Journal of Inherited Metabolic Disease

, Volume 27, Issue 3, pp 305–317 | Cite as

After the genome—the phenome?

  • C. R. Scriver


Summary: What next? The Human Genome Project signifies complexity rather than simplification in the relationship between genotype and phenotype. Genotypes are embedded in genomes. Individuality in phenotypes is embedded in components of the phenome (transcriptome, metabolome, proteome, etc.). The phenome, its layers, and its nodes, links and networks, require elucidation; there is a need for a Human Phenome Project (Freimer and Sabatti 2003). Biology has largely been a reductive science in the recent past; integrative biology lies ahead. Clinician-scientists (including human biochemical geneticists) will be recognized as key participants in the ‘medical’ Phenome Project as it reveals components of individuality, and their contributions, in simple or combinatorial fashion, to Mendelian and complex traits; better ways to treat ‘genetic disease’ will be by-products of the project.

Although the Word is common to all, most men live as if each had a private wisdom of his own.



Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Avise JC (2001) Evolving genomic metaphors: a new look at the language of DNA. Science 294: 86–87.PubMedCrossRefGoogle Scholar
  2. Badano JL, Katsanis N (2002) Beyond Mendel: an evolving view of human genetic disease transmission. Nat Rev Genet 3: 779–789.PubMedCrossRefGoogle Scholar
  3. Bearn AG (ed.) (1993) Archibald Garrod and the Individuality of Man. Oxford: Clarendon Press.Google Scholar
  4. Bell JI (2003) The double helix in clinical practice. Nature 421: 414–416.PubMedCrossRefGoogle Scholar
  5. Bray D (2003) Molecular prodigality. Science 299: 1189–1190.PubMedCrossRefGoogle Scholar
  6. Caspi A, Sugden K, Moffitt TE, et al (2003) Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene. Science 301: 386–389.PubMedCrossRefGoogle Scholar
  7. Cavalli-Sforza LL, Menozzi P, Piazza A (1993) Demic expansions and human evolution. Science 259: 639–646.PubMedGoogle Scholar
  8. Chakravarti A, Little P (2003) Nature, nurture and human disease. Nature 421: 412–414.PubMedCrossRefGoogle Scholar
  9. Chesney RW, Friedman A, Kanto WP Jr, Stanton BF, Stull TL (2002) Pediatric practice and education in the genomic/postgenomic era. J Pediatr 141: 453–458.PubMedCrossRefGoogle Scholar
  10. Cheung VG, Conlin LK, Weber TM, et al (2003) Natural variation in human gene expression assessed in lymphoblastoid cells. Nature Genetics 33: 422–425.PubMedCrossRefGoogle Scholar
  11. Childs B (1999) Genetic Medicine. A Logic of Disease. Baltimore, MD: The Johns Hopkins University Press.Google Scholar
  12. Collins FS, Green ED, Guttmacher AE, Guyer MS, USNHGRI (2003) A vision for the future of genomics research. Nature 422: 835–847.PubMedCrossRefGoogle Scholar
  13. Cowles CR, Hirshorn JN, Altshuler D, Lander ES (2002) Detection of regulatory variation in mouse genes. Nature Genetics 32: 432–437.PubMedCrossRefGoogle Scholar
  14. Dennis C and Campbell P (2003) The eternal molecule. Nature 421: 396.CrossRefGoogle Scholar
  15. Dobzhansky T (1973) Nothing in biology makes sense except in the light of evolution. Am Biol Teacher 35: 125–129.Google Scholar
  16. Evans WE, Relling MV (1999) Pharmacogenomics: translating functional genomics into rational therapeutics. Science 286: 487–491.PubMedCrossRefGoogle Scholar
  17. Freimer N, Sabatti C (2003) The Human Phenome Project. Nature Genetics 34: 15–21.PubMedCrossRefGoogle Scholar
  18. Gavin A-C, Bosche M, Krause R, et al (2002) Functional organization of the yeast proteome by systematic analysis of protein complexes. Nature 415: 141–147.PubMedCrossRefGoogle Scholar
  19. Glazier AM, Nadeau JH, Altman TJ (2002) Finding genes that underlie complex traits. Science 298: 2345–2349.PubMedCrossRefGoogle Scholar
  20. Goldstein JL, Brown MS (1997) The clinical investigator: bewitched, bothered and bewildered-but still beloved. J Clin Invest 99: 2803–2812.PubMedGoogle Scholar
  21. Hall JG (2003) A clinician's plea. Nature Genetics 33: 440–442.PubMedCrossRefGoogle Scholar
  22. Hariharan IK, Haber DA (2003) Yeast, flies, worms, and fish in the study of human disease. N Engl J Med 348: 2457–2463.PubMedCrossRefGoogle Scholar
  23. Harris H, Hopkinson DA, Edwards YH (1977) Polymorphism and the subunit structure of enzymes: a contribution to the neutralist selectionist controversy. Proc Natl Acad Sci USA 74: 697–701.Google Scholar
  24. Hartman JL, Garvik B, Hartwell L (2001) Principles for the buffering of genetic variation. Science 291 (Feb. 9): 1001–1004.PubMedCrossRefGoogle Scholar
  25. Ho Y, Gruhler A, Heilbut A, et al (2002) Systematic identification of protein complexes in Saccharomyces cerevisiae by mass spectrometry. Nature 415: 180–183.PubMedCrossRefGoogle Scholar
  26. Hudson TJ (2003) Wanted: regulatory SNPs. Nature Genetics 33: 439–440.PubMedCrossRefGoogle Scholar
  27. Ideker T, Thorsson V, Ranish JA, et al (2001) Integrated genomic and proteomic analyses of a systematically perturbed metabolic network. Science 292: 929–934.PubMedCrossRefGoogle Scholar
  28. International Human Genome Sequencing Consortium (2001) Initial sequencing and analysis of the human genome. Nature 409: 860–921.CrossRefGoogle Scholar
  29. Jacob F (1977) Evolution and tinkering. Science 196: 1161–1166.PubMedGoogle Scholar
  30. Jeong H, Tombor B, Albert R, Otlval ZN, Barabasi AL (2000) The large-scale organization of metabolic networks. Nature 407 (Oct. 5): 651–654.PubMedCrossRefGoogle Scholar
  31. Jimenez-Sanchez G, Childs B, Valle D (2001) Human disease genes. Nature 409: 853–855.PubMedCrossRefGoogle Scholar
  32. Kacser H, Porteous JW (1987) Control of metabolism: What do we have to measure? Trends Biochem Sci 12: 5–14.CrossRefGoogle Scholar
  33. Kauffman SA (1993) The Origins of Order. New York: Oxford University Press.Google Scholar
  34. Kumar A, Snyder M (2002) Protein complexes take the bait. Nature 415: 123–124.PubMedCrossRefGoogle Scholar
  35. Lau NC, Bartel DP (2003) Censors of the genome. Sci Am August: 34–41.Google Scholar
  36. Legrain P, Wojcik J, Gauthier J-M (2001) Protein-protein interaction maps: a lead towards cellular functions. Trends Genet 17: 346–352.PubMedCrossRefGoogle Scholar
  37. Maddox B (2003) The double helix and the 'wronged heroine'. Nature 421: 407–408.PubMedCrossRefGoogle Scholar
  38. Maurer SM, Firestone RB, Scriver CR (2000) Science's neglected legacy. Nature 405: 117–120.PubMedCrossRefGoogle Scholar
  39. McManus MT, Sharp PA (2002) Gene silencing in mammals by small interfering RNAs. Nat Rev Genet 3: 737–747.PubMedCrossRefGoogle Scholar
  40. Muntau AC, Roschinger W, Habich M et al (2002) Tetrahydrobiopterin as an alternative treatment for mild phenylketonuria. N Engl J Med 347: 2122–2132.PubMedCrossRefGoogle Scholar
  41. Nadeau JH (2001) Modifier genes in mice and humans. Nature Genetics 2: 165–174.Google Scholar
  42. Oltvai ZN, Barabasi AL (2002) Life's complexity pyramid. Science 298: 763–764.PubMedCrossRefGoogle Scholar
  43. Ouzounis CA, Coulson RMR, Enright AJ, Kunin V, Pereira-Leal JB (2003) Classification schemes for protein structure and function. Nat Rev Genet 4: 508–519.PubMedCrossRefGoogle Scholar
  44. Prigogine I (1980) From Being to Becoming. Time and Complexity in the Physical Sciences. New York: WH Freeman.Google Scholar
  45. Rees J (2002) Complex disease and the new clinical sciences. Science 296: 698–701.PubMedCrossRefGoogle Scholar
  46. Rose S (2001) The biology of the future and the future of biology. Perspect Biol Med 44(Autumn): 473–484.PubMedGoogle Scholar
  47. Rosenberg LE (1999) The physician-scientist: an essential-and fragile-link in the medical research chain. J Clin Invest 103: 1621–1626.PubMedCrossRefGoogle Scholar
  48. Scriver CR (1993) Genetics and society: what society expects of geneticists-overview. Trans R Soc Canada IV: 3–10.Google Scholar
  49. Scriver CR (2001) Garrod's foresight; our hindsight. J Inherit Metab Dis 24: 93–116.PubMedCrossRefGoogle Scholar
  50. Scriver CR (2002a) Does hereditary metabolic disease modulate senescence and ageing? J Inherit Metab Dis 25: 235–251.PubMedCrossRefGoogle Scholar
  51. Scriver CR (2002b) Why mutation analysis does not always predict clinical consequences: explanations in the era of genomics. J Pediatr 140: 502–506.PubMedCrossRefGoogle Scholar
  52. Scriver CR (2003) Tinkered masterpieces or master tinker. American Society for Human Genetics. (website).Google Scholar
  53. Scriver CR, Gregory DM, Sovetts D, Tissenbaum G (1985) Normal plasma free amino acid values in adults: the influence of some common physiological variables. Metabolism 34: 868–873.PubMedCrossRefGoogle Scholar
  54. Scriver CR, Nowacki PM (1999) Genomics, mutations and the internet: the naming and use of parts. J Inherit Metab Dis 22: 519–530.PubMedCrossRefGoogle Scholar
  55. Sober E (1984) The Nature of Selection. Evolutionary Theory in Philosophical Focus. Cambridge, MA: MIT Press.Google Scholar
  56. Strohman R (2003) ThermodynamicsDold laws in medicine and complex diseases. Nature Biotechnology 21: 477–479.PubMedCrossRefGoogle Scholar
  57. Tong AHY, Evangelista M, Parsons AB, et al (2001) Systematic genetic analysis with ordered arrays of yeast deletion mutants. Science: 2364–2368.Google Scholar
  58. Venter JC, Adams MD, Myers EW, et al (2001) The sequence of the human genome. Science 291(Feb. 16): 1304–1351.PubMedCrossRefGoogle Scholar
  59. Waters PJ Parniak MA, Akerman BR, et al (1999) Missense mutations in the phenylalanine hydroxylase gene (PAH) can cause accelerated proteolytic turnover of PAH enzyme: a mechanism underlying phenylketonuria. J Inherit Metab Dis 22: 208–212.PubMedCrossRefGoogle Scholar
  60. Watson JD, Crick FHC (1953) Molecular structure of nucleic acids: a structure for deoxyribose nucleic acid. Nature 171: 737–738.PubMedCrossRefGoogle Scholar
  61. Weiss KM, Buchanan AV (2003) Evolution by phenotype: a biomedical perspective. Perspect Biol Med 46(2): 159–182.PubMedGoogle Scholar
  62. Willett WC (2002) Balancing life-style and genomics research for disease prevention. Science 296: 695–698.PubMedCrossRefGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • C. R. Scriver
    • 1
  1. 1.Departments of Biology, Human Genetics, and PediatricsMcGill University, McGill University Health Center, A-721, Montreal Children's HospitalCanada

Personalised recommendations