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1. A recent biography of Sir Archibald Garrod is A. G. Bearn, Archibald Garrod and the Individuality of Man (New York: Oxford University Press, 1993).

2. Given the huge numbers of DNA polymorphisms already observed in human populations, the number of potential genotypes is astronomical. Suppose that a mere two hundred polymorphisms were present (more than an order of magnitude fewer than have been documented to date), each with the minimum possible two alleles. Under the logic of Mendelian heredity, the number of distinct genotypes that in principle could be generated by the shuffling action of recombination is 3 . About 6,000,000,000 humans currently inhabit the Earth. Thus, only a minuscule fraction of the available human "genotypic space" is realized, and the probability of joint occupancy of any given genotypic slot is infinitesimally low.

3. Symptoms of the alkaptonuric condition also can be precipitated in nonalkap-tonuric patients by the prolonged exposure to carbolic acid dressings for chronic cutaneous ulcers. This example of a phenocopy (a nongenetically produced pheno-type resembling a genetically determined one) highlights how some metabolic disorders can have both genetic and environmental etiologies. In this case, the symptoms stem from an imbalance between the environmental challenge and the genetically-based capacity for appropriate response.

4. C. R. Scriver, A. L. Beaudet, W. S. Sly, and D. Valle, eds., The Metabolic and Molecular Bases of Inherited Disease, 7th ed. (New York: McGraw-Hill, 1995). V. A. McKusick, ed., Mendelian Inheritance in Man, 11th ed. (Baltimore, Md.: Johns Hopkins University Press, 1994); the online update can be accessed via the World Wide Web at

5. C. R. D. Brothers, "Huntington's Chorea in Victoria and Tasmania," J. Neurol. Sci. 1 (1964): 405-420.

6. N. S. Wexler et al., "Homozygotes for Huntington's Disease," Nature 326 (1987): 194-197.

7. J. F. Gusella et al., "A Polymorphic DNA Marker Genetically Linked to Huntington's Disease," Nature 306 (1983): 234-238.

8. Other disease genes with unstable numbers of short (trinucleotide) sequence repeat motifs include the fragile X syndrome (a form of mental retardation produced by an allele on the X chromosome), Kennedy syndrome (a motor neuron disease transmitted as a recessive allele also on the X), spinocerebellar ataxia type 1 (neurologic disorders with dominant allelic transmission on chromosome 6), denta-torubro-pallidoluysian atrophy (a neurodegenerative disorder due to a dominant allele on chromosome 12), and myotonic dystrophy (a progressive disorder of muscle weakness encoded by a dominant allele on chromosome 19). The unstable expansion of trinucleotide repeats at such "microsatellite genes" may be a common denominator for many dominantly inherited neurodegenerative disorders. See C. T. Ashley,

Jr. and S. T. Warren, "Trinucleotide Repeat Expansion and Human Disease," Annu. Rev. Genetics 29 (1995): 703—728; S. Karlin and C. Burge, "Trinucleotide Repeats and Long Homopeptides in Genes and Proteins Associated with Nervous System Disease and Development," Proc. Natl. Acad. Sci. USA 93 (1996): 1560-1565.

"Minisatellite loci" constitute another class of genetic elements with tandem-repeat motifs, but the repeated units are longer individually (typically fourteen to a hundred nucleotides each). Instabilities in minisatellite repeat numbers at some genes, such as the Ha-ras and insulin loci, contribute to the heritable risk of various cancers (carcinomas of the breast, the colon, the urinary bladder, and acute leukemia), and insulin-dependent diabetes, respectively. See T. G. Krontiris, "Minisatellites and Human Disease," Science 269 (1995): 1682-1683.

9. N. S. Wexler, "The Tiresias Complex: Huntington's Disease as a Paradigm of Testing for Late-Onset Disorders," FASEBJ. 6 (1992): 2820-2825.

10. N. A. Campbell, Biology, 2nd ed. (Redwood City, Calif.: Benjamin-Cummings, 1990), p. 247.

11. The nucleotide substitution is a guanine for an adenine at position 578 in the gene encoding the sixth transmembrane helix of the receptor for leutenizing hormone.

12. The clinical presentation in this gender also can depend, however, on the degree of skewness in the pattern of X-chromosome inactivation. In female mammals, including humans, one of the two X chromosomes in each somatic cell is inactivated early in embryonic development. This phenomenon, known as the "Lyon effect" after Mary Lyon, who first described the process in mice in 1961, is related to the metabolic desirability of compensating for the gene dosage differences that otherwise would exist between females (with two copies of the X per cell) and males (with only one copy).

13. The pathways involved are oxidative phosphorylation and electron transport. These pathways result in the production of molecules of ATP (adenosine triphos-phate) that act like batteries in storing cellular energy (in this case, in phosphate bonds).

14. Although mtDNA is transmitted almost exclusively from the mother, instances are known in other species where mtDNA molecules in offspring occasionally trace to their father's sperm, a phenomenon referred to as paternal leakage.

