Human Genome Project

Background

The Human Genome Project was an international collaboration to map all the genetic information found in humans and several organisms of importance in biological research.

From 1990 to 2003, more than 2,000 scientists from universities and research facilities worldwide sequenced more than 3 billion base pairs of a genetic tapestry built from 20 individuals.

The $2.7B project produced a reference human genome that could be used to identify gene variants responsible for diseases, opening the door to personalized gene therapy.

History

The HGP was proposed in the mid-1980s as a joint initiative by the National Institutes of Health and the US Department of Energy (see timeline).

The NIH was interested in finding the genetic mechanisms behind illnesses—a connection first established by scientists when they identified alkaptonuria as a genetic disorder in 1902.

The DOE saw the HGP as a step toward developing methods to determine the genetic risks of radiation and chemicals related to energy production (read the initial project goals here).

With funding allocated by Congress for genome sequencing—determining the order of nucleotide bases in a DNA molecule—of humans and several model organisms, including E. coli, the fruit fly, and the mouse, the HGP began October 1, 1990.

Throughout the project, data was added in real-time to GenBank as the genomes were processed in 20 universities and research centers across the US, the UK, China, France, Germany, and Japan.

Methodology

To obtain human DNA samples, HGP scientists recruited 20 volunteers from Buffalo, New York, to donate blood to the Roswell Park Comprehensive Cancer Center, which had experience in preparing DNA for sequencing.

Although the original plan had been to take no more than 10% of the genome from any one individual (from which a composite human genome would be created), 70% of the eventual reference sequence was made from one donor, codenamed RP11 (listen to the ethics of this decision here).

The patchwork genome then underwent hierarchical shotgun sequencing. This process used restriction enzymes—"molecular scissors," so to speak—to cut the genome into overlapping fragments 150,000 base pairs long, which were then inserted into bacteria for replication.

Different bacteria were shipped to different sequencing centers, where the fragments were cut into smaller pieces before Sanger sequencing was used to determine the order of nucleotides in each piece (watch explainer). The sequencing data from each piece was then combined to reassemble the entire genome.

This approach was also followed for model organism genomes, with all pieces being sequenced multiple times to catch errors and identify discrepancies.

Results and Impacts

A working draft of the human genome was announced June 26, 2000, and its subsequent initial analysis revealed humans to have about 35,000 genes (later revised to 20,000).

A final version was published three years later, marking the 50th anniversary of the discovery of DNA’s double helix structure. Although this version only covered 92% of the human genome sequence, additional coverage was not possible until 2022, when new sequencing technologies were developed.

Beyond creating the foundation for future gene discoveries, the HGP is credited with accelerating bioinformatics by forcing the development of genome browsers and databases and promoting faster, less expensive sequencing methods.

It also spun off several genomic projects aimed at improving cancer diagnosis, finding alternative energy sources, exploring the effects of microbial cells, and more.