Rate and breadth of protein evolution are only weakly correlated

<p>Abstract</p> <p>Background</p> <p>Evolution at a protein site can be characterized from two different perspectives, by its rate and by the breadth of the set of acceptable amino acids.</p> <p>Results</p> <p>There is a weak positive correlation between rates and breadths of evolution, both across individual amino acid sites and across proteins.</p> <p>Conclusions</p> <p>Rate and breadth are two distinct, and only weakly correlated, characteristics of protein evolution. The most likely explanation of their positive correlation is heterogeneity of selective constraint, such that less functionally important sites evolve faster and can accept more amino acids.</p> <p>Reviewers</p> <p>This article was reviewed by Eugene V. Koonin, Arcady R. Mushegyan, and Eugene I. Shakhnovich.</p

Comparison of the calculated and experimental dataof the extracted electron beam profile

The current commercial use of electron accelerators grows in research, industry,medical diagnosis and treatment. Due to this fact, the creation of a model describing theelectron beam profile and shape is an actual task. The model of the TPU microtron extractedelectron beam created in the program "Computer Laboratory (PCLab)" is described andcompared with experimental results in this article. The value of the internal electron beamdivergence determination is illustrated. The experimental data of the electron beam profilesat the selected distances from the output window are analysed and compared with thesimulation data. The simulation data of the electron beam profiles are shown

Transcriptome‐based phylogeny of endemic Lake Baikal amphipod species flock: fast speciation accompanied by frequent episodes of positive selection

Endemic species flocks inhabiting ancient lakes, oceanic islands and other long‐lived isolated habitats are often interpreted as adaptive radiations. Yet molecular evidence for directional selection during species flocks radiation is scarce. Using partial transcriptomes of 64 species of Lake Baikal (Siberia, Russia) endemic amphipods and two nonendemic outgroups, we report a revised phylogeny of this species flock and analyse evidence for positive selection within the endemic lineages. We confirm two independent invasions of amphipods into Baikal and demonstrate that several morphological features of Baikal amphipods, such as body armour and reduction in appendages and sensory organs, evolved in several lineages in parallel. Radiation of Baikal amphipods has been characterized by short phylogenetic branches and frequent episodes of positive selection which tended to be more frequent in the early phase of the second invasion of amphipods into Baikal when the most intensive diversification occurred. Notably, signatures of positive selection are frequent in genes encoding mitochondrial membrane proteins with electron transfer chain and ATP synthesis functionality. In particular, subunits of both the membrane and substrate‐level ATP synthases show evidence of positive selection in the plankton species Macrohectopus branickii, possibly indicating adaptation to active plankton lifestyle and to survival under conditions of low temperature and high hydrostatic pressures known to affect membranes functioning. Other functional categories represented among genes likely to be under positive selection include Ca‐binding muscle‐related proteins, possibly indicating adaptation to Ca‐deficient low mineralization Baikal waters.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/136009/1/mec13927.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/136009/2/mec13927_am.pd

Early on-treatment transcriptional profiling as a tool for improving pathological response prediction in HER2-positive inflammatory breast cancer

Background: Inflammatory breast cancer (IBC) is a rare and understudied disease, with 40% of cases presenting with human epidermal growth factor receptor 2 (HER2)-positive subtype. The goals of this study were to (i) assess the pathologic complete response (pCR) rate of short-term neoadjuvant dual-HER2-blockade and paclitaxel, (ii) contrast baseline and on-treatment transcriptional profiles of IBC tumor biopsies associated with pCR, and (iii) identify biological pathways that may explain the effect of neoadjuvant therapy on tumor response. Patients and Methods: A single-arm phase II trial of neoadjuvant trastuzumab (H), pertuzumab (P), and paclitaxel for 16 weeks was completed among patients with newly diagnosed HER2-positive IBC. Fresh-frozen tumor biopsies were obtained pretreatment (D1) and 8 days later (D8), following a single dose of HP, prior to adding paclitaxel. We performed RNA-sequencing on D1 and D8 tumor biopsies, identified genes associated with pCR using differential gene expression analysis, identified pathways associated with pCR using gene set enrichment and gene expression deconvolution methods, and compared the pCR predictive value of principal components derived from gene expression profiles by calculating and area under the curve for D1 and D8 subsets. Results: Twenty-three participants were enrolled, of whom 21 completed surgery following neoadjuvant therapy. Paired longitudinal fresh-frozen tumor samples (D1 and D8) were obtained from all patients. Among the 21 patients who underwent surgery, the pCR and the 4-year disease-free survival were 48% (90% CI 0.29-0.67) and 90% (95% CI 66-97%), respectively. The transcriptional profile of D8 biopsies was found to be more predictive of pCR (AUC = 0.91, 95% CI: 0.7993-1) than the D1 biopsies (AUC = 0.79, 95% CI: 0.5905-0.9822). Conclusions: In patients with HER2-positive IBC treated with neoadjuvant HP and paclitaxel for 16 weeks, gene expression patterns of tumor biopsies measured 1 week after treatment initiation not only offered different biological information but importantly served as a better predictor of pCR than baseline transcriptional analysis

