To obtain a snapshot of the fitness effect of all segregating variation (i.e., independently of whether sites are lost or transmitted to the following generation), we partitioned segregating sites into three categories corresponding to very deleterious, mildly deleterious, and nearly neutral (Materials and Methods).
In an elegant study using a MMTV- WNT1 mouse mammary tumour model, they generated p53 R172H (corresponding to the deleterious human codon 175 mutation), p53 -/- and p21 -/- mice.
The distribution of S among novel mutations clearly shows a multimodal distribution with one large peak around nearly neutral mutations (−2 < S < −2) and with another peak corresponding to highly deleterious mutations (S < −10).
The first intensive studies to evaluate the evolution of these lesions were performed by Kischner et al., who attempted to simulate the induction of solid and necrotic granulomas, corresponding to protective and deleterious responses respectively, in macaques infected with M. tuberculosis [9].
Moreover, positive displacements in T1 greater than or equal to 1.0 second were more deleterious than corresponding negative displacements, when comparing the impact on CTp values in relation to the reference.
However, because zinc is such an important cofactor ubiquitously involved in many fundamental biological reactions, reduction of zinc to a critical level may substantially affect the corresponding processes and become deleterious to organism's survival.
Of course, it also suffers from some disadvantage when homozygote, by being in individuals that are more likely also to be homozygotes for the remaining alleles of their group, but still the resulting expected fitness can be higher than that corresponding to an uncoupled deleterious copy.
The MutPred tool calculates the probability of a deleterious mutation and corresponding hypothesis of disrupted molecular mechanism.
In the context of the E. coli data that we are analyzing, we predict that epistatic deviations tend to more positive values when the component mutations have more deleterious effects (thus corresponding to greater distances from the local peak).
