Evolutionary conservation and somatic mutation hotspot maps of p53: correlation with p53 protein structural and functional features

Missense mutations in p53 frequently occur at 'hotspot' amino acids which a re highly conserved and represent regions of structural or functional impor tance. Using the p53 mutation database and the p53 DNA sequences for 11 spe cies, we more precisely defined the relationships among conservation, mutat ion frequency and protein structure. We aligned the p53 sequences codon-by- codon and determined the degree of substitution among them. As a whole, p53 is evolving at an average rate for a mammalian protein-coding gene. As exp ected, the DNA binding domain is evolving more slowly than the carboxy and amino termini, A detailed map of evolutionary conservation shows that withi n the DNA binding domain there are repeating peaks and valleys of higher an d lower evolutionary constraint, Mutation hotspots were identified by compa ring the observed distribution of mutations to the pattern expected from a random multinomial distribution, Seventy-three hotspots were identified; th ese 19% of codons account for 88% of all reported p53 mutations. Both high evolutionary constraint and mutation hotspots are noted at amino acids clos e to the protein-DNA interface and at others more distant from DNA, often b uried within the core of the folded protein but sometimes on its surface. T he results indicate that targeting highly conserved regions for mutational and functional analysis may be efficient strategies for the study of cancer -related genes.