Complex Selection on Human Polyadenylation Signals Revealed by Polymorphism and Divergence Data

Polyadenylation is a step of mRNA processing which is crucial for its expression and stability. The major polyadenylation signal (PAS) represents a nucleotide hexamer that adheres to the AATAAA consensus sequence. Over a half of human genes have multiple cleavage and polyadenylation sites, resulting in a great diversity of transcripts differing in function, stability, and translational activity. Here, we use available whole-genome human polymorphism data together with data on interspecies divergence to study the patterns of selection acting on PAS hexamers. Common variants of PAS hexamers are depleted of single nucleotide polymorphisms (SNPs), and SNPs within PAS hexamers have a reduced derived allele frequency (DAF) and increased conservation, indicating prevalent negative selection; at the same time, the SNPs that “improve” the PAS (i.e., those leading to higher cleavage efficiency) have increased DAF, compared to those that “impair” it. SNPs are rarer at PAS of “unique” polyadenylation sites (one site per gene); among alternative polyadenylation sites, at the distal PAS and at exonic PAS. Similar trends were observed in DAFs and divergence between species of placental mammals. Thus, selection permits PAS mutations mainly at redundant and/or weakly functional PAS. Nevertheless, a fraction of the SNPs at PAS hexamers likely affect gene functions; in particular, some of the observed SNPs are associated with disease

Methylated Arginine Analogues: Their Potential Role in Atherosclerosis and Cognition Using the Poloxamer 407-induced Mouse Model of Dyslipidemia

An experimental mouse model of dyslipidemia and atherosclerosis was utilized to study the generation of methyarginines in vivo, as well as any potential behavioral changes in mice associated with the production of excess methylarginines. Following 14 weeks of poloxamer 407 treatment, mice developed atherosclerosis and the plasma concentrations of monomethylarginine and asymmetric dimethylarginine were found to be significantly greater than corresponding concentrations in control mice. This finding may have contributed to the development of aortic atherosclerotic lesions in poloxamer-treated mice by interfering with nitric oxide availability and hence, normal function of vascular endothelium. Poloxamer 407-treated mice also showed a significant decrease in locomotor and exploratory activity, together with signs of emotional stress and anxiety relative to controls. Passive/avoidance testing to assess learning and memory provided suggestive evidence that poloxamer-treated mice could potentially be characterized as having undergone a disruption in the process of forgetting about an aversive event; specifically, a foot shock, when compared to control mice. Thus, it is also suggested that the increase in both plasma monomethylarginine and asymmetric dimethylarginine in poloxamer-407-treated mice may somehow influence learning and memory, since endothelial dysfunction caused by reduced nitric oxide availability has been hypothesized to negatively influence cognitive function.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Excessive Parallelism in Protein Evolution of Lake Baikal Amphipod Species Flock

Repeated emergence of similar adaptations is often explained by parallel evolution of underlying genes. However, evidence of parallel evolution at amino acid level is limited. When the analyzed species are highly divergent, this can be due to epistatic interactions underlying the dynamic nature of the amino acid preferences: The same amino acid substitution may have different phenotypic effects on different genetic backgrounds. Distantly related species also often inhabit radically different environments, which makes the emergence of parallel adaptations less likely. Here, we hypothesize that parallel molecular adaptations are more prevalent between closely related species. We analyze the rate of parallel evolution in genome-size sets of orthologous genes in three groups of species with widely ranging levels of divergence: 46 species of the relatively recent lake Baikal amphipod radiation, a species flock of very closely related cichlids, and a set of significantly more divergent vertebrates. Strikingly, in genes of amphipods, the rate of parallel substitutions at nonsynonymous sites exceeded that at synonymous sites, suggesting rampant selection driving parallel adaptation. At sites of parallel substitutions, the intraspecies polymorphism is low, suggesting that parallelism has been driven by positive selection and is therefore adaptive. By contrast, in cichlids, the rate of nonsynonymous parallel evolution was similar to that at synonymous sites, whereas in vertebrates, this rate was lower than that at synonymous sites, indicating that in these groups of species, parallel substitutions are mainly fixed by drift