Why are proteins so robust to site mutations?

There have been repeated observations that proteins are surprisingly robust to site mutations, enduring significant numbers of substitutions with little change in structure, stability, or function. These results are almost paradoxical in light of what is known about random heteropolymers and the sensitivity of their properties to seemingly trivial mutations. To address this discrepancy, the preservation of biological protein properties in the presence of mutation has been interpreted as indicating the independence of selective pressure on such properties. Such results also lead to the prediction that de novo protein design should be relatively easy, in contrast to what is observed. Here, we use a computational model with lattice proteins to demonstrate how this robustness can result from population dynamics during the evolutionary process. As a result, sequence plasticity may be a characteristic of evolutionarily derived proteins and not necessarily a property of designed proteins. This suggests that this robustness must be re-interpreted in evolutionary terms, and has consequences for our understanding of both in vivo and in vitro protein evolution.     

Associations between infection intensity categories and morbidity prevalence in school-age children are much stronger for Schistosoma haematobium than for S. mansoni

BackgroundWorld Health Organization (WHO) guidelines for measuring global progress in schistosomiasis control classify individuals with Schistosoma spp. infections based on the concentration of excreted eggs. We assessed the associations between WHO infection intensity categories and morbidity prevalence for selected S. haematobium and S. mansoni morbidities in school-age children.MethodologyA total of 22,488 children aged 6–15 years from monitoring and evaluation cohorts in Burkina Faso, Mali, Niger, Uganda, Tanzania, and Zambia from 2003–2008 were analyzed using Bayesian logistic regression. Models were utilized to evaluate associations between intensity categories and the prevalence of any urinary bladder lesion, any upper urinary tract lesion, microhematuria, and pain while urinating (for S. haematobium) and irregular hepatic ultrasound image pattern (C-F), enlarged portal vein, laboratory-confirmed diarrhea, and self-reported diarrhea (for S. mansoni) across participants with infection and morbidity data.Principal findingsS. haematobium infection intensity categories possessed consistent morbidity prevalence across surveys for multiple morbidities and participants with light infections had elevated morbidity levels, compared to negative participants. Conversely, S. mansoni infection intensity categories lacked association with prevalence of the morbidity measures assessed.Conclusions/significanceCurrent status infection intensity categories for S. haematobium were associated with morbidity levels in school-age children, suggesting urogenital schistosomiasis morbidity can be predicted by an individual’s intensity category. Conversely, S. mansoni infection intensity categories were not consistently indicative of childhood morbidity at baseline or during the first two years of a preventive chemotherapy control program.