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Many little things: one geneticist's view of complex diseases

Nature Reviews Genetics volume 6, pages 419–425 (2005)Cite this article

Abstract

Gene targeting is commonly used to knock out genes in order to understand their function. It has also been used successfully to model the relatively rare human genetic diseases that are caused by homozygous loss of gene function. Modelling the much more common multifactorial diseases that have strong genetic and environmental causes is less easy. Here, I describe my personal voyage into this challenging field, using gene targeting to alter the expression of genes that impact on hypertension and diabetes.

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Figure 1: Page 55 from Oliver Smithies' notebook ϕ.
Figure 2: A self-teaching diagram outlining elements of the renin–angiotensin system.
Figure 3: Page 53 from Oliver Smithies' notebook ψ.
Figure 4: Gene-deletion and gene-duplication constructs.
Figure 5: Page 55 from Oliver Smithies' notebook ψ.
Figure 6: Effects of varying the number of copies of AGT and ACE on concentration of their protein products and blood pressure.

References

  1. Smithies, O., Gregg, R. G., Boggs, S. S., Koralewski, M. A. & Kucherlapati, R. S. Insertion of DNA Sequences into the human chromosomal β-globin locus by homologous recombination. Nature 317, 230–234 (1985).

    Article  CAS  Google Scholar 

  2. Doetschman, T. et al. Targetted correction of a mutant HPRT gene in mouse embryonic stem cells. Nature 330, 576–578 (1987).

    Article  CAS  Google Scholar 

  3. Thomas, K. R. & Capecchi, M. R. Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells. Cell 51, 503–512 (1987).

    Article  CAS  Google Scholar 

  4. Koller, B. H. et al. Germ-line transmission of a planned alteration made in a hypoxanthine phosphoribosyl-transferase gene by homologous recombination in embryonic stem cells. Proc. Natl Acad. Sci. USA 86, 8927–8931 (1989).

    Article  CAS  Google Scholar 

  5. Thomas, K. R. & Capecchi, M. R. Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development. Nature 346, 847–850 (1990).

    Article  CAS  Google Scholar 

  6. Austin, C. P. et al. The Knockout Mouse Project. Nature Genet. 36, 921–924 (2004).

    Article  CAS  Google Scholar 

  7. Snouwaert, J. N. et al. An animal model for cystic fibrosis made by gene targeting. Science 257, 1083–1088 (1992).

    Article  CAS  Google Scholar 

  8. Zhang, S. H., Reddick, R. L., Piedrahita, J. A. & Maeda, N. Spontaneous hypercholesterolemia and arterial lesions in mice lacking apolipoprotein E. Science 258, 468–471 (1992).

    Article  CAS  Google Scholar 

  9. Hilbert, P. et al. Chromosomal mapping of two genetic loci associated with blood-pressure regulation in hereditary hypertensive rats. Nature 353, 521–529 (1991).

    Article  CAS  Google Scholar 

  10. Jacob, H. J. et al. Genetic mapping of a gene causing hypertension in the stroke-prone spontaneously hypertensive rat. Cell 67, 213–224 (1991).

    Article  CAS  Google Scholar 

  11. Kreutz, R., Hubner, N., Ganten, D. & Lindpaintner, K. Genetic linkage of the ACE gene to plasma angiotensin-converting enzyme activity but not to blood pressure. A quantitative trait locus confers identical complex phenotypes in human and rat hypertension. Circulation 92, 2381–2384 (1995).

    Article  CAS  Google Scholar 

  12. Laragh, J. H. & Brenner, B. M. (eds) Hypertension: Pathophysiology, Diagnosis, and Management (Raven Press, New York, 1990).

    Google Scholar 

  13. Jeunemaitre, X. et al. Molecular basis of human hypertension: role of angiotensinogen. Cell 71, 169–180 (1992).

    Article  CAS  Google Scholar 

  14. Harris, H. The Principles of Human Biochemical Genetics (Elsevier Science, New York, 1970).

    Google Scholar 

  15. Epstein, C. J. in The Metabolic Basis of Inherited Disease 6th edn Vol. 1 (eds Scriver, C. R., Beaudet, A. R., Sly, W. S. & Valle, D.) 291–326 (McGraw-Hill, New York, 1989).

    Google Scholar 

  16. Valancius, V. & Smithies, O. Double-strand gap repair in a mammalian gene targeting reaction. Mol. Cell Biol. 11, 4389–4397 (1991).

