In 2005, with the discovery of the JAK2V617F mutation, a substantial breakthrough in the understanding of the pathogenesis of Ph-negative MPNs led to the rapid development of new class of agents.
However, in asexual populations, modifiers that increase the genomic mutation rate (mutators) can rise in frequency if associated with beneficial mutations, and a substantial experimental literature in support of such mutator hitchhiking has developed [ 4- 8].
We show that interference interactions can drastically affect process and state in large asexual populations: Adaptation generates beneficial driver mutations, but a substantial fraction of allele changes are passenger mutations, whose chance of fixation depends only weakly on their selection coefficient.
For these variants, the decreased association rate constants relative to WT suggest that the mutations have a substantial effect on the population of the association-competent fraction of the conformational ensemble representing the M state [37].
Despite this progress, however, the mutations causing a substantial number of hereditary diseases remain to be identified.
We actually demonstrated a small population of melanoma cells harbouring activating BRAF mutations in a substantial number of tumours that were wild type by direct sequencing.
Overall, LRRK2 mutations represent a substantial advance in our understanding of lifetime risk of PD, while slightly complicating our knowledge of the relationship between symptoms and pathology.
The idea, then, is to let natural selection check each mutation and let through only the useful ones, and thus gradually accumulate the small, additive effects of many such mutations into a substantial phenotypic change [ 190].
In Figure 6, we have also added several subplots that show more clearly that in our model deleterious mutations contribute a substantial fraction of fitness variance in the viral population.
In particular, conventional PCR followed by high-resolution melting (HRM) or sequencing failed to detect mutations in a substantial number of samples due to the limited sensitivity of this approach.
