The Human Genome Project

The Human Genome Project is the first large international effort in the history of biological research.7 The overall objective of the Human Genome Project was to determine the sequence of the bases throughout each chromosome of the human genome, which is a total of 3 billion bases. The Human Genome Project was initiated on October 1, 1990, to be completed in the year 2005.8 The National Institutes of Health and the Department of Energy in the United States are expected to produce 60 to 70 percent of the sequences, with the remainder from the Sanger Institute, at Cambridge, England, and other international partners.7 However, with improvements in technology and increasing demands, the timetable has been accelerated. Initially, the Human Genome Project announced that it would have all of the genes sequenced by the year 2003, and most recently it was announced that a rough draft of 90 percent of the human sequences will be available by the spring of 2000.7 At least two commercial enterprises involved in sequencing human genes have claimed they will have all of the human genes sequenced by the year 2001.9 Regardless of the precise timetable and whether every gene is to be identified as indicated, it is now evident there will be an avalanche of genes available to the cardiologist within the next 2 to 3 years. At the end of 1999, only one-third of the human genome was sequenced, and there were less than 1000 human genes available in GenBank. There will be at least 20,000 to 30,000 genes, if not more, available within the first couple of years of the new millenium. It is part of the policy of the Human Genome Project that all of these genes will be available to the public. As it is sequenced, each gene is entered into a publicly accessible database and available at no cost. In the United States, GenBank (accessible at ;H; run by the National Center for Biotechnology Information, serves as the public repository of sequence information. The results of the efforts of the publicly funded Human Genome Project consist not only of DNA sequences of the various genes but also of the intervening sequences. In addition, each sequence is anchored to one of the known genetic markers, integrating the physical and genetic maps. The first chromosome to be sequenced was chromosome 22, which was announced in November 1999. Investigators from Great Britain, the United States, and Japan teamed up to sequence 32,000,000 bases. While there remain some gaps, there is general agreement that essentially all of the genes of chromosome 22, together with most of the intervening sequences, have been sequenced.40

Charles Delisi, of the Department of Energy, in commenting on the initiation of the Human Genome Project, stated that the goal was to decipher the blueprint for the development of a single fertilized egg into a complex organism of more than 1013 cells. The blueprint is written in a coded message given by the sequence of nucleotide bases-the As, Cs, Gs, and Ts-that are strung along the DNA molecules in the human genome. The goal was to sequence from one end to the other and then to try to decipher all of the instructions included in this massive coding sequence. In 1990, the best of the laboratories were probably sequencing only a few hundred bases per day; at that rate, it would have required centuries to complete the human genome. However, technological improvements have enabled some laboratories engaged in the Human Genome Project to sequence more than 1 million bases per day. While the overall objective was to sequence the human genome, other goals completed along the way markedly accelerated the efforts of all investigators involved in biological or medical research. The first goal was to develop a genetic map. This meant developing markers along each chromosome that would be readily identifiable and highly informative signposts for the identification of nearby genes. This goal has now been achieved. Investigators in France and the United States published 6000 markers spaced less than 1 million base pairs apart throughout the entire human genome.!! Thus, a complete set of genetic markers is now available for each chromosome. This provided the necessary tool for widespread application of genetic linkage analysis, a technique that has led to the mapping of numerous genes responsible for disease of the cardiovascular system (Chap. 62) and other organs.

The next goal was to develop a genomic physical map. This map would involve sequence tagged sites (STSs) throughout the genome that has been completed.12 Over 50,000 STSs were given their approximate chromosomal location which made it possible to relate them to the location of a locus genetically linked to a disease of interest.13 The next goal was to develop a physical map of that part of the DNA that is expressed as genes. These markers are referred to as expressed sequence tags (ESTs) and contain short sequences of 200 to 300 base pairs. These sequences are unique and believed to represent a specific gene. If, indeed, each one of these ESTs represents a gene, we are at present in the position of having available 60,000 genes to be identified.14 One may wonder how it is possible to obtain such ESTs and be certain that they represent only sequences that are expressed in genes. As indicated previously, all genes are first synthesized as single-stranded mRNA that leaves the nucleus to travel to the ribosome in the cytoplasm, where it serves as a template for its unique protein product. Thus, if one extracted all of the RNA in the cell, it would include all of the mRNAs and, thus, at that moment in time, all of the genes expressed in that cell. This is, in fact, the approach for obtaining ESTs: mRNA is isolated from cells of all organs in the body, and collectively they represent all of the body's expressed genes. The mRNA is then converted to complementary deoxyribonucleic acid (cDNA) with the enzyme reverse transcriptase, and sequences from these cDNAs are amplified by polymerase chain reaction. From these amplified sequences, unique sequences are selected and entered into GenBank as ESTs. These ESTs are cloned in vehicles such as bacteria and, thus, provide a library of human ESTs. Many of these ESTs are now being mapped to their chromosomal location to be used as markers to find genes responsible for disease. The ultimate aim is to have an EST every 100,000 base pairs evenly distributed throughout the 23 chromosomes. The development of the genetic map and that of the physical map, which followed, were great contributions that have tremendously accelerated the efforts of all investigators throughout the world in identifying genes responsible for disease.


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