Rodent Serpins : Accelerated Evolution and Novel Specificities

  • John D. Inglis
  • Robert E. Hill
Part of the NATO ASI Series book series (NSSA, volume 191)


In the basic studies of mammalian physiology, development, pharmacology, anatomy, and other disciplines, rodents (rats and inbred mice) have been assumed to be appropriate model systems in the study of human biology and diseases. In many cases, direct comparisons are valid and valuable. However, recently several disappointing results have been reported using the mouse as a model for studying human diseases. The deletion by homologous recombination of the mouse HPRTase gene has not resulted in Lesch-Nyan Disease1 and the mdx mutation of the dystrophin gene shows few phenotypic similarities to muscular dystrophy.2 In the HPRTase deficiency in mouse, the neurological pathology of Lesch-Nyan is bypassed by a more efficient manner of dealing with toxic metabolites of uric acid.2 These physiological differences are simply due to the fact that the present day rodents and primates shared their last common ancestor some 80 million years ago (Mya). Therefore, different evolutionary pressures have been operating on these species’ ancestors for an appreciable evolutionary time period.


Neutral Theory Immunoglobulin Heavy Chain Cosmid Clone Cosmid Library Bovine Pancreatic Trypsin Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    T. Doetschman, R.G. Gregg, N. Maeda, M.L. Hooper, D.W. Melton, S. Thompson, and O. Smithies, Targeted correction of a mutant HPRT gene in mouse embryonic stem cells. Nature 330: 576 (1987).CrossRefPubMedGoogle Scholar
  2. 2.
    R.P. Erickson, Why isn’t a mouse more like a man? Trends Genet. 5: 1 (1989).CrossRefPubMedGoogle Scholar
  3. 3.
    K.L. Bennett, PA. Lalley, R.K. Barth, and N.D. Hastie, Mapping the structural genes coding for the major urinary proteins in the mouse: combined use of recombinant inbred strains and somatic cell hybrids. Proc. Natl. Acad. Sci. USA 79: 1220 (1982).Google Scholar
  4. 4.
    R.E. Hill,F.H. Shaw, R.K. Barth, and N.D. Hastie, A genetic locus closely linked to a protease inhibitor gene complex controls the level of multiple mRNA transcripts. Molec. Cell Biol. 5: 2114 (1985).PubMedGoogle Scholar
  5. 5.
    E. Ehrich, A. Craig, A. Poustka, A.-M. Frischauf, and H. Lehrach, A family of cosmid vectors with the multi-copy R6K replication origin. Gene 57: 229 (1987).CrossRefPubMedGoogle Scholar
  6. 6.
    T. Maniatis, E.F. Fritsch, and J. Sambrook, Amplification, storage, and screening of cosmid libraries, in: “Molecular Cloning: A Laboratory Manual” CSH, Cold Spring Harbor, NY p 304 (1982).Google Scholar
  7. 7.
    F. Sanger, S. Nicklen, and A.R. Coulson, DNA sequencing with chain terminating inhibitors. Proc. Natl. Acad. Sci. USA 74: 5463 (1977).Google Scholar
  8. 8.
    J.-J. Bao, L. Reed-Fourquet, R.N. Sifers, U.J. Kidd, and S.L.C. Woo, Molecular structure and sequence homology of a gene related to al-antitrypsin in the human genome. Genomics 2: 165 (1988).CrossRefPubMedGoogle Scholar
  9. 9.
    G.D. Kelsey, M. Parkar, and S. Povey, The human alpha-l-anti-trypsin-related sequence gene: isolation and investigation of its expression. Ann. Hum. Genet. 52: 151 (1988).Google Scholar
  10. 10.
    D.W. Cox, V.D. Markovic, and I.E. Teshima, Genes for immunoglobulin heavy chains and for at-antitrypsin are localized to specific regions of chromosome 14q. Nature 297: 428 (1982).CrossRefPubMedGoogle Scholar
  11. 11.
    M. Rabin, M. Watson, V. Kidd, S.L.C. Woo, W.R. Beeg, and F.H. Ruddle, Regional Localization of a1-antichymotrypsin and Œl-antitrypsin genes on human chromosome 14. Som. Cell Mol. Genet. 12: 209 (1986).Google Scholar
  12. 12.
    G.D. Kelsey, D. Abeliovich, C.J. McMahon, D. Whitehouse, G. Corney, S. Povey, DA. Hopkinson, J. Wolfe, G. Mieli Vergani, and A.P. Mowat, Cloning of the human Ct antichymotrypsin gene and genetic analysis of the gene in relation to at antitrypsin deficiency. J. Med. Genet. 25: 361 (1988).Google Scholar
  13. 13.
    R. Carrell, Therapy by instant evolution. Nature 312: 14 (1984).CrossRefPubMedGoogle Scholar
  14. 14.
    M.C. Owen, S.O. Brennan, J.H. Lewis, and R.W. Carrell, Mutation of antitrypsin to antithrombin. New Engl. J. Med. 309: 694 (1983).Google Scholar
  15. 15.
    A.W. Stephens, B.S. Thalley, and C.H.W. Hirs, Antithrombin III Denver, a reactive site variant. J. Biol. Chem. 262: 1044 (1987).Google Scholar
  16. 16.
    W.E. Holmes, H.R. Lijnen, and D. Collen, Characterization of recombinant human a2- antiplasmin and of mutants obtained by site directed mutagens is of the reactive site. Biochemistry 26: 5133 (1987).CrossRefPubMedGoogle Scholar
  17. 17.
    W.E. Holmes, H.R. Lijnen, L. Nelles, C. Kluft, H.K. Nieuwenhuis, D.C. Rijken, and D. Collen, a2-Antiplasmin Enschede: alanine insertion and abolition of plasmin inhibitory activity. Science 238: 209 (1987).CrossRefPubMedGoogle Scholar
  18. 18.
    M. Kimura, The neutral theory of molecular evolution. Cambridge Univ Press, London (1983).Google Scholar
  19. 19.
    W.H. Li, and M. Tanimura, The molecular clock runs more slowly in man than in apes and monkeys. Nature 326: 93 (1987).CrossRefPubMedGoogle Scholar
  20. 20.
    R.E. Hill, and N.D. Hastie, Accelerated evolution in the reactive centre regions of serine protease inhibitors. Nature 326: 96 (1987).CrossRefPubMedGoogle Scholar
  21. 21.
    W.-H. Li, C.-I. Wu, and C.-C. Luo, A new method for estimating synonymous and nonsynonymous rates of nucleotide substitution considering the relative likelihood of nucleotide and codon changes. Molec. Biol. Evol. 2: 150 (1985).Google Scholar
  22. 22.
    R.E. Hill, P.H. Shaw, PA. Boyd, H. Banmann, and N.D. Hastie, Plasma protease inhibitors in mouse and man: divergence within the reactive centre regions. Nature 311: 175 (1984).CrossRefPubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1990

Authors and Affiliations

  • John D. Inglis
    • 1
  • Robert E. Hill
    • 1
  1. 1.Medical Research Council Human Genetics UnitWestern General HospitalEdinburghUK

Personalised recommendations