Cold sensitivity was also observed for the Escherichia coli SecG deletion [21], although it was dependent on a second mutation in glpR, involved in glycerol phosphate regulation [49].
In addition, in a mouse model of metastatic melanoma that was dependent on a B-Raf mutation CI-1040 was preventing the formation of new pulmonary metastases and caused rapid regression of already established pulmonary metastases [ 22].
This pattern is consistent with the Knudson's 'two hit' model, which states that (if an inherited malignancy is dependent on inactivating mutation of a tumour-suppressor gene) one copy of the defective gene is inherited and the second copy is mutated during development/growth, subsequently leading to a more rapid oncogenic transformation (Knudson, 1971).
In contrast, the FGFR1-equivalent substitution in FGFR3 (V555M) is highly likely to occur and was previously identified in the context of a cancer cell line (multiple myeloma KMS-11) dependent on an FGFR3 Y373C driver mutation (Chell et al., 2013).
1. Cancer is an inherently stochastic process dependent on random mutation accumulation and a very noisy (sampling noise) process of cell proliferation when cancer cell numbers are low.
Moreover, a different study found an epistatic interaction between ANK3 and KCNQ2 SNPs in bipolar disorder, i.e. the effect of a mutation in one gene was dependent on the mutation present in the other gene [ 72].
BMPR2 is the gene mutated in most familial PAH; adult mice expressing smooth-muscle specific mutations in BMPR2 develop PAH, although with a phenotype somewhat dependent on the mutation used[ 26, 27].
Direct experimental study of the look-ahead effect is still lacking but population-genetic models indicate that phenotypic mutations can be sufficient for alleles carrying only one mutation required for a trait dependent on two mutations to spread in a population provided the selective advantage of the combination of two mutations is high enough [ 51].
We also observed that robustness consistently fostered long-term adaptation in the simple environment, a result which was weakly dependent on the mutation rate.
The other unexplainable phenomena by mutation theory above can be explained by the WOWH mechanism: (1) The chance to have a clinical cancer is not dependent on gene mutation numbers, but on the underlying wounds and the wound healing capacity.