15. Two reviews are D. C. Wallace, "Mitochondrial Genetics: A Paradigm for Aging and Degenerative Diseases?" Science 256 (1992): 628-632; and D. C. Wallace, "Diseases of the Mitochondrial DNA," Annu. Rev. Biochem. 61 (1992): 1175-1212.

16. Free radical or oxygen radical molecules are destructive because they lack an electron, and this makes them prone to snatch electrons from other molecules (oxidation).

17. The distinction between simple and multifactorial genetic diseases is to some extent definitional. For example, cardiovascular diseases collectively arise from al terations in any of a multitude of genes that influence the morphogenesis and physiology of the circulatory system, often in combination with environmental stresses. Yet, particular cardiovascular disorders such as DiGeorge syndrome sometimes can be attributed to specifiable single-gene mutations that produce symptoms so characteristic as to warrant recognition as a distinct clinical syndrome.

18. W. K. Cavenee and R. L. White, "The Genetic Basis of Cancer," Sci. Amer. 272 (1995): 72-79.

19. For example, a gene known as p53 resides on the short arm of human chromosome 17. Known to be involved in more than fifty different cancers when mutated, this gene in its normal state produces a protein that functions in several biochemical pathways, including those involved in the repair of DNA damages and the suppression of tumors. Because of its medical importance, p53 won the "Molecule of the Year Award" from Science magazine (a sort of Academy Award in the scientific world).

20. Cellular genes that control normal proliferation of cells are referred to as proto-oncogenes. A proto-oncogene can be converted to an oncogene (carcinogenic form) by a somatic mutation, or by contact with a virus. Viruses that promote cancerous growth in humans do so either by introducing to cells altered forms of human genes picked up during their infective travels, or by activating host genes that otherwise are quiescent.

21. A recent issue of Science [272 (1996)] devoted to cardiovascular disease provides a useful introduction to this topic.

22. The last human in the world to contract smallpox was a Somalian man, Ali Maow Maalin. The year was 1977. It had taken nearly two centuries, following Edward Jenner's demonstration in 1796 of the efficacy of smallpox vaccination, for the world to be rid of this dreaded affliction. For a history of the victory over smallpox, see M. Pines, ed., The Race Against Lethal Microbes, (Chevy Chase, Md.: Howard Hughes Medical Institute, 1996).

23. In Biology as Ideology: The Doctrine of DNA (New York: Harper Perennial, 1992), Richard Lewontin suggests that the tubercle bacillus is necessary but not sufficient for tuberculosis. He notes that the disease was common in sweatshops and factories of the nineteenth century, but much rarer among country people and the upper classes. He concludes "we might be justified in claiming that the cause of tuberculosis is unregulated industrial capitalism, and if we did away with that system of social organization, we would not need to worry about the tubercle bacillus. When we look at the history of health and disease in modern Europe, that explanation makes at least as good sense as blaming the poor bacterium." Such reasoning, though unorthodox, nonetheless serves to emphasize that many disease agents such as the tubercle bacillus are only a component of a broader nexus of causality that can include environmental factors that facilitate the action of the proximate agent itself.

24. AIDS (acquired immune deficiency syndrome) is merely among the latest of infectious pandemics with considerable demographic impact on human populations. The following describe human genetic variation in susceptibility to infection by the AIDS virus: M. Samson et al., "Resistance to HIV-1 Infection in Caucasian Individuals Bearing Mutant Alleles of the CCR-5 Chemokine Receptor Gene," Nature 382 (1996): 722-725; R. Liu et al., "Homozygous Defect in HIV-1 Coreceptor Accounts for Resistance of some Multiply-Exposed Individuals to HIV-1 Infection," Cell 86 (1996): 367-377.

25. D. J. Weatherall, The New Genetics and Clinical Practice, 2nd ed. (New York: Oxford University Press, 1985) as reported in E. H. McConkey, Human Genetics, the Molecular Revolution (Boston, Mass.: Jones & Bartlett, 1993).

26. At a balance between mutation (at rate m) to a deleterious allele, and purifying selection (as quantified by the relative selection intensity [s] against the defective genotypes), the equilibrium frequency of a detrimental allele in a population is given by q = (m/s)1/2 if the allele is completely recessive, or by q = m/hs if the allele is partially dominant (where h is the degree of dominance).

27. C. Ruwende et al., "Natural Selection of Hemi- and Heterozygotes for G6PD Deficiency in Africa by Resistance to Severe Malaria," Nature 376 (1995): 246-249.

28. Let s and t designate the relative selection intensities against A/A and S/S homozygotes, respectively. At equilibrium, the predicted frequency of the S allele is given by q = s/(s + t), and that of the A allele by t/(s + t). For example, if S/S homozygosity is lethal (t = 1), and A/A homozygosity diminishes fitness by 50 percent on average relative to the heterozygous condition (s = 0.5), then the expected equilibrium frequency of the S allele is q = 0.33. Thus, frequencies attainable for variant alleles under overdominant selection (selection in which heterozygotes have higher fitness than either homozygote) can be much higher than those typically associated with recurrent mutation alone.

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  • tiia holmen
    What is a genetic malady?
    11 months ago

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