Human Genome Project (1990-2003): Mapping Human DNA

The Human Genome Project was an international scientific effort, formally launched in October 1990 and declared essentially complete in April 2003, to read the full sequence of human DNA. Laboratories in six countries worked out the order of roughly three billion chemical “letters” that make up the human genetic code and released the data freely. The project transformed biology and medicine and led to a race with a private company that made headlines worldwide.

Background: from the double helix to sequencing

In 1953 James Watson and Francis Crick described the double helix structure of DNA, showing how genetic information is stored in a sequence of four chemical bases: adenine (A), cytosine (C), guanine (G) and thymine (T). In 1977 the British biochemist Frederick Sanger and, separately, Allan Maxam and Walter Gilbert in the United States developed methods to read short stretches of DNA.

By the mid-1980s some scientists began to imagine reading the entire human genome. Meetings at the University of California, Santa Cruz in 1985 and a workshop organised by the US Department of Energy (DOE) in Santa Fe in 1986 discussed the idea. The DOE was interested because of its long-standing research on how radiation damages genes.

Many biologists were sceptical. They feared a huge, dull project would drain money from other research, and much of the genome was then thought to be “junk”. A 1988 report by the US National Research Council endorsed the plan, recommending that it should also map simpler organisms and improve technology.

Launching the project

The US National Institutes of Health (NIH) and the DOE began the Human Genome Project on 1 October 1990, with a plan to finish in 15 years at a cost of about 3 billion dollars. James Watson, co-discoverer of the double helix, led the NIH’s genome effort from 1988 until 1992. The geneticist Francis Collins, known for finding the gene for cystic fibrosis, took over in 1993.

From the start the project set aside a share of its budget, about 3 to 5 percent, for research on ethical, legal and social issues, such as genetic privacy and discrimination. This was the largest commitment of its kind in science up to that time.

Other countries soon joined. The Wellcome Trust funded the Sanger Centre near Cambridge, England, led by John Sulston, which went on to sequence nearly a third of the genome. Centres in Japan, France, Germany and China also took part, together forming the International Human Genome Sequencing Consortium of about 20 institutions.

Method and early years

The public project followed a cautious strategy. It first built maps of the genome, then broke DNA into large pieces of known position, copied them in bacteria and sequenced each piece in turn. Early work concentrated on mapping and on sequencing smaller genomes, including those of yeast, the roundworm C. elegans (completed in 1998) and the fruit fly.

In 1996 leaders of the consortium met in Bermuda and agreed the Bermuda Principles: all sequence data would be released to public databases within 24 hours. This commitment to open data became one of the project’s defining features.

Sequencing machines improved rapidly. Automated capillary sequencers, introduced in the late 1990s, could read DNA far faster than earlier gel-based methods, and large “genome centres” ran hundreds of them around the clock.

The basic technique remained the method developed by Frederick Sanger, known as chain-termination sequencing. Copies of a DNA fragment were made in which each chain stopped at a particular letter, marked with a fluorescent dye. Lasers in the sequencing machines read the colours as the fragments passed through thin capillary tubes, producing reads of several hundred letters at a time. Computers then had to assemble millions of these overlapping reads into a continuous sequence, a task that made bioinformatics a major discipline in its own right.

The race with Celera

In May 1998 the biologist Craig Venter announced that a new company, Celera Genomics, backed by the instrument maker PerkinElmer, would sequence the human genome within three years. Celera planned to use a “whole-genome shotgun” approach, breaking the entire genome into millions of small random fragments and reassembling them by computer.

The announcement caused alarm that Celera might patent genes or control access to the data. The public consortium, with extra funding from the Wellcome Trust and the NIH, accelerated its timetable and decided to produce a rough “working draft” first.

The competition became bitter and was widely reported. In the end, under political pressure, the two sides agreed to announce their results together. On 26 June 2000, at the White House, President Bill Clinton, joined by British Prime Minister Tony Blair by video link, announced that both teams had completed working drafts of the human genome.

