Recent studies have revealed the mutational signatures underlying the somatic evolution of cancer, and the prevalences of associated somatic genetic variants. Here we estimate the intensity of positive selection that drives mutations to high frequency in tumors, yielding higher prevalences than expected on the basis of mutation and neutral drift alone. We apply this approach to a sample of 525 head and neck squamous cell carcinoma exomes, producing a rank-ordered list of gene variants by selection intensity. Our results illustrate the complementarity of calculating the intensity of selection on mutations along with tallying the prevalence of individual substitutions in cancer: while many of the most prevalently-altered genes were heavily selected, their relative importance to the cancer phenotype differs from their prevalence and from their P value, with some infrequent variants exhibiting evidence of strong positive selection. Furthermore, we extend our analysis of effect size by quantifying the degree to which mutational processes (such as APOBEC mutagenesis) contributes mutations that are highly selected, driving head and neck squamous cell carcinoma. We calculate the substitutions caused by APOBEC mutagenesis that make the greatest contribution to cancer phenotype among patients. Lastly, we demonstrate via in vitro biochemical experiments that the APOBEC3B protein can deaminate the cytosine bases at two sites whose mutant states are subject to high net realized selection intensities—PIK3CA E545K and E542K. By quantifying the effects of mutations, we deepen the molecular understanding of carcinogenesis in head and neck squamous cell carcinoma.
Background: 1,8-Cineole, a commercially important monoterpene, was identified as a fungal product. Results: The 1,8-cineole synthase was identified from a Hypoxylon fungal genome, and mutagenesis revealed a critical asparagine residue. Conclusion:The fungal 1,8-cineole synthase uses a mechanism similar to the plant version. Significance: This is the first identified fungal monoterpene synthase and may facilitate future terpene synthase identification and production.
Human apolipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3 (A3) proteins are a family of cytidine deaminases that catalyze the conversion of deoxycytidine (dC) to deoxyuridine (dU) in single-stranded DNA (ssDNA). A3 proteins act in the innate immune response to viral infection by mutating the viral ssDNA. One of the most well-studied human A3 family members is A3G, which is a potent inhibitor of HIV-1. Each A3 protein prefers a specific substrate sequence for catalysis—for example, A3G deaminates the third dC in the CCCA sequence motif. However, the interaction between A3G and ssDNA is difficult to characterize due to poor solution behavior of the full-length protein and loss of DNA affinity of the truncated protein. Here, we present a novel DNA-anchoring fusion strategy using the protection of telomeres protein 1 (Pot1) which has nanomolar affinity for ssDNA, with which we captured an A3G-ssDNA interaction. We crystallized a non-preferred adenine in the -1 nucleotide-binding pocket of A3G. The structure reveals a unique conformation of the catalytic site loops that sheds light onto how the enzyme scans substrate in the -1 pocket. Furthermore, our biochemistry and virology studies provide evidence that the nucleotide-binding pockets on A3G influence each other in selecting the preferred DNA substrate. Together, the results provide insights into the mechanism by which A3G selects and deaminates its preferred substrates and help define how A3 proteins are tailored to recognize specific DNA sequences. This knowledge contributes to a better understanding of the mechanism of DNA substrate selection by A3G, as well as A3G antiviral activity against HIV-1.
Objective: The purpose of this study was to investigate the myocardial fatty acid metabolism in patients with hypertrophic cardiomyopathy (HCM) from dynamic SPECT through a compartment model analysis. Methods: Twenty-four normal controls, 7 patients with left ventricular hypertrophy (LVH) due to essential hypertension (eHT), and 30 patients with HCM were studied. I-123 BMIPP and Tc-99m tetrofosmin SPECT were performed. All the myocardium was divided into 13 segments, and totally 390 segments of HCM were categorized into early, moderately and severely advanced HCM segments, based on these SPECT imaging.By using the myocardial and blood pool time-activity curves, BMIPP pharmacokinetics was analyzed through a 2-compartment model. We defined k1 and k2 as influx and outflux rate constants between blood and myocardial reversible component, k3 as specific uptake rate constant between myocardial reversible and irreversible compartments. Results: The averages of k3 in HCM were higher than in normal. In contrast, the averages of k1/k2 in HCM were lower than in normal, and gradually decreased with progression of HCM. There are no significant differences in these indexes between normal controls and patients with LVH due to eHT.Conclusion: k3 might be a sensitive predictor for early detection of HCM, and k1/k2 could be a useful index to evaluate its progression. A mathematical compartment model analysis with BMIPP SPECT study might be useful not only for identification of HCM in very early stage, but also for evaluation of the progression of HCM.
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