Evolution of Protein Molecules

Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

/pdf/mutations-in-prion-like-domains-in-hnrnpa2b1-and-hnrnpa1-1s364rekqd.pdf

Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS

Large volume of new data on the natural history and treatment of chronic hepatitis B virus (HBV) infection have become available since 2008. These include further studies in asymptomatic subjects with chronic HBV infection and community-based cohorts, the role of HBV genotype/naturally occurring HBV mutations, the application of non-invasive assessment of hepatic fibrosis and quantitation of HBV surface antigen and new drug or new strategies towards more effective therapy. To update HBV management guidelines, relevant new data were reviewed and assessed by experts from the region, and the significance of the reported findings was discussed and debated. The earlier "Asian-Pacific consensus statement on the management of chronic hepatitis B" was revised accordingly. The key terms used in the statement were also defined. The new guidelines include general management, indications for fibrosis assessment, time to start or stop drug therapy, choice of drug to initiate therapy, when and how to monitor the patients during and after stopping drug therapy. Recommendations on the therapy of patients in special circumstances, including women in childbearing age, patients with antiviral drug resistance, concurrent viral infection, hepatic decompensation, patients receiving immune suppression or chemotherapy and patients in the setting of liver transplantation and hepatocellular carcinoma, are also included.

/pdf/asian-pacific-consensus-statement-on-the-management-of-4kdky2cjbj.pdf

Asian-Pacific consensus statement on the management of chronic hepatitis B: a 2012 update.

Many organisms that cause infectious diseases, particularly RNA viruses, mutate so rapidly that their evolutionary and ecological behaviours are inextricably linked. Consequently, aspects of the transmission and epidemiology of these pathogens are imprinted on the genetic diversity of their genomes. Large-scale empirical analyses of the evolutionary dynamics of important pathogens are now feasible owing to the increasing availability of pathogen sequence data and the development of new computational and statistical methods of analysis. In this Review, we outline the questions that can be answered using viral evolutionary analysis across a wide range of biological scales.

/pdf/evolutionary-analysis-of-the-dynamics-of-viral-infectious-5fginwfn7w.pdf

Evolutionary analysis of the dynamics of viral infectious disease

Control of cccDNA function in hepatitis B virus infection

DNA Surveillance is a Web-based application that assists in the identification of the species and population of unknown specimens by aligning user-submitted DNA sequences with a validated and curated data set of reference sequences. Phylogenetic analyses are performed and results are returned in tree and table format summarizing the evolutionary distances between the query and reference sequences. DNA Surveillance is implemented with mitochondrial DNA (mtDNA) control region sequences representing the majority of recognized cetacean species. Extensions of the system to include other gene loci and taxa are planned. The service, including instructions and sample data, is available at http:// www.dna-surveillance.auckland.ac.nz.

/pdf/dna-surveillance-web-based-molecular-identification-of-2jglv99pvt.pdf

DNA Surveillance: Web-Based Molecular Identification of Whales, Dolphins, and Porpoises

SUMMARY SQUINT is a sequence alignment tool, and combines both automated progressive sequence alignment with facilities for manual editing. The program imports nucleotide or amino acid sequence multiple alignment files in standard formats, and permits users to view two translations of the same multiple alignment simultaneously. Edits in one view are instantaneously reflected in the other, and the scoring cost of the changes are shown in real-time. Progressive multiple alignments, using a variety of alignment parameters, can be performed on any block of sequences, including blocks embedded in the existing alignment. AVAILABILITY The software is freely available for download at http://www.cebl.auckland.ac.nz

/pdf/squint-a-multiple-alignment-program-and-editor-4yqa0wax9j.pdf

SQUINT: a multiple alignment program and editor.

The estimation of evolutionary rates from serially sampled sequences has recently been the focus of several studies. In this paper, we extend these analyzes to allow the estimation of a joint rate of substitution, omega, from several evolving populations from which serial samples are drawn. In the case of viruses evolving in different hosts, therapy may halt replication and therefore the accumulation of substitutions in the population. In such cases, it may be that only a proportion, p, of subjects are nonresponders who have viral populations that continue to evolve. We develop two likelihood-based procedures to jointly estimate p and omega, and empirical Bayes' tests of whether an individual should be classified as a responder or nonresponder. An example data set comprising HIV-1 partial envelope sequences from six patients on highly active antiretroviral therapy is analyzed.

Inferring Evolutionary Rates Using Serially Sampled Sequences from Several Populations

The PEBBLE (Phylogenetics, Evolutionary Biology, and Bioinformatics in a moduLar Environment) application is a relative newcomer to the field of phylogenetic applications Although designed as a customizable generalist application, PEBBLE was initially developed to implement procedures for the analysis of sequences associated with different sampling times, eg, rapidly evolving viral genes sampled over the course of infection, or ancient DNA sequences The basic protocol describes the use of PEBBLE to infer a phylogenetic tree using the sUPGMA algorithm, and the inference of substitution rate parameters using maximum likelihood The alternate and support protocols describe the simulation capabilities of PEBBLE, and general use of the PEBBLE application, respectively

Using PEBBLE for the evolutionary analysis of serially sampled molecular sequences.

The Phylogenetic Analysis Library (PAL) is a Java class library for performing phylogenetic inference and analysis of primarily molecular sequence data. In this paper the features of PAL are described, in particular the new features since version 1.1. Practical examples of the usage of PAL are also given.

A brief introduction to the Phylogenetic Analysis Library version 1.5

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