The dispute also had a commercial side. Celera planned to sell access to its data through subscriptions, while it could also draw on the public consortium’s freely released sequence. On 14 March 2000 President Clinton and Prime Minister Blair issued a joint statement saying that raw data on the human genome should be freely available to scientists everywhere. Share prices of several biotechnology companies fell sharply in the days that followed, although the statement did not ban patents on genuine inventions based on genes.

Drafts and completion

The draft sequences were published in February 2001: the public consortium’s in the journal Nature and Celera’s in Science. Both covered about 90 percent of the genome but contained many gaps and errors.

The consortium continued to refine its sequence. On 14 April 2003, close to the 50th anniversary of the double helix paper, it announced that the Human Genome Project was complete. The finished sequence covered about 99 percent of the gene-containing regions with an accuracy of better than 99.99 percent, and the project came in under budget and about two years early.

What the genome revealed

The most surprising finding was the small number of genes. Earlier estimates had ranged as high as 100,000, but the sequence pointed to about 20,000 to 25,000 protein-coding genes; later analyses put the number close to 20,000. That is similar to a roundworm or a mouse, suggesting that human complexity comes largely from how genes are regulated and combined.

Only about 1 to 2 percent of the genome codes for proteins. Around half consists of repeated sequences, many of them remnants of ancient viruses and mobile genetic elements. Any two people share roughly 99.9 percent of their DNA sequence.

Key people

• James Watson: first director of the NIH genome programme, 1988-1992.
• Francis Collins: director of the US National Human Genome Research Institute from 1993, leader of the public project.
• John Sulston: director of the Sanger Centre and a leading advocate of free data.
• Craig Venter: founder of Celera Genomics and pioneer of shotgun sequencing.
• Eric Lander: head of the Whitehead Institute/MIT genome centre, the largest US contributor.

Consequences and legacy

The Human Genome Project created a reference sequence that underpins almost all modern biology. It enabled the search for genes linked to thousands of diseases, the development of genetic tests and targeted cancer drugs, and new fields such as personal genomics and studies of human ancestry.

The cost of sequencing a human genome fell dramatically, from roughly 100 million dollars around 2001 to about a thousand dollars by the late 2010s. Large projects such as HapMap and the 1000 Genomes Project mapped human genetic variation, and in 2008 the United States passed the Genetic Information Nondiscrimination Act to protect people from genetic discrimination in health insurance and employment.

Some regions, particularly highly repetitive parts near the centres and ends of chromosomes, could not be read with the technology of 2003. In 2022 the Telomere-to-Telomere consortium used new long-read sequencing methods to publish the first gapless sequence of a human genome.

Concerns raised by the project’s ethics programme remain live. They include who may see a person’s genetic information, how genetic tests should be explained to patients, and the risk that genetic differences could be misused to support discrimination, as the eugenics movements of the early twentieth century had done. The project also renewed interest in older work on inheritance, from Gregor Mendel’s pea experiments onward, and came only a few years after the cloning of Dolly the sheep had shown how much could be done with a cell’s DNA.

Myths and facts

• Myth: the project sequenced one person’s DNA. The reference was a composite from several anonymous donors, though a large share came from one individual.
• Myth: the genome was finished in 2000. The 2000 announcement covered rough drafts; the finished reference came in 2003, and full completion only in 2022.
• Myth: knowing the sequence means understanding it. Scientists are still working out what many genes and regulatory regions do.

Timeline

• 1953: Watson and Crick describe the structure of DNA.
• 1977: Sanger and others develop practical DNA sequencing methods.
• 1990, 1 October: The Human Genome Project formally begins in the United States.
• 1996, February: The Bermuda Principles commit the project to rapid public release of data.
• 1998, May: Craig Venter announces the founding of Celera Genomics.
• 2000, 26 June: Working drafts are announced at the White House.
• 2001, February: Draft sequences are published in Nature and Science.
• 2003, 14 April: The consortium announces the completed human genome sequence.
• 2022: The Telomere-to-Telomere consortium publishes a gapless human genome.

Why it matters

The Human Genome Project gave humanity its first full reading of its own genetic instructions and established the principle that such basic data should be shared freely. It opened the way to genomic medicine and to a deeper understanding of human evolution, health and diversity.