Functional census of mutation sequence spaces: the example of p53 cancer rescue mutants

IEEE/ACM Trans Comput Biol Bioinform. 2006 Apr-Jun;3(2):114-25. doi: 10.1109/TCBB.2006.22.

Abstract

Many biomedical problems relate to mutant functional properties across a sequence space of interest, e.g., flu, cancer, and HIV. Detailed knowledge of mutant properties and function improves medical treatment and prevention. A functional census of p53 cancer rescue mutants would aid the search for cancer treatments from p53 mutant rescue. We devised a general methodology for conducting a functional census of a mutation sequence space by choosing informative mutants early. The methodology was tested in a double-blind predictive test on the functional rescue property of 71 novel putative p53 cancer rescue mutants iteratively predicted in sets of three (24 iterations). The first double-blind 15-point moving accuracy was 47 percent and the last was 86 percent; r = 0.01 before an epiphanic 16th iteration and r = 0.92 afterward. Useful mutants were chosen early (overall r = 0.80). Code and data are freely available (http://www.igb.uci.edu/research/research.html, corresponding authors: R.H.L. for computation and R.K.B. for biology).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Artificial Intelligence
  • Binding Sites / genetics
  • Computational Biology / methods*
  • Humans
  • Internet
  • Models, Molecular
  • Models, Statistical*
  • Mutation / genetics*
  • Mutation / physiology
  • Mutation, Missense / genetics
  • Mutation, Missense / physiology
  • Neoplasms / drug therapy
  • Neoplasms / genetics
  • Protein Folding
  • Protein Structure, Tertiary
  • ROC Curve
  • Suppression, Genetic / genetics
  • Suppression, Genetic / physiology
  • Surface Properties
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / genetics*

Substances

  • Tumor Suppressor Protein p53