The Human Genome Project (HGP) project was initiated in 1989 and funded by the U.S. government, with one of its explicit goals set as the understanding and cure of genetic disease. The HGP's initial task was to locate and identify all the coding genes in the human genome by the year 2005. A secondary goal, to sequence the DNA in the entire human genome, was expected to take somewhat longer. The American HGP was eventually combined with the international Human Genome Organization (HUGO) to make the project global in scope. Currently, the worldwide HGP is substantially ahead of schedule. One of the major findings of the rough draft of the human genome, completed early in 2001, was that the number of human genes may be closer to 30,000 than to the previously higher estimate of 70,000, and that the enormous library of human proteins is produced by fewer complete cistrons (coding sequences) than initially estimated. The human genome thus has an apparent protein: gene ratio higher than 3 : 1, yet some other species maintain a ratio that is closer to 1 : 1. This seems to be due in humans (and some other organisms) to differential splicing of segments of genes called exons ("exon shuffling"). The human genome appears to be composed of thousands, perhaps even hundreds of thousands, of these smaller functional segments, rather than complete and contiguous larger genes. Through differential splicing of these exons, many large and complex genes can apparently be constructed. This organization of the human genome has dramatically affected how research in genetic disease is being approached.
Many of these smaller segments are almost identical in their DNA sequences to segments found in "lower" species such as mice, fruit flies, and even yeast. One can use the analogy of an arm to understand that it might be constructed of functional exons that separately code for elbows, long bones, carpals, and metacarpals, rather than from one large gene called "human arm." The elegance of this strategy is that each of the many smaller segments, such as a molecular "elbow," had to evolve only once, and that through "exon shuffling" they can be used in many different ways in many different organisms. The function of such genes within other organisms can be studied, and the results extrapolated to humans. This study of the differential use of linear DNA and the assembly of nearly identical segments of DNA across species is known as genomics. Processes that occur within the organism after the genes are transcribed are called epigenetic processes.
Interest in epigenetic processes is increasing dramatically, and the prion diseases provide an illustration. "True" genetic diseases are transmitted vertically; that is, from one generation to the next. The discovery in 1957 that certain genetic conditions also have phenocopies— conditions that mimic a known genetic disease or a genetic mode of transmission, but that can also be transmitted horizontally, by infection—was startling. Even more surprising was a suggestion made in the 1980s by Stanley Prusiner, known as the "protein only hypothesis," that the agent of these phenocopy infections lacked DNA, unlike any then-known infectious agent. Prusiner's "pro-teinaceous infectious particles," or prions, were soon validated (Prusiner & Scott, 1997), and they quickly blurred the distinction between vertical (genetic) and horizontal (infectious) transmission.
Although scrapie was known to cause neurodegeneration in sheep, the first of these prion-transmitted conditions to be described in humans was Kuru, a neu-rodegenerative disease found in the Highlands of New Guinea, and now well known to medical anthropologists (Gajdusek & Zigas, 1957; Matthews et al., 1968; Rhodes, 1997). Kuru was at first thought to be a genetic disease, as family members of those afflicted with Kuru, primarily females and children, were eventually also affected. Kuru was next thought to be the action of a "slow virus," when infected human tissue caused the onset of similar symptoms in a chimpanzee infected experimentally. Only much later was the infectious agent shown to be a prion, passed to women and children who customarily ate the brains and other parts of cadavers, which men almost never did. Today, Kuru is thought of as an infectious disease. Whether or not this perception is valid will depend upon future research on the prion diseases (see below).
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