Detailed computational study of p53 and p16: using evolutionary sequence analysis and disease-associated mutations to predict the functional consequences of allelic variants.

摘要: Deciding whether a missense allelic variant affects protein function is important in many contexts. We previously demonstrated that detailed analysis of p53 intragenic conservation correlates with somatic mutation hotspots. Here we refine these evolutionary studies and expand them to the p16/Ink4a gene. calculated order for 'absolute conservation' codon across multiple species achieve P or =5 mutations also likely indicate functionally critical residues, even though P0.05. p16 evolution using amino acid substitution matrices nucleotide distances. looked parameters at each would predict were disease associated disrupted function. The current database too small determine observations are statistically significant. Increasing number sequences from three seven significantly improved predictive value computations. sensitivity specificity scores predicting association codons 70-80%. Despite sequence database, our calculations high correctly predicted loss cell cycle arrest 75% tested codons, low wild-type 80-90% codons. These data validate hypothesis analyses help consequences amino-acid variants.