181 research outputs found
Testing for dependence on tree structures
No full textTree structures, showing hierarchical relationships and the latent structures between samples, are ubiquitous in genomic and biomedical sciences. A common question in many studies is whether there is an association between a response variable measured on each sample and the latent group structure represented by some given tree. Currently, this is addressed on an ad hoc basis, usually requiring the user to decide on an appropriate number of clusters to prune out of the tree to be tested against the response variable. Here, we present a statistical method with statistical guarantees that tests for association between the response variable and a fixed tree structure across all levels of the tree hierarchy with high power while accounting for the overall false positive error rate. This enhances the robustness and reproducibility of such findings
Using host genetics to infer the global spread and evolutionary history of HCV subtype 3a
No full textStudies have shown that hepatitis C virus subtype 3a (HCV-3a) is likely to have been circulating in South Asia before its global spread. However, the time and route of this dissemination remain unclear. For the first time, we generated host and virus genome-wide data for more than 500 patients infected with HCV-3a from the UK, North America, Australia, and New Zealand. We used the host genomic data to infer the ancestry of the patients and used this information to investigate the epidemic history of HCV-3a. We observed that viruses from hosts of South Asian ancestry clustered together near the root of the tree, irrespective of the sampling country, and that they were more diverse than viruses from other host ancestries. We hypothesized that South Asian hosts are more likely to have been infected in South Asia and used the inferred host ancestries to distinguish between the location where the infection was acquired and where the sample was taken. Next, we inferred that three independent transmission events resulted in the spread of the virus from South Asia to the UK, North America, and Oceania. This initial spread happened during or soon after the end of World War II. This was subsequently followed by many independent transmissions between the UK, North America, and Oceania. Using both host and virus genomic information can be highly informative in studying the virus epidemic history, especially in the context of chronic infections where migration histories need to be accounted for
Inference of the properties of the recombination process from whole bacterial genomes
No full textPatterns of linkage disequilibrium, homoplasy, and incompatibility are difficult to interpret because they depend on several factors, including the recombination process and the population structure. Here we introduce a novel model-based framework to infer recombination properties from such summary statistics in bacterial genomes. The underlying model is sequentially Markovian so that data can be simulated very efficiently, and we use approximate Bayesian computation techniques to infer parameters. As this does not require us to calculate the likelihood function, the model can be easily extended to investigate less probed aspects of recombination. In particular, we extend our model to account for the bias in the recombination process whereby closely related bacteria recombine more often with one another. We show that this model provides a good fit to a data set of Bacillus cereus genomes and estimate several recombination properties, including the rate of bias in recombination. All the methods described in this article are implemented in a software package that is freely available for download at http://code.google.com/p/clonalorigin/
Inference of recombination properties in bacteria from whole genomes
No full textThe concept of species in bacteria is a matter of contention. The current definition is based on DNA-DNA hybridisation and does not account for evolutionary forces that are important in demarcating species. In this thesis we investigate two evolutionary forces that are important in speciation in bacteria, propose novel statistical models for them and infer parameters of interest.
We present the first attempt at inferring the bias in the recombination process from whole bacterial genomes. Despite empirical evidence that recombination is biased and theoretical results that this bias is important in speciation, it is usually ignored. We propose a coalescent based model that accounts for the bias in the recombination process. We use approximate Bayesian computation for inference and describe an efficient method for simulating from the model. We show that our method performs well on simulated datasets and is robust to slight misspecification of the history of the samples. Application of our method to a Bacillus cereus dataset shows that it contain evidence that the recombination process depends on the evolutionary distance between donors and recipients. We demonstrate that the rate of bias in the recombination process for this dataset is far lower than what theoretical studies require for the spontaneous generation of populations that can be called species under neutral model.
