We have represented the fraction of mutations at each of the 96 mutated trinucleotides as a heat map for each cancer and normalized it according to the prevalence of each trinucleotide in the genome.
We then integrate over all mutational effects to estimate f SDM, the fraction of mutations that have deleterious effects in the range given by s c, so that U SDM = U TOT * f SDM.
Although Y220C represents only a fraction of mutations in p53 that lead to cancer, this protein is so frequently mutated in cancer that even this fraction represents a large patient population that could be effectively treated with this compound.
Selection against deleterious mutations will increase the fraction of mutations segregating at low frequencies in the sample.
We then calculate the fraction of mutations for buried and exposed sites, fb and fe, and use these values to parameterize our binomial model.
In contrast to this, in populations thriving in changing environments a larger fraction of mutations have beneficial effects, providing the diversity necessary to adapt to new conditions.
Finally, the tethered factors may create chromatin that is more accessible to mismatch repair, so a significant fraction of mutations could in principle be reverted, to create a large class of mutants with only single base changes.
We calculated the fraction of mutations at buried sites within and outside of mutation clusters, and carried out a paired t-test to determine whether clustered mutations were more or less buried than non-clustered mutations.
This data can be seen in another form by examining the fraction of mutations with a given score cutoff that are classified as either deleterious, neutral, or activating (Fig. 2B).
We also expect that the contributions of different proteins to a given phenotype are likely to vary: whereas one protein might be absolutely central to that phenotype, such that a large fraction of amino acid mutations could cause the phenotype, in a protein that participates in only part of that function, perhaps only a small fraction of mutations could cause that specific phenotype.
Eq. 3 would still apply if we interpreted nb and ne as the total number of buried and exposed amino acids in the sphere, and fb and fe as the fraction of mutations at buried and exposed sites in the protein.
