More details on the formula used to evaluate individual back-mutation importance are reported as Supplementary Material.
When compared to the constant fitness case, cooperative lineage expansion with early mutator mutation limits the importance of mutator pathways when few oncogenic mutations are required for cancer (C = 2) and to some extent at C = 3 with a low wild type mutation rate (kmut), but for higher values of C, α50% continues to be well within commonly observed ranges.
In discussing the expression of the induced mutations, the importance of dominant mutations and of heterozygous effects of deletions and other recessives is pointed out.
The suggestion that de novo mutation gains importance under temporally gradual environmental change and/or short generation times (Barrett and Hendry 2012) also remains to be tested with models.
This is paramount when the performance of a single animal compared with a control data set may define a new mutation of importance; thus, care must be taken to define standardized protocols (32, 36– 36).
Depending on the distribution of fitness effects of new mutations, the importance of these evolutionary forces may differ in species with different effective population sizes.
The evolution of resistance to neuraminidase in H1N1 viruses required the accumulation of permissive mutations whose importance had not been anticipated.
Recently, Almeida et al. [ 12] emphasized the clinical heterogeneity of skeletal dysplasias (achondroplasia and hypochondroplasia) associated with FGFR3 mutations, and the importance of undertaking mutation analysis to confirm the clinical diagnosis and to establish an appropriate prognosis and genetic counseling [ 12].
In addition to rare driver mutations of obvious importance, there are numerous passenger mutations found at low allelic frequency within the tumor population, presumably due to ongoing genetic stress within the tumor that results in tumor heterogeneity [ 5, 7, 12, 13].
The circadian rhythm of IgA secretion was weakened by an SCN lesion and Clock gene mutation, suggesting the importance of the SCN and Clock gene on this rhythm.
Interestingly, a microarray analysis of RUNX1 mutation suggested the importance of miR-223 [ 39].
