Among mutations exclusively detected in post-treatment samples, there were 3 truncating mutations and 17 missense mutations predicated to impact the functions of associated genes by PolyPhen-221 and 9 genes were previously reported to be associated with chemoresistance in several types of cancer (Supplementary Data 7).
This question could readily be addressed by crossing pIgR-sufficient and -deficient mice with mice bearing other genetic mutations known to impact intestinal homeostasis.
In fact, these mutations seem to impact the PON1mut active site by directly reducing the catalytic core flexibility, while maintaining a significant mobility of the switch regions delineated by the loops surrounding the active site.
Most disease-causing mutations were predicted to impact protein function.
These rare deleterious mutations are unlikely to impact inferences about population structure and historical relationships; however, they may impact the frequency spectrum of polymorphisms and produce excess low frequency variation that could otherwise suggest the hypothesis of a population expansion.
Although these mutations are assumed to impact primarily on cell cycle regulation, RB1 has many additional roles, including regulation of chromosome stability, senescence and cellular differentiation (Indovina et al, 2013).
Our two hypotheses were: (i) we assumed that regular secondary structure is difficult to maintain evolutionarily, i.e. single residue mutations are likely to impact helices and strands and that we would lose regular secondary structure and transit into 'loopy' polypeptide chains with increasing random mutations away from the native state.
This result shows that orientation with respect to the replication fork can have an impact on mutation rate for a single base-pair substitution; however, this is unlikely to impact mutation rates in our experiment because we are detecting loss-of-function mutations over an entire gene, which will average out these small-scale effects.
Synonymous mutations are often thought to impact both gene expression and fitness through modifications to codon usage bias, mRNA stability or protein folding, but these mechanisms seem unlikely explanations for our results.
Identification of mismatch repair gene mutations has the potential to impact screening and treatment decisions in these women.
