"All human disease is genetic in origin,'' Nobel laureate Paul Berg of Stanford University told a cancer symposium a few years ago.

Berg was exaggerating, but only slightly. It has become increasingly evident that virtually all human afflictions, from cancer to psychiatric disorders and susceptibility to infection, are rooted in our genes. "What we need to do now is find those genes," says James Watson, who shared a Nobel Prize for deciphering the structure of DNA.

Mapping the human genome actually began in 1911, when the gene responsible for red-green color blindness was assigned to the X chromosome. This flowed from the observation that color blindness was passed on to sons by mothers who saw colors normally. Females, who have two X chromosomes, are protected from this disorder by a normal copy of the gene on their second X chromosome—unlike males, who have one X and one Y chromosome.

Some other disorders that affect only males were likewise mapped to the X chromosome, but the other 22 pairs of chromosomes remained virtually uncharted until the late 1960s. At that time, biologists fused human and mouse cells to create hybrid cells and found that these uneasy hybrids cast off their human chromosomes until only one or a few of the human chromosomes remained. Any recognizable human proteins found in such cells would therefore have to be produced by genes located on the remaining human chromosomes. Narrowing down the number of chromosomes in this fashion allowed scientists to assign about 100 genes to specific chromosomes.

Map-making really took off a few years later, when geneticists discovered characteristic light and dark stripes, or bands, across each chromosome after it was stained with a chemical. These bands, which fluoresced under ultraviolet light, provided the chromosomal equivalent of latitudes. They made it easier to identify individual human chromosomes in hybrid cells and some 1,000 genes were soon assigned to specific chromosomes on which these bands served as rough landmarks.

Almost simultaneously, recombinant DNA technology began to revolutionize biology by allowing researchers to snip out pieces of DNA and splice them into bacteria, where they could be grown, or cloned, in large quantities. This led to new mapping strategies, including the use of DNA variations as markers on the human genome. These advances resulted in a flood of new markers and an explosion of knowledge about the locations of human genes.

Meanwhile, scientists learned to sequence the genes they isolated. This became possible in the mid-1970s, when Frederick Sanger at Cambridge University and Walter Gilbert and Allan Maxam at Harvard University developed efficient new methods for determining the order of the four bases, A, T, G, and C, in a strand of DNA. Automated high-speed sequencing by machine followed in the 1980s. Once a new gene was identified, it could then be sequenced to understand the nature of the protein it codes for and to identify any disease-related mutations.

Sequencing the entire genome, however, meant sequencing at least 3 billion base pairs of DNA—one chromosome from each of the 23 pairs of chromosomes in a human cell. This demanded a huge international effort. In 2001, in a great celebration, two teams of researchers—one lead by the National Human Genome Research Institute of NIH and the other by Celera Genomics, Inc. a private biotechnology company—announced that they had completed a rough draft of the entire human genome. A more accurate version of the human genome is expected in 2003.

If the full human genome had been mapped and sequenced when researchers set out to find the cystic fibrosis gene, their task would have taken only a fraction of the time and cost. The investigators would not have had to clone region after region looking for the gene. They could have just reached into the freezer, pulled out all the DNA from the suspect regions, and rapidly zeroed in on the gene itself. Once they had identified the gene, its entire sequence would be available for analysis. And the same would be true for many other diseases.

— Beverly Merz

Top of page

A previously uncharted fragment of human DNA is mapped to chromosome 11 with the aid of probes that glow in red. The 22 pairs of autosomal (non-sex) chromosomes in the genome plus one X and one Y chromosome, are arranged in order. Each chromosome appears double because it was caught in the process of division.

Image: Anthony Baldini and David Ward, Genomics Vol. 9, pages 770-774, April 1991, ©1991 by Academic Press, Inc.

© 2013 Howard Hughes Medical Institute. A philanthropy serving society through biomedical research and science education.
4000 Jones Bridge Road Chevy Chase, MD 20815-6789 | (301) 215-8500 | email: webmaster@hhmi.org