The first "rough draft" of the human genome arrived last February with great fanfare. Two independent research teams, racing each other and the clock, published their results simultaneously in two of the world's most prestigious journals—Nature and Science. The magnitude of their effort is almost inconceivable. The complete sequence of the human genome is so enormous (3.2 billion letters) that it can be made available only on the Internet. The New York Times estimated that it would take 75,490 pages of its newspaper to just print the entire sequence.
Even though the formidable task of sequencing the human genome is coming to a close, however, its impact on society is just beginning. As one scientist observed, there is a big difference between having the parts list to a Boeing 777 and understanding how it works. We now have a laundry list of human genes, but we must understand their specific functions, and how they work together, to unlock their enormous potential.
Food Insight is pleased to present a three-part series on the human genome. This, the first article, will review basic DNA structure and function and discuss some of the powerful new analytical tools that are being used to understand it. The second article will examine some of the health applications of the human genome (e.g., assessing disease risk, gene therapy, and new drugs), and the final article will explore some of the ethical issues (e.g., privacy, human rights, and eugenics) that are beginning to surface.
DNA Structure and Function
DNA (deoxyribonucleic acid) is found in the nucleus of cells. It is a very long double-stranded molecule that looks like a twisted ladder. The sides of the ladder are chains of sugar molecules (deoxyribose) and the rungs consist of chemical compounds called bases. There are four possible bases, and each one is matched to a specific partner on the opposite chain. Adenine (A) is paired with thymine (T), and guanine (G) accompanies cytosine (C). All the information necessary for a cell to function and reproduce (whether it is a single-cell bacterium or a cell in a human being) is locked into the sequence made up of this four-letter genetic alphabet.
When a cell needs to use a particular piece of information, the appropriate section(s) of the double-stranded DNA molecule is opened like a zipper, and one of the strands is used as a template to synthesize a new molecule called messenger RNA (mRNA). mRNA is a long, single-stranded molecule that looks like a comb. It is composed of a long chain of ribose (a sugar) molecules with one of the four chemical bases attached to each ribose chain. The most important feature about mRNA is that its sequence of bases is an exact complement to the section of DNA that was used to create it. mRNA, can therefore carry the DNA's message out of the cell's nucleus and be used to direct the synthesis of a specific protein at another location-a process called translation. During translation, amino acids are linked to each other, one at a time, to form a new protein. The exact order of amino acids is determined by "reading" the sequence of bases in mRNA, three at a time. Each triplet of bases codes for 1 of the 20 amino acids found in humans. The amino acid is then added to the growing polypeptide (protein) chain until a complete protein has been manufactured.
The Human Genome
The human genome is enormous. If the DNA molecules in a single cell were stretched end-to-end they would be approximately 6 feet long! This DNA is arranged in 23 chromosome pairs with one chromosome in each pair donated by each parent. In the simplest terms, a gene corresponds to a section of the DNA molecule that codes for a protein. Proteins are the workhorses of the body and can be used as structural components (e.g. muscle and hair) or as enzymes that catalyze biochemical reactions.
Data from the Human Genome Project will ultimately enable scientists to understand the functions of human genes and the laws that regulate how they are turned off and on. At this point, however, there are just as many questions as answers. For example, the Human Genome Project discovered that humans have only about 30,000 genes rather than the 100,000 or so that were expected. That's only about 50 percent more genes than the number of genes in a 959-cell roundworm called Caenorhabditis elegans. How does the vastly more complex human get by on so few genes? In addition, our genes occupy a scant 1 to 1.5 percent of the total genome. The remaining 98 percent or more of our DNA appears to be nothing but genetic "junk." Is this DNA really useless?
These questions are far from answered, but scientists are already beginning to explain how humans get by on so few genes. Part of the answer is that a single gene codes for more than a single protein. During the process of transcription, segments within a gene that are used to create mRNA may be skipped over, or mixed with segments on entirely different genes. This skipping process may be influenced by some of the "junk" DNA in noncoding segments. The result is that many different mRNAs can be made by a small number of genes.
Furthermore, a single mRNA may be used to synthesize many different proteins. Entire sections of mRNA can be cut out or rearranged before the mRNA is used to direct the synthesis of a new protein. Finally, proteins themselves can be modified in many ways to alter their function, or in some cases the same protein may perform a variety of different tasks. The end result is a staggeringly complex biochemical dance that allows humans to function with relatively few genes.
Unlocking the secrets
The key to unlocking the secrets of the human genome will be to understand how the individual genes are regulated and how they interact with one another. Even with a mere 30,000 genes, this task is daunting. Fortunately, a powerful new tool called microarray analysis is enabling researchers to examine thousands of genes simultaneously. The process uses a gene "chip," which is composed of tiny spots of DNA from many known genes attached to a solid surface (like a glass slide) in a grid-like array. To identify which genes in a sample of cells are active, their mRNAs are isolated and converted in a test tube to another molecule called complementary DNA (cDNA). A fluorescent label is then attached to the cDNAs and the cDNAs are allowed to mix with the DNA spots on the array. The cDNAs with a sequence that matches the sequence of one of the gene fragments sticks to the fragment like glue, and the cDNA with a sequence that doesn't match is washed away. A computerized detector is then used to measure the amount of fluorescence associated with each spot. The brighter the fluorescence, the more active the gene was in the original cell. The patterns of light that emerge from the array represent a snapshot of the genes that were active in the cell at a single point in time. Examination of many such patterns from different cells exposed to different conditions at different times will help scientists understand the basic genetics of normal and diseased cells. This information has the potential to dramatically increase our ability to understand and treat human disease.
What does your DNA say?
Microarrays can also be used to gather information about the genetic endowment of an individual. This technique works by exposing the microarray to a sample of DNA (rather than the cDNA described above). By using DNA, a gene will be detected by the array even if it was not being expressed at the time that the sample was taken. This technique has the potential to screen people for a specific gene, a mutation, or any combination of genes. As more information about the human genome becomes available, it may be possible to screen entire populations for virtually any genetically derived trait-disease susceptibility, intelligence, longevity, and many, many more.
Another technique, called DNA amplification makes it possible to analyze minute quantities of DNA. This technique takes advantage of the fact that DNA can reproduce itself. By exposing a DNA sample to specialized enzymes and other chemicals, it can be induced to copy itself. The process can be repeated over and over to increase the amount of DNA by hundreds of millions of times in a matter of hours. Because DNA is a very stable molecule, a tiny sample many years old can be examined. It was recently reported that a sample of DNA taken from the leg bone of a 3-year-old child believed to be buried around the year 450 A.D. near Rome was amplified by this technique. Analysis of the sample revealed that it was nearly identical to the DNA of people infected with a very potent form of malaria-strong evidence that this disease may have contributed to the fall of the Roman Empire.
Welcome to the Brave New World
The potential of functional genomics to benefit humankind is literally unsurpassed. The food and pharmaceutical industries are among those poised to use this new information in their research and development efforts. As it becomes possible to assess an individual's genetic susceptibility to disease, it will become possible to create functional foods and drugs uniquely tailored to help manage that susceptibility. At the same time, these new technologies will spark profound ethical and human rights challenges. No one knows what the future of genomics will bring (predictions range from Utopia to Armageddon), but one thing seems certain; the world is in for a very big change.
