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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