CpG transition strand asymmetry and hitch-hiking mutations as measures of tumorigenic selection in shaping the p53 mutation spectrum.
By the genetic code, the average protein perturbation expected from a CpG-->TpG transition is strand-specific and smallest when it originates with the C on the transcribed (noncoding) strand. To distinguish the effects of selection from mutagenesis, we measured strand asymmetry for CpG-->TpG transitions fixed in active p53 genes and pseudogenes during vertebrate evolution, and for p53 genes from human tumors with one (singlet) and two (doublet) p53 point mutations. Mutagenesis appears to generate the transitions symmetrically while selection usually acts asymmetrically being most sensitive to the larger protein perturbations. Tumorigenic selection acting on the central domain of the p53 gene appears exceptional in that it often senses gain of function amino acid substitutions whose altered function is unrelated to degree of protein perturbation. In doublets, the selection on some gain of function substitutions is relaxed as evidenced by a return to the transition strand symmetry.
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Document Type: Research Article
Affiliations: Beckman Research Institute, City of Hope, Duarte, CA 91010, USA.
Publication date: January 1, 1998
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- The International Journal of Molecular Medicine is a monthly, peer-reviewed journal devoted to the publication of high quality studies related to the molecular mechanisms of human disease. The journal welcomes research on all aspects of molecular and clinical research, ranging from biochemistry to immunology, pathology, genetics, human genomics, microbiology, molecular pathogenesis, molecular cardiology, molecular surgery and molecular psychology.
The International Journal of Molecular Medicine aims to provide an insight for researchers within the community in regard to developing molecular tools and identifying molecular targets for the diagnosis and treatment of a diverse number of human diseases.
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