By David N. Leff
Editor's Note: The following is a selection from the 21 articles comprising Nature's special issue, dated Feb. 15, 2001, devoted to sequencing of the human genome by the International Consortium.
Addiction, whether to drugs of abuse or the more natural peccadilloes that drive addicts to overeating, pathological gambling, compulsive shopping, even excessive exercise, can be studied at the level of neurons and synapses. They control the three states that define addiction:
Tolerance describes diminishing sensitivity to a drug's effects after repeated exposure. Sensitization denotes the opposite. Dependence is an altered physiological state, caused by repeated exposure to the addiction, which leads to withdrawal symptoms when the reward is discontinued.
Principal author of the paper in Nature titled, "Learning about addiction from the genome" is research psychiatrist Eric Nestler, at the University of Texas Southwestern Medical Center in Dallas. Nestler said, "Sequencing of the human and other mammalian genomes will help us understand the biology of addiction, by enabling us to identify the genes that contribute to individual risk for addiction and those through which drugs cause addiction."
He illustrated this potential impact by searching a draft sequence of the human genome for genes related to sensitization of receptors that control the actions on the nervous system exerted by drugs of abuse.
One-time addicts who have succeeded in kicking their habit nevertheless remain at lifelong risk of relapsing, even after years of abstinence. Trying to trace the molecular, cellular and neuronal changes involved in this long-term latent hangover is analogous, the paper suggests, to the field of learning and memory, which also plays a role in inducing addiction.
"Epidemiological studies," Nestler writes, "indicate that 40 [percent] to 60 percent of an individual's risk for an addiction, whether to alcohol, opiates or cocaine, is genetic. However," he adds, "we have not identified the specific genes involved in humans or animal models, nor do we understand how external factors (including stress or the drugs themselves) interact with those genetic variations to produce addiction. The draft sequence of the human genome indicates the diversity of the molecular components implicated in addiction.
"For example," he continued, "cocaine acts on the re-uptake transporters for dopamine and other monoamine neurotransmitters. We will soon know how many subtypes of such transporters are expressed in humans." Moreover, "Access to the complete human genome sequence will also help efforts to identify addiction vulnerability genes."
The co-authors scoured the human genome for relatives of genes encoding brain receptors involved in drug addiction. Their findings are likely to improve the understanding of addiction-related brain changes, and why some people are more vulnerable than others to substance abuse.
Scrutiny Of 923 Human Disease Genes Relates Their Hallmark Pathologies To Gene Products
One gene/one disease was the rule when biotechnology made its initial forays into human pathology. Now, increasingly, the trail leads from monogenic to polygenic ills, and beyond to proteomic and other complex etiologies.
Pediatric pathologist David Valle is senior author of the Nature paper titled: "Human disease genes." Seeking general principles of human disease, he and his co-authors analyzed functional categories for 923 disease-linked DNA sequences, of which 97 percent were monogenic, while the remaining 3 percent increased susceptibility for complex traits.
Their paper reports "striking correlations between the function of the gene product and features of disease, such as age of onset, mode of inheritance, frequency, severity and association with malformations." It predicts that as knowledge of disease genes grows, integration of medicine with biology will be enhanced.
The team derived its 923-gene sample from two standard reference sources of inherited diseases. Their results indict genes encoding enzymes as causing 31.2 percent of the total, followed by modulators of protein function, 13.6 percent. The remaining 12 categories accounted for less that 10 percent each of the total sample.
"Interestingly," they found, "each of our functional categories has a different peak age at onset. For transcription factors, the peak is in utero; for enzymes, in year one; for receptors, between that first year and puberty. For modifiers of protein function, it is in early adulthood. These correlations," they conclude, "hint at additional principles of disease."
International Consortium's Human Genome Draft Falls Short In Search To Identify New Cancer Genes
Research oncologist Michael Stratton, a member of the International Human Genome Sequencing Consortium's British arm, is senior author of the Nature paper titled: "Cancer and genomics." He and his co-authors sought to mine the nearly completed DNA sequence map of Homo sapiens to identify the genes that cause cancer oncogenesis. Cancer is the most common genetic disease, he pointed out. One in three people in the Western world develops malignancies, and one in five dies from them.
All cancers, he pointed out, are caused by abnormalities in DNA sequence - mutagens and mistakes in replication. Some 30 tumor-suppressor genes have been identified, as well as more than 100 dominant oncogenes.
"We searched the proteins from the draft human genome sequence for paralogs [genes similar to those of 29 previously known major cancers]," Stratton reported, "but no novel genes were identified." He and his co-authors then endeavored to search directly for oncogenic sequence changes in cancer cells by comparing cancer genome sequences against the draft genome. That experiment generated a high level of false positives.
"The lack of novel paralogs," Stratton surmised, "may reflect the biological and medical importance of these gene families; most of their members may have already been found. So we may learn more about the mutations driving cancer," he continued, "if we are not too heavily influenced by past experience. Instead, we should persevere in exploring every gene or protein, whatever its structure or putative function, as a possible candidate."
Stratton concluded, "The working draft will not immediately reveal the nature of the abnormalities in cancer cell genomes. New technology will be required." n