Next we propose a model for occurrence of adaptive events on a phylogenetic tree. We use the model to infer the boundaries of clusters on a phylogenetic tree that correspond to ecologically distinct lineages. we characterise our method using simulated datasets and show that it is conservative in estimating the number of adaptive events. Finally we apply our method to two bacterial datasets of Salmonella enterica and Vibrionaceae. We show that there is decisive evidence that isolates in these datasets partition into numerous ecologically distinct lineages and use our method to delineate the boundaries of these lineages.</p
Inference of recombination properties in bacteria from whole genomes
No full textThe concept of species in bacteria is a matter of contention. The current definition is based on DNA-DNA hybridisation and does not account for evolutionary forces that are important in demarcating species. In this thesis we investigate two evolutionary forces that are important in speciation in bacteria, propose novel statistical models for them and infer parameters of interest. We present the first attempt at inferring the bias in the recombination process from whole bacterial genomes. Despite empirical evidence that recombination is biased and theoretical results that this bias is important in speciation, it is usually ignored. We propose a coalescent based model that accounts for the bias in the recombination process. We use approximate Bayesian computation for inference and describe an efficient method for simulating from the model. We show that our method performs well on simulated datasets and is robust to slight misspecification of the history of the samples. Application of our method to a Bacillus cereus dataset shows that it contain evidence that the recombination process depends on the evolutionary distance between donors and recipients. We demonstrate that the rate of bias in the recombination process for this dataset is far lower than what theoretical studies require for the spontaneous generation of populations that can be called species under neutral model. Next we propose a model for occurrence of adaptive events on a phylogenetic tree. We use the model to infer the boundaries of clusters on a phylogenetic tree that correspond to ecologically distinct lineages. we characterise our method using simulated datasets and show that it is conservative in estimating the number of adaptive events. Finally we apply our method to two bacterial datasets of Salmonella enterica and Vibrionaceae. We show that there is decisive evidence that isolates in these datasets partition into numerous ecologically distinct lineages and use our method to delineate the boundaries of these lineages
Bayesian Inference of the Evolution of a Phenotype Distribution on a Phylogenetic Tree
No full textThe distribution of a phenotype on a phylogenetic tree is often a quantity of interest. Many phenotypes have imperfect heritability, so that a measurement of the phenotype for an individual can be thought of as a single realisation from the phenotype distribution of that individual. If all individuals in a phylogeny had the same phenotype distribution, measured phenotypes would be randomly distributed on the tree leaves. This is however often not the case, implying that the phenotype distribution evolves over time. Here we propose a new model based on this principle of evolving phenotype distribution on the branches of a phylogeny, which is different from ancestral state reconstruction where the phenotype itself is assumed to evolve. We develop an efficient Bayesian inference method to estimate the parameters of our model and to test the evidence for changes in the phenotype distribution. We use multiple simulated datasets to show that our algorithm has good sensitivity and specificity properties. Since our method identifies branches on the tree on which the phenotype distribution has changed, it is able to break down a tree into components for which this distribution is unique and constant. We present two applications of our method, one investigating the association between HIV genetic variation and human leukocyte antigen, and the other studying host range distribution in a lineage of Salmonella enterica, and we discuss many other potential applications. All the methods described in this paper are implemented in a software package called TreeBreaker which is freely available for download at https://github.com/ansariazim/TreeBreaker
Extensive C->U transition biases in the genomes of a wide range of mammalian RNA viruses; potential associations with transcriptional mutations, damage- or host-mediated editing of viral RNA.
No full textThe rapid evolution of RNA viruses has been long considered to result from a combination of high copying error frequencies during RNA replication, short generation times and the consequent extensive fixation of neutral or adaptive changes over short periods. While both the identities and sites of mutations are typically modelled as being random, recent investigations of sequence diversity of SARS coronavirus 2 (SARS-CoV-2) have identified a preponderance of C->U transitions, proposed to be driven by an APOBEC-like RNA editing process. The current study investigated whether this phenomenon could be observed in datasets of other RNA viruses. Using a 5% divergence filter to infer directionality, 18 from 36 datasets of aligned coding region sequences from a diverse range of mammalian RNA viruses (including Picornaviridae, Flaviviridae, Matonaviridae, Caliciviridae and Coronaviridae) showed a >2-fold base composition normalised excess of C->U transitions compared to U->C (range 2.1x-7.5x), with a consistently observed favoured 5' U upstream context. The presence of genome scale RNA secondary structure (GORS) was the only other genomic or structural parameter significantly associated with C->U/U->C transition asymmetries by multivariable analysis (ANOVA), potentially reflecting RNA structure dependence of sites targeted for C->U mutations. Using the association index metric, C->U changes were specifically over-represented at phylogenetically uninformative sites, potentially paralleling extensive homoplasy of this transition reported in SARS-CoV-2. Although mechanisms remain to be functionally characterised, excess C->U substitutions accounted for 11-14% of standing sequence variability of structured viruses and may therefore represent a potent driver of their sequence diversification and longer-term evolution