    Article  CAS  Google Scholar 

  17. Kim, H-.S. et al. Genetic control of blood pressure and the angiotensinogen locus. Proc. Natl Acad. Sci. USA 92, 2735–2739 (1995).

    Article  CAS  Google Scholar 

  18. Krege, J. H. et al. Angiotensin-converting enzyme gene mutations, blood pressures, and cardiovascular homeostasis. Hypertension 29, 150–157 (1997).

    Article  CAS  Google Scholar 

  19. Krege, J. H., Hodgin, J. B., Hagaman, J. R. & Smithies, O. A noninvasive computerized tail-cuff system for measuring blood pressure in mice. Hypertension 25, 1111–1115 (1995).

    Article  CAS  Google Scholar 

  20. Inoue, I. et al. A nucleotide substitution in the promoter of human angiotensinogen is associated with essential hypertension and affects basal transcription in vitro. J. Clin. Invest. 99, 1786–1797 (1997).

    Article  CAS  Google Scholar 

  21. Smithies, O., Kim, H-.S., Takashi, N. & Edgell, M. H. Importance of quantitative genetic variations in the etiology of hypertension. Kidney Int. 58, 2265–2280 (2000).

    Article  CAS  Google Scholar 

  22. Smithies, O. Why the kidney glomerulus does not clog: a gel permeation/diffusion hypothesis of renal function. Proc. Natl Acad. Sci. USA 100, 4108–4113 (2003).

    Article  CAS  Google Scholar 

  23. Ogston, A. G. The spaces in a uniform random suspension of fibres. Trans. Faraday Soc. 54, 1754–1757 (1958).

    Article  Google Scholar 

  24. Smithies, O. Alexander George Ogston. 30 January 1911–29 June 1996. Biographical Memoirs Fellows R. Soc. 45, 349–364 (1999).

    Article  Google Scholar 

  25. Takahashi, N. & Smithies, O. Human genetics, animal models and computer simulations for studying hypertension. Trends Genet. 20, 136–145 (2004).

    Article  CAS  Google Scholar 

  26. Niederberger, P., Prasad, R., Miozzari, G. & Kacser, H. A strategy for increasing an in vivo flux by genetic manipulations. The tryptophan system of yeast. Biochem. J. 287, 473–479 (1992).

    Article  CAS  Google Scholar 

  27. Rigat, B. et al. An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels. J. Clin. Invest. 86, 1343–1346 (1990).

    Article  CAS  Google Scholar 

  28. Hadjadj, S. et al. Prognostic value of angiotensin-I converting enzyme I/D polymorphism for nephropathy in type 1 diabetes mellitus: a prospective study. J. Am. Soc. Nephrol. 12, 541–549 (2001).

    CAS  PubMed  Google Scholar 

  29. Huang, W. et al. Genetically increased angiotensin-I converting enzyme level and renal complications in the diabetic mouse. Proc. Natl. Acad. Sci. USA 98, 13330–13334 (2001).

    Article  CAS  Google Scholar 

  30. Yoshioka, M., Kayo, T., Ikeda, T. & Koizumi, A. A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice. Diabetes 46, 887–894 (1997).

    Article  CAS  Google Scholar 

  31. Borkowski, J. A. et al. Targeted disruption of a B2 bradykinin receptor gene in mice eliminates bradykinin action in smooth muscle and neurons. J. Biol. Chem. 270, 13706–13710 (1995).

    Article  CAS  Google Scholar 

  32. Kakoki, M., Takahashi, N., Jennette, J. C. & Smithies, O. Diabetic nephropathy is markedly enhanced in mice lacking the bradykinin B2 receptor. Proc. Natl Acad. Sci. USA 101, 13302–13305 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

Most of my work on complex genetic diseases has been funded by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, 27599-7525, North Carolina, USA

    Oliver Smithies

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  1. Oliver Smithies
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Correspondence to Oliver Smithies.

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Related links

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DATABASES

Entrez

ACE

AGT

CFTR

HPRT

OMIM

atherosclerosis

cystic fibrosis

diabetes

erythroleukaemia

hypertension

Lesch–Nyhan disease

nephropathy

pre-eclampsia

sickle-cell anaemia

thalassaemia

FURTHER INFORMATION

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Smithies, O. Many little things: one geneticist's view of complex diseases. Nat Rev Genet 6, 419–425 (2005). https://doi.org/10.1038/nrg1605

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