Human Genome Project

I

Introduction

Human Genome Project, international scientific collaboration that seeks to understand the entire genetic blueprint of a human being (see Genetics). This genetic information is found in each cell of the body, encoded in the chemical deoxyribonucleic acid (DNA). Through a process known as sequencing, the Human Genome Project has identified nearly all of the estimated 20,000 to 25,000 genes (the basic units of heredity) in the nucleus of a human cell. The project has also mapped the location of these genes on the 23 pairs of human chromosomes, the structures containing the genes in the cell’s nucleus.

The data derived from mapping and sequencing the human genome will help scientists associate specific human traits and inherited diseases with particular genes at precise locations on the chromosomes. This advance will help provide an unparalleled understanding of the fundamental organization of human genes and chromosomes. Many scientists believe that the Human Genome Project has the potential to revolutionize both therapeutic and preventive medicine by providing insights into the basic biochemical processes that underlie many human diseases.

The idea of undertaking a coordinated study of the human genome arose from a series of scientific conferences held between 1985 and 1987. The Human Genome Project began in earnest in the United States in 1990 with the expansion of funding from the National Institutes of Health (NIH) and the Department of Energy (DOE). One of the first directors of the U.S. program was American biochemist James Watson, who in 1962 shared the Nobel Prize for physiology or medicine with British biophysicists Francis Crick and Maurice Wilkins for the discovery of the structure of DNA. Many nations have official human genome research programs as part of this collaboration, including the United Kingdom, France, Germany, and Japan. In a separate project intended to speed up the sequencing process and commercialize the results, Celera Genomics, a privately funded biotechnology company, used a different method to assemble the sequence of the human genome. Both the public consortium and Celera Genomics completed the first phase of the project, and they each published a draft of the human genome simultaneously, although in separate journals, in February 2001. Scientists from the public consortium completed the final sequencing of the human genome in April 2003.

II

The Structure of DNA

The most important component of a chromosome is the single continuous molecule of DNA. This double-stranded molecule, shaped like a twisted ladder, is composed of linked chemical compounds known as nucleotides. Each nucleotide consists of three parts: a sugar known as deoxyribose, a phosphate compound, and any one of four bases—adenine, thymine, guanine, or cytosine. These parts are linked together so that the sugar and the phosphate form the two parallel sides of the DNA ladder. The bases from each side join in pairs to form the rungs of the ladder—specifically, adenine always pairs with thymine, and guanine always pairs with cytosine.

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The genetic code is specified by the order of adenines, thymines, guanines, and cytosines in the DNA ladder. A particular section of the DNA ladder usually has a unique sequence of base pairs. Because a gene is merely one of these sections of the DNA ladder, it too possesses a unique sequence of base pairs, and this sequence can be used to distinguish the gene from other genes and to map its location on the chromosome.

III

The Human Genome

A genome is the complete collection of an organism’s genetic material. The human genome is composed of about 20,000 to 25,000 genes located on the 23 pairs of chromosomes in a human cell. A single human chromosome may contain more than 250 million DNA base pairs, and scientists estimate that the entire human genome consists of about 3 billion base pairs.

The DNA analyzed in the Human Genome Project came from small samples of blood or tissue obtained from many different people. Although the genes in each person’s genome are made up of unique DNA sequences, the average variation in the genomes of two different people is estimated to be 0.05 to 0.1 percent. That is, approximately 1 in 1,000 to 1 in 2,000 nucleotides will be different from one individual to another. Thus the differences between human DNA samples from various sources are small in comparison to their similarities.

IV

Mapping and Sequencing

There are two main categories of gene-mapping techniques: linkage, or genetic, mapping, a method that identifies only the relative order of genes along a chromosome; and physical mapping, more precise methods that can place genes at specific distances from one another on a chromosome. Both types of mapping use markers in the DNA sequence, detectable physical or molecular characteristics that differ among individuals and that are passed from one generation to the next.

Linkage mapping was developed in the early 1900s by American geneticist Thomas Hunt Morgan. By observing how frequently certain characteristics were inherited in combination in numerous generations of fruit flies, he concluded that traits that were often inherited in combination must be associated with genes that were near one another on the chromosome. From his studies, Morgan was able to create a rough map showing the relative order of these associated genes on the chromosomes, and in 1933 he was awarded the Nobel Prize for physiology or medicine for his work.

Human linkage maps are created mainly by following inheritance patterns in large families over many generations. Originally, these studies were limited to inherited physical traits that could be observed easily in each family member. Today, however, sophisticated laboratory techniques allow researchers to create more detailed linkage maps by comparing the position of the target gene relative to the order of genetic markers, or specific known segments of DNA.

Physical mapping determines the physical distance between landmarks on the chromosomes. The most precise physical mapping techniques combine robotics, lasers, and computers to measure the distance between genetic markers. For these maps, DNA is extracted from human chromosomes and randomly broken into many pieces. The DNA fragments are then duplicated numerous times in the laboratory so that the resulting identical copies, called clones, can be tested individually for the presence or absence of specific genetic landmarks. Those clones that share several landmarks are likely to come from overlapping segments of the chromosome. The overlapping regions of the clones can then be compared to determine the overall order of the landmarks along the chromosome and the exact sequence in which the cloned pieces of DNA originally existed in the chromosome.

Very detailed physical maps that indicate the precise order of cloned pieces of a chromosome are usually required to determine the actual sequence of nucleotides. The Human Genome Project most commonly used the DNA sequencing method developed by British biochemist and two-time Nobel laureate Frederick Sanger. In Sanger’s method, specific pieces of DNA are replicated and modified so that each ends in a fluorescent form of one of the four nucleotides. In modern automated DNA sequencers, pioneered by American molecular biologist Leroy E. Hood, the modified nucleotide at the end of such a chain is detected with a laser, and the exact number of nucleotides in the chain is determined. This information is then combined by computer to reconstruct the sequence of base pairs in the original DNA molecule.

Duplicating DNA accurately and quickly is of critical importance to both mapping and sequencing. Scientists first replicated fragments of human DNA by cloning them in single-celled organisms that divide rapidly, such as bacteria or yeast. This technique can be time consuming and labor intensive. In the late 1980s, however, a revolutionary method of reproducing DNA, known as the polymerase chain reaction (PCR), came into widespread use. PCR is easily automated and can copy a single molecule of DNA many millions of times in a few hours. In 1993 American biochemist Kary Mullis was awarded the Nobel Prize for chemistry for developing this technique.

American molecular biologist J. Craig Venter, founder of Celera Genomics, and American molecular biologist Hamilton O. Smith developed an alternative approach that determines and assembles the sequence of entire genomes without the laborious and time-consuming physical mapping phase. Since 1995 their approach has been used to sequence the genomes of a number of bacteria, the fruit fly Drosophila melanogaster, and the human genome.

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