Proposal for a New Economic Framework Based On Islamic Principles
No full textThis book provides a holistic socio-economic framework working in conformity with the Islamic principles. Chapter 2 builds the ground for the proposed framework by discussing the foundations of the ethical precepts of Islam. It discusses the thesis of religion, answers some of the questions in the comparative study of religion and tries to resolve few of the misconceptions about the faith of Islam. Chapter 3 outlines the economic teachings of Islam with regard to earning and spending. It discusses at length the ideals Islam set before its adherents in the ethical sphere of life. The ethical principles are discussed based on the study of relevant Quranic text and the narrations of Prophet Muhammad (PBUH). Chapter 4 studies the comparative economic systems. It analyzes Capitalism, Socialism, Mixed Economy and Islamic economic system. Chapter 5 introduces the salient features of the proposed economic framework with special focus on fiscal reforms. It discusses the potential of the institution of Zakat to meet fiscal needs of the government and to assist it in doing away with deficit financing, fiscal bleeding, crowding out private sector and reducing deadweight loss by parting the way with private sector so as to ensure market economy operating on its own as far as possible and playing an active regulatory role. Chapter 6 introduces the monetary reforms. It discusses how savings would feature despite discontinuation of interest, how inflation will be checked with central banks not having at their disposal conventional OMO, how liquidity will be managed in banking sector when a central bank wants to inject liquidity or mop up funds. How and to what extent the institution of Zakat would enable the government to meet its fiscal targets and does not crowd out private sector with public borrowing. How balance of payments and exchange rate stability can be managed in an interest free economy. If in the short term, the government or central bank needs alternative source of revenue other than Zakat, they can issue GDP linked bonds. This could replace T-bill and provide a base instrument for OMO and liquidity management in the banking and financial sector. Chapter 7 introduces the currently practiced Islamic Banking and Finance. Since Islamic economic principles have more prominently been used in banking and finance, much of the discussion centers on Islamic banking and finance in lieu of analyzing the existing practices and then in the next chapter, preferable alternatives in areas where shortcoming is observed and need for improvement is felt are suggested. Chapter 8 discusses the financial system in the proposed framework with the role of institutions and the discussion on comprehensive need fulfillment mechanisms to serve every major need of a sophisticated contemporary financial system. Some important novel changes are recommended, such as introduction of options in mortgage financing, which will allow the bank to separate the tenancy and sale contract in a distinctive way. This will still ensure that it locks the sale with the borrower or with the third party without making both contracts dependent on each other. It will benefit the bank as well as the borrower, who will have an option but not an obligation to buy the asset at maturity. The modified role of bank entering in a Mudarabah contract as a “Rabb-ul-maal” (investor) will ensure that the bank takes on operational risk. It will enable the resources to go into productive avenues rather than in financial instruments. This modification will generate employment and productive activities in the economy in a more direct manner. The division of Mudarabah corporate and Mudarabah consumer will target two very distinct markets and will result in channeling of funds from saving surplus units to saving-deficient units. Reforms in equity markets and alternatives for insurance are also suggested. Chapter 9 introduces feasibility and structure of Micro credit as an alternative for interest based micro finance. It discusses how the potential obstacles in the form of lack of trust, funding commitment, lack of collateral arrangement, lack of documentation etc would be handled.Interest Free Economy, Islamic Economy, Islamic Economic System, Islamic Monetary Policy, Islamic Fiscal Policy, Interest, Zakat, Riba, Usury, Development, Redistribution, Economic Systems, Financial System, Financial Intermediation, Saving, Investment.
Chemically Cross-Linked Poly(acrylic-co-vinylsulfonic) Acid Hydrogel for the Delivery of Isosorbide Mononitrate
No full textWe report synthesis, characterization, and drug release attributes of a series of novel pH-sensitive poly(acrylic-co-vinylsulfonic) acid hydrogels. These hydrogels were prepared by employing free radical polymerization using ethylene glycol dimethacrylate (EGDMA) and benzyl peroxide (BPO) as cross-linker and initiator, respectively. Effect of acrylic acid (AA), polyvinylsulfonic acid (PