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No post-genetics era in human disease research


In the 1980s, linkage emerged as a route to discovering genetic defects, spurring the rise of genomics and making gene-based approaches available to previously phenotype-orientated researchers. In the post-genomics era, genetics is fundamental to understanding disease at all stages of the pathogenic process.

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Figure 1: Genotypic and phenotypic approaches to the pathogenic process.
Figure 2: Potential model systems for investigating human disease mechanisms.
Figure 3: Genotype–phenotype correlations in Huntington disease patients.


  1. 1

    Martin, J. B. & Gusella, J. F. Huntington's disease. Pathogenesis and management. N. Engl. J. Med. 315, 1267–1276 (1986).

    CAS  Article  Google Scholar 

  2. 2

    Vonsattel, J. P. & DiFiglia, M. Huntington disease. J. Neuropathol. Exp. Neurol. 57, 369–384 (1998).

    CAS  Article  Google Scholar 

  3. 3

    Vonsattel, J. P. et al. Neuropathological classification of Huntington's disease. J. Neuropathol. Exp. Neurol. 44, 559–577 (1985).

    CAS  Article  Google Scholar 

  4. 4

    Bhan, A. K., Mizoguchi, E., Smith, R. N. & Mizoguchi, A. Colitis in transgenic and knockout animals as models of human inflammatory bowel disease. Immunol. Rev. 169, 195–207 (1999).

    CAS  Article  Google Scholar 

  5. 5

    Coyle, J. T. An animal model for Huntington's disease. Biol. Psychiatry 14, 251–276 (1979).

    CAS  PubMed  Google Scholar 

  6. 6

    Beal, M. F. Does impairment of energy metabolism result in excitotoxic neuronal death in neurodegenerative illnesses? Ann. Neurol. 31, 119–130 (1992).

    CAS  Article  Google Scholar 

  7. 7

    Brouillet, E., Conde, F., Beal, M. F. & Hantraye, P. Replicating Huntington's disease phenotype in experimental animals. Prog. Neurobiol. 59, 427–468 (1999).

    CAS  Article  Google Scholar 

  8. 8

    Beverstock, G. C. The current state of research with peripheral tissues in Huntington disease. Hum. Genet. 66, 115–131 (1984).

    CAS  Article  Google Scholar 

  9. 9

    Ptacek, L. J. Channelopathies: ion channel disorders of muscle as a paradigm for paroxysmal disorders of the nervous system. Neuromuscul. Disord. 7, 250–255 (1997).

    CAS  Article  Google Scholar 

  10. 10

    Tolleshaug, H., Hobgood, K. K., Brown, M. S. & Goldstein, J. L. The LDL receptor locus in familial hypercholesterolemia: multiple mutations disrupt transport and processing of a membrane receptor. Cell 32, 941–951 (1983).

    CAS  Article  Google Scholar 

  11. 11

    The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).

  12. 12

    Janus, C. & Westaway, D. Transgenic mouse models of Alzheimer's disease. Physiol. Behav. 73, 873–886 (2001).

    CAS  Article  Google Scholar 

  13. 13

    LaFerla, F. M., Tinkle, B. T., Bieberich, C. J., Haudenschild, C. C. & Jay, G. The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice. Nature Genet. 9, 21–30 (1995).

    CAS  Article  Google Scholar 

  14. 14

    Nakano, Y. et al. Accumulation of murine amyloid β42 in a gene-dosage-dependent manner in PS1 'knock-in' mice. Eur. J. Neurosci. 11, 2577–2581 (1999).

    CAS  Article  Google Scholar 

  15. 15

    Citron, M. et al. Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice. Nature Med. 3, 67–72 (1997).

    CAS  Article  Google Scholar 

  16. 16

    Siman, R. et al. Presenilin-1 P264L knock-in mutation: differential effects on Aβ production, amyloid deposition, and neuronal vulnerability. J. Neurosci. 20, 8717–8726 (2000).

    CAS  Article  Google Scholar 

  17. 17

    Moechars, D. et al. Early phenotypic changes in transgenic mice that overexpress different mutants of amyloid precursor protein in brain. J. Biol. Chem. 274, 6483–6492 (1999).

    CAS  Article  Google Scholar 

  18. 18

    Hackam, A. S., Singaraja, R., Zhang, T., Gan, L. & Hayden, M. R. In vitro evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in Huntington's disease. Hum. Mol. Genet. 8, 25–33 (1999).

    CAS  Article  Google Scholar 

  19. 19

    Cooper, J. K. et al. Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture. Hum. Mol. Genet. 7, 783–790 (1998).

    CAS  Article  Google Scholar 

  20. 20

    Persichetti, F. et al. Mutant huntingtin forms in vivo complexes with distinct context-dependent conformations of the polyglutamine segment. Neurobiol. Dis. 6, 364–375 (1999).

    CAS  Article  Google Scholar 

  21. 21

    Li, S. H., Cheng, A. L., Li, H. & Li, X. J. Cellular defects and altered gene expression in PC12 cells stably expressing mutant huntingtin. J. Neurosci. 19, 5159–5172 (1999).

    CAS  Article  Google Scholar 

  22. 22

    Saudou, F., Finkbeiner, S., Devys, D. & Greenberg, M. E. Huntingtin acts in the nucleus to induce apoptosis but death does not correlate with the formation of intranuclear inclusions. Cell 95, 55–66 (1998).

    CAS  Article  Google Scholar 

  23. 23

    Lunkes, A. & Mandel, J. L. A cellular model that recapitulates major pathogenic steps of Huntington's disease. Hum. Mol. Genet. 7, 1355–1361 (1998).

    CAS  Article  Google Scholar 

  24. 24

    Hackam, A. S. et al. The influence of huntingtin protein size on nuclear localization and cellular toxicity. J. Cell Biol. 141, 1097–1105 (1998).

    CAS  Article  Google Scholar 

  25. 25

    Jackson, G. R. et al. Polyglutamine-expanded human huntingtin transgenes induce degeneration of Drosophila photoreceptor neurons. Neuron 21, 633–642 (1998).

    CAS  Article  Google Scholar 

  26. 26

    Faber, P. W., Alter, J. R., MacDonald, M. E. & Hart, A. C. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc. Natl Acad. Sci. USA 96, 179–184 (1999).

    CAS  Article  Google Scholar 

  27. 27

    Kim, M. et al. Mutant huntingtin expression in clonal striatal cells: dissociation of inclusion formation and neuronal survival by caspase inhibition. J. Neurosci. 19, 964–973 (1999).

    CAS  Article  Google Scholar 

  28. 28

    Mangiarini, L. et al. Exon 1 of the HD gene with an expanded CAG repeat is sufficient to cause a progressive neurological phenotype in transgenic mice. Cell 87, 493–506 (1996).

    CAS  Article  Google Scholar 

  29. 29

    Gusella, J. F. & MacDonald, M. E. Molecular genetics: unmasking polyglutamine triggers in neurodegenerative disease. Nature Rev. Neurosci. 1, 109–115 (2000).

    CAS  Article  Google Scholar 

  30. 30

    Heath, K. E. et al. Nonmuscle myosin heavy chain iia mutations define a spectrum of autosomal dominant macrothrombocytopenias: may-hegglin anomaly and fechtner, sebastian, epstein, and alport-like syndromes. Am. J. Hum. Genet. 69, 1033–1045 (2001).

    CAS  Article  Google Scholar 

  31. 31

    Girard, T. et al. Genotype–phenotype comparison of the Swiss malignant hyperthermia population. Hum. Mutat. 18, 357–358 (2001).

    CAS  Article  Google Scholar 

  32. 32

    Lia-Baldini, A. S. et al. A molecular approach to dominance in hypophosphatasia. Hum. Genet. 109, 99–108 (2001).

    CAS  Article  Google Scholar 

  33. 33

    Stokowski, R. P. & Cox, D. R. Functional analysis of the neurofibromatosis type 2 protein by means of disease-causing point mutations. Am. J. Hum. Genet. 66, 873–891 (2000).

    CAS  Article  Google Scholar 

  34. 34

    Gutmann, D. H., Geist, R. T., Xu, H., Kim, J. S. & Saporito-Irwin, S. Defects in neurofibromatosis 2 protein function can arise at multiple levels. Hum. Mol. Genet. 7, 335–345 (1998).

    CAS  Article  Google Scholar 

  35. 35

    Davies, S. W. et al. Formation of neuronal intranuclear inclusions underlies the neurological dysfunction in mice transgenic for the HD mutation. Cell 90, 537–548 (1997).

    CAS  Article  Google Scholar 

  36. 36

    Sathasivam, K. et al. Formation of polyglutamine inclusions in non-CNS tissue. Hum. Mol. Genet. 8, 813–822 (1999).

    CAS  Article  Google Scholar 

  37. 37

    Scherzinger, E. et al. Huntingtin-encoded polyglutamine expansions form amyloid-like protein aggregates in vitro and in vivo. Cell 90, 549–558 (1997).

    CAS  Article  Google Scholar 

  38. 38

    DiFiglia, M. et al. Aggregation of huntingtin in neuronal intranuclear inclusions and dystrophic neurites in brain. Science 277, 1990–1993 (1997).

    CAS  Article  Google Scholar 

  39. 39

    Huang, C. C. et al. Amyloid formation by mutant huntingtin: threshold, progressivity and recruitment of normal polyglutamine proteins. Somat. Cell Mol. Genet. 24, 217–233 (1998).

    CAS  Article  Google Scholar 

  40. 40

    Scherzinger, E. et al. Self-assembly of polyglutamine-containing huntingtin fragments into amyloid-like fibrils: implications for Huntington's disease pathology. Proc. Natl Acad. Sci. USA 96, 4604–4609 (1999).

    CAS  Article  Google Scholar 

  41. 41

    Narain, Y., Wyttenbach, A., Rankin, J., Furlong, R. A. & Rubinsztein, D. C. A molecular investigation of true dominance in Huntington's disease. J. Med. Genet. 36, 739–746 (1999).

    CAS  Article  Google Scholar 

  42. 42

    Heiser, V. et al. Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington's disease therapy. Proc. Natl Acad. Sci. USA 97, 6739–6744 (2000).

    CAS  Article  Google Scholar 

  43. 43

    Gurney, M. E. et al. Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation. Science 264, 1772–1775 (1994).

    CAS  Article  Google Scholar 

  44. 44

    Dal Canto, M. C. & Gurney, M. E. A low expressor line of transgenic mice carrying a mutant human Cu,Zn superoxide dismutase (SOD1) gene develops pathological changes that most closely resemble those in human amyotrophic lateral sclerosis. Acta Neuropathol. (Berl.) 93, 537–550 (1997).

    CAS  Article  Google Scholar 

  45. 45

    Forlino, A., Porter, F. D., Lee, E. J., Westphal, H. & Marini, J. C. Use of the Cre/lox recombination system to develop a non-lethal knock-in murine model for osteogenesis imperfecta with an α1(I) G349C substitution. Variability in phenotype in BrtlIV mice. J. Biol. Chem. 274, 37923–37931 (1999).

    CAS  Article  Google Scholar 

  46. 46

    Spring, K. et al. Atm knock-in mice harboring an in-frame deletion corresponding to the human ATM 7636del9 common mutation exhibit a variant phenotype. Cancer Res. 61, 4561–4568 (2001).

    CAS  PubMed  Google Scholar 

  47. 47

    Bobet, J., Mooney, R. F. & Gordon, T. Force and stiffness of old dystrophic (mdx) mouse skeletal muscles. Muscle Nerve 21, 536–539 (1998).

    CAS  Article  Google Scholar 

  48. 48

    Giovannini, M. et al. Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev. 14, 1617–1630 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49

    Li, H., Li, S. H., Yu, Z. X., Shelbourne, P. & Li, X. J. Huntingtin aggregate-associated axonal degeneration is an early pathological event in Huntington's disease mice. J. Neurosci. 21, 8473–8481 (2001).

    CAS  Article  Google Scholar 

  50. 50

    Lin, C. H. et al. Neurological abnormalities in a knock-in mouse model of Huntington's disease. Hum. Mol. Genet. 10, 137–144 (2001).

