In general, PRPS1 gain-of-function mutations determine a loss of feedback regulation and hence enzyme superactivity, which in turn causes excessive uric acid production and gout.
On the other hand, the DFE of deleterious mutations, in particular the proportion of weakly deleterious mutations, determine a population's expected drift load the reduction in fitness due to multiple small-effect deleterious mutations that individually are close enough to neutral to occasionally escape selection, but can collectively have important impacts on fitness.
As reported for sulfoxidized variants at positions M206, M213 (MO213, MO213 and MO206 213) [32], the E196K, F198S, E200K, V210I and E211Q mutations determine an enhancement of flexibility that is restricted to the region 165 175 [Figure 2B].
By generating these two mutants we observed that the T198A mutation determines a drastic reduction of p27 protein expression as previously reported by others [18].
At the opposite side of the spectrum of effects, the T188K mutation determines a large increase in the coordinated motions of residue pairs.
Consistently, this V232fs frameshift mutation determines a NGF protein in which the terminal 15 aminoacids are replaced with a novel 43 aminoacid terminal sequence, resulting in a functionally null protein [28].
This mutation determines a temperature-related loss of function, with the T allele having an enzyme activity of approximately 35% of the values observed in individuals carrying the C allele.
The S59P mutation determines a constitutive activation of the IL-1R pathway, inhibition of apoptosis, and an enhanced and persistent NF-κB activation and cytokines secretion in response to IL-1β stimulation.
The strength of selection for new driver mutations determined whether a mutator phenotype would evolve; very strong or very weak selection for driver mutations suppressed the evolution of a mutator phenotype (Fig. S3A).
On the other hand, R172H p53 mutant, equivalent to human R175H, is a structure defective mutant whose point mutation determines an important conformational alteration [46].
