Abstract:

The genome denotes the entire DNA content present in a cell. Advances in DNA sequencing technology led scientists to think about the large-scale genome sequencing projects. The Human Genome Project (HGP) was one of the most ambitious and controversial biological projects ever. In this chapter, the goals, the challenges and the institutions involved in the HGP are discussed.

Key words

DOE

ELSI

genome

genome project

genomics

HGP

human genome

HUGO

NIH

It is essentially immoral not to get it [the human genome sequence] done as fast as possible

James D. Watson

Key concepts

•. The Human Genome Project (HGP) was conceived and initiated by the Department of Energy (DOE) in the USA in 1985. Officially, the HGP started in 1990 for a period of 15 years.

•. The National Institute of Health (NIH) and the DOE took the initiative to fund the project. Along with these two agencies, 25 laboratories in five countries were also involved in this project.

•. The estimated cost of the project was US$200 million per year for 15 years.

•. The ultimate aim of the HGP was to determine the order of the 3 billion nucleotides that make up the human genome.

•. ELSI related to human genome sequencing was seriously considered and 2 per cent of the money allocated was spent on this.

•. Only 1–2 per cent of the human genome contains the protein coding DNA sequences; the remaining 98 per cent of the genome is made up of repeat sequences whose function is yet to be elucidated.

•. The human genome consists of 23 pairs of chromosomes. Each chromosome contains euchromatic and heterochromatic regions. The DNA present in the euchromatic region is sequenced, and it is about 2.91 billion base pairs.

•. Initially, the publicly funded NIH group was carrying out the sequencing of the human genome; later, a privately funded institute, Celera genomics, also started sequencing it. Both these groups reported the sequence of the human genome in 2003.

2.1 The history of the HGP

The Human Genome Project (HGP) is one of the largest biological projects ever in human history. It is an attempt by human beings to map their own genome. The scientific thinking on sequencing of the human genome has its roots in the post-Second World War effects of atomic bombs which were dropped on Japan, on Hiroshima and Nagasaki, on the 5th and 6th August 1945, respectively. Reports and scientific studies on the post-war effects on the Japanese population due to atomic radiation were undertaken. Many studies were carried out throughout the world on the survivors of the Japanese atomic bomb explosion. After many years of study it is now understood that the effects of radiation are limited not only to the current population, they have also been transmitted to the following generations. It has been conclusively shown that radiation has a major effect on the genetic make-up of living organisms. Reports show that the incidence of cancer is higher in residents of Hiroshima and Nagasaki than in the rest of the Japanese population. Therefore, many studies were undertaken on the radiation damage to the human genetic material and its ill-effects on subsequent generations.

The Department of Energy (DOE), in the USA, and the International Commission for Protection Against Environmental Mutagens and Carcinogens jointly organized a meeting on 9–13 December 1984 in Alta, Utah, to discuss the serious issues related to environmental mutagens and their effect on the tiny but very important human biomolecule, i.e. DNA. The specific aim of the meeting was to develop techniques to detect mutations in the survivors of Hiroshima and Nagasaki atomic bomb explosions. Discussions were also undertaken on the possibilities of reading the human genetic material and understanding its interaction with the mutagens. This meeting ignited the idea of the HGP. A meeting was organized at the University of California, Santa Cruz, under the chairmanship of well-known molecular biologist, Robert L. Sinsheimer in 1985, which also discussed the possibility of sequencing the human genome. In 1986, Charles DeLisi, a biophysicist and administrator of the Health and Environmental Research Committee (HERAC) of the DOE, convened a meeting on the possibility of sequencing the human genome and transformed the idea into reality by proposing a three-point programme which included genome mapping, sequencing, and computer-aided arrangement of the sequences. He prepared a document entitled ‘Human Genome Initiative’ and submitted it to the Office of Technology Assessment (OTA) for approval. After a year-long debate on various aspects, the National Research Council of the USA recommended a multi-phased research project. In 1988, the US Congress approved the HGP and the fund was allocated through the NIH and DOE budget. The HGP officially started in 1990 and the duration of the project was fixed for 15 years. The International Human Genome Sequencing Consortium (IHGSC) was established to coordinate the HGP operations in different institutions throughout the world.

Map-based cloning sequencing strategy was followed by the publicly funded project. This method is known as BAC-based method or clone-by-clone sequencing method. In 1998, a privately funded organization led by Dr Craig J. Venter also started human genome sequencing using a separate strategy in which sequencing was done without preparing a high density map, and this is known as the ‘shotgun method’ of sequencing. It became a competition between the publicly funded HGP and the privately funded HGP to complete the human genome sequence. But later both agencies agreed to work together and jointly announced the completion of the human genome sequence in 2003. The HGP was completed two years ahead of the planned schedule.

The HGP was initially headed by J. D. Watson and later headed by Francis S. Collins, the Director of the NIH. The draft sequence was released in 2000 and the completed sequence was released in 2003. Subsequently, the IHGSC finished genome sequencing with many gaps and the completely assembled human genome sequence was released, covering 99 per cent of the euchromatic region. With an error rate of 1 error per 100,000 bases, 2,851,330,913 nucleotides were sequenced. The human genome sequence is deposited in NCBI Human Build 35 denoted as NC000001-NC000024.

2.2 The budget for the HGP

When the human genome project was aired, many scientists argued that it was unnecessary to sequence the entire genome as it involved a lot of money. Therefore, specific objectives were developed which involved the most efficient techniques which would cost less. The initial estimate for the HGP was US$200 million per year for 15 years. Rapid progress was made in mapping and sequencing techniques which paved the way for the completion of the HGP ahead of its target schedule 2005. Therefore, the project cost was less than what had been expected. The budget of the HGP was only approximately US$2.7 billion instead of US$3.0 billion. About 50 per cent of the fund was provided by the USA and the rest came from other countries, mainly the UK, France, Germany, Japan, Australia, and Canada. In 1988, the Office of Technology Assessment sanctioned funds for the HGP through the NIH and DOE, which were US$17.3 million and US$11.8 million, respectively.

2.3 Goals of the HGP

The idea behind the HGP was to learn the genetic mechanisms that control the human development from zygote, its interactions with the environment, genetic disorders, the aging process, etc. It is impossible to understand all these in a single experiment. Therefore, specified goals for the HGP were established which covered not only the issues which were related directly to the human being but also addressed other related problems. When the HGP started, available mapping and sequencing technologies were not advanced enough to sequence the 3 billion bases of the human genome in the specified time frame. They were costly, slow, and not accurate. Therefore, specific goals were set to increase the...