    CAS  Article  Google Scholar 

  51. 51

    Wheeler, V. C. et al. Long glutamine tracts cause nuclear localization of a novel form of huntingtin in medium spiny striatal neurons in HdhQ92 and HdhQ111 knock-in mice. Hum. Mol. Genet. 9, 503–513 (2000).

    CAS  Article  Google Scholar 

  52. 52

    Li, H., Li, S. H., Johnston, H., Shelbourne, P. F. & Li, X. J. Amino-terminal fragments of mutant huntingtin show selective accumulation in striatal neurons and synaptic toxicity. Nature Genet. 25, 385–389 (2000).

    CAS  Article  Google Scholar 

  53. 53

    Shelbourne, P. F. et al. A Huntington's disease CAG expansion at the murine Hdh locus is unstable and associated with behavioural abnormalities in mice. Hum. Mol. Genet. 8, 763–774 (1999).

    CAS  Article  Google Scholar 

  54. 54

    Lorenzetti, D. et al. Repeat instability and motor incoordination in mice with a targeted expanded CAG repeat in the Sca1 locus. Hum. Mol. Genet. 9, 779–785 (2000).

    CAS  Article  Google Scholar 

  55. 55

    MacDonald, M. E. et al. Evidence for the GluR6 gene associated with younger onset age of Huntington's disease. Neurology 53, 1330–1332 (1999).

    CAS  Article  Google Scholar 

  56. 56

    Rubinsztein, D. C. et al. Genotypes at the GluR6 kainate receptor locus are associated with variation in the age of onset of Huntington disease. Proc. Natl Acad. Sci. USA 94, 3872–3876 (1997).

    CAS  Article  Google Scholar 

  57. 57

    Persichetti, F. et al. Huntington's disease CAG trinucleotide repeats in pathologically confirmed post-mortem brains. Neurobiol. Dis. 1, 159–166 (1994).

    CAS  Article  Google Scholar 

  58. 58

    Kieburtz, K. et al. Trinucleotide repeat length and progression of illness in Huntington's disease. J. Med. Genet. 31, 872–874 (1994).

    CAS  Article  Google Scholar 

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The author's work on HD is supported by the Huntington's Disease Society of America's Coalition for the Cure, the Hereditary Disease Foundation and by the National Institutes of Health.

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Corresponding author

Correspondence to James Gusella.

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apolipoprotein E











presenilin 1

presenilin 2



Alzheimer disease


dentatorubropallidoluysian atrophy

Duchenne muscular dystrophy

familial hypercholesterolaemia

Huntington disease

hyperkalaemic periodic paralysis


hypokalaemic periodic paralysis


long QT syndrome

macrothrombocytopaenia syndromes

myotonia congenita

neurofibromatosis 2

osteogenesis imperfecta

paramyotonia congenita

ryanodine receptor






spinal and bulbar muscular atrophy



Specific structures made up of insoluble, relatively inert fibres of protein in β-sheet conformation.


Clusters of neurons located deep in the brain that relay messages between the most anterior part of the cortex that is involved in problem solving and complex thought, and the lower motor and sensory areas; includes the striatum.


Part of the basal ganglia that bulges into the lateral ventricle and forms part of the striatum.


Superficial layer of grey matter that is involved in higher functions, including initiation of voluntary movements, cognition and emotion.


Ceaseless, involuntary, jerking movements of the body, face, or extremities.


One form of a protein that can exist in different conformations.


Toxicity to electrically excitable cells due to excessive electrical stimulation.


A neuron that uses γ-aminobutyric acid (GABA), a principal neurotransmitter, and sends axons to other brain regions.


Abnormal intracellular accumulation of a microtubule-associated protein called tau, characteristic of Alzheimer disease.


Appearance of activated glial cells in regions of brain injury.


Neurons that lie in the striatum — an area of the brain involved in fine movements, emotion and cognition.

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Gusella, J., MacDonald, M. No post-genetics era in human disease research. Nat Rev Genet 3, 72–79 (2002).

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