved. Examples include advanced drafts of the sequences of the mouse and rat genomes, as well as a catalog of variable bases in the human genome.

What is a draft vs. finished genome sequence?

On June 26, 2000, the International Human Genome Sequencing Consortium announced the production of a rough draft of the human genome sequence. In April, 2003, the International Human Genome Sequencing Consortium is announcing an essentially finished version of the human genome sequence. This version, which is available to the public, provides nearly all the information needed to do research using the whole genome.

The difference between the draft and finished versions is defined by coverage, the number of gaps and the error rate. The draft sequence covered 90 percent of the genome at an error rate of one in 1,000 base pairs, but there were more than 150,000 gaps and only 28 percent of the genome had reached the finished standard. In the April 2003 version, there are less than 400 gaps and 99 percent of the genome is finished with an accuracy rate of less than one error every 10,000 base pairs. The differences between the two versions are significant for scientists using the sequence to conduct research.Who owns the human genome?

Who owns the human genome?

Every part of the genome sequenced by the Human Genome Project was made public immediately, and new information about the genome is posted almost every day in freely accessible databases or published in scientific journals (which may or may not be freely available to the public).

The Supreme Court ruled in 2013 that naturally occurring human genes are not an invention and therefore cannot be patented. However, private companies can apply for patents on edited or synthetic genes, which have been altered significantly from their natural versions to count as a new, patentable, product.

Who participated?

The Human Genome Project could not have been completed s quickly and as effectively without the strong participation of international institutions. In the United States, contributors to the effort include the National Institutes of Health (NIH), which began participation in 1988 when it created the Office for Human Genome Research, later upgraded to the National Center for Human Genome Research in 1990 and then the National Human Genome Research Institute (NHGRI) in 1997; and the U.S. Department of Energy (DOE), where HGP discussions began as early as 1984. However, almost all of the actual sequencing of the genome was conducted at numerous universities and research centers throughout the United States, the United Kingdom, France, Germany, Japan and China.

The International Human Genome Sequencing Consortium included:

• The Whitehead Institute/MIT Center for Genome Research, Cambridge, Mass., U.S.
• The Wellcome Trust Sanger Institute, The Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, U. K.
• Washington University School of Medicine Genome Sequencing Center, St. Louis, Mo., U.S.
• United States DOE Joint Genome Institute, Walnut Creek, Calif., U.S.
• Baylor College of Medicine Human Genome Sequencing Center, Department of Molecular and Human Genetics, Houston, Tex., U.S.
• RIKEN Genomic Sciences Center, Yokohama, Japan
• Genoscope and CNRS UMR-8030, Evry, France
• GTC Sequencing Center, Genome Therapeutics Corporation, Waltham, Mass., USA
• Department of Genome Analysis, Institute of Molecular Biotechnology, Jena, Germany
• Beijing Genomics Institute/Human Genome Center, Institute of Genetics, Chinese Academy of Sciences, Beijing, China
• Multimegabase Sequencing Center, The Institute for Systems Biology, Seattle, Wash.
• Stanford Genome Technology Center, Stanford, Calif., U.S.
• Stanford Human Genome Center and Department of Genetics, Stanford University School of Medicine, Stanford, Calif., U.S.
• University of Washington Genome Center, Seattle, Wash., U.S.
• Department of Molecular Biology, Keio University School of Medicine, Tokyo, Japan
• University of Texas Southwestern Medical Center at Dallas, Dallas, Tex., U.S.
• University of Oklahoma's Advanced Center for Genome Technology, Dept. of Chemistry and Biochemistry, University of Oklahoma, Norman, Okla., U.S.
• Max Planck Institute for Molecular Genetics, Berlin, Germany
• Cold Spring Harbor Laboratory, Lita Annenberg Hazen Genome Center, Cold Spring Harbor, N.Y., U.S.
• GBF - German Research Centre for Biotechnology, Braunschweig, GermanyHow much did it cost U.S. taxpayers?

How much did it cost?

In 1990, Congress established funding for the Human Genome Project and set a target completion date of 2005. Although estimates suggested that the project would cost a total of $3 billion over this period, the project ended up costing less than expected, about $2.7 billion in FY 1991 dollars. Additionally, the project was completed more than two years ahead of schedule.

It is also important to consider that the Human Genome Project will likely pay for itself many times over on an economic basis - if one considers that genome-based research will play an important role in seeding biotechnology and drug development industries, not to mention improvements in human health.Why does NHGRI study ethical implications?

Why does NHGRI study ethical issues?

Since the beginning of the Human Genome Project, it has been clear that expanding our knowledge of the genome would have a profound impact on individuals and society. The leaders of the Human Genome Project recognized that it would be important to address a wide range of ethical and social issues related to the acquisition and use of genomic information, in order to balance the potential risks and benefits of incorporating this new knowledge into research and clinical care. The Ethical, Legal, and Social Implications (ELSI) program at NHGRI was established in 1990 to oversee research in these areas.

The United States Congress mandates that no less than five percent of the annual NHGRI budget is dedicated to studying the ethical, legal and social implications of human genome research, as well as recommending policy solutions and stimulating public discussion. The ELSI program at NHGRI, which is unprecedented in biomedical science in terms of scope and level of priority, provides an effective basis from which to assess the implications of genome research.

Since its inception the ELSI program at NHGRI has made several notable contributions to the genomics field. Among these are major changes to the way investigators and institutional review boards handle the consent process for genomics studies. Another is key guidance on the NIH’s genomic data sharing policy, notably the need to balance open science with personal privacy and autonomy. The ELSI program has been effective in promoting dialogue about the implications of genomics, and shaping the culture around the approach to genomics in research, medical, and community settings.

What is the future of medical science?

Having the essentially complete sequence of the human genome is similar to having all the pages of a manual needed to make the human body. The challenge to researchers and scientists now is to determine how to read the contents of all these pages and then understand how the parts work together and to discover the genetic basis for health and the pathology of human disease. In this respect, genome-based research will eventually enable medical science to develop highly effective diagnostic tools, to better understand the health needs of people based on their individual genetic make-ups, and to design new and highly effective treatments for disease.

Individualized analysis based on each person's genome will lead to a very powerful form of preventive medicine. We'll be able to learn about risks of future illness based on DNA analysis. Physicians, nurses, genetic counselors and other health-care professionals will be able to work with individuals to focus efforts on the things that are most likely to maintain health for a particular individual. That might mean diet or lifestyle changes, or it might mean medical surveillance. But there will be a personalized aspect to what we do to keep ourselves healthy. Then, through our understanding at the molecular level of how things like diabetes or heart disease or schizophrenia come about, we should see a whole new generation of interventions, many of which will be drugs that are much more effective and precise than those available today.

How did it impact research?

Biological research has traditionally been a very individualistic enterprise, with researchers pursuing medical investigations more or less independently. The magnitude of both the technological challenge and the necessary financial investment prompted the Human Genome Project to assemble interdisciplinary teams, encompassing engineering and informatics as well as biology; automate procedures wherever possible; and concentrate research in major centers to maximize economies of scale.

As a result, research involving other genome-related projects (e.g., the International HapMap Project to study human genetic variation and the Encyclopedia of DNA Elements, or ENCODE, project) is now characterized by large-scale, cooperative efforts involving many institutions, often from many different nations, working collaboratively. The era of team-oriented research in biology is here.

In addition to introducing large-scale approaches to biology, the Human Genome Project has produced all sorts of new tools and technologies that can be used by individual scientists to carry out smaller scale research in a much more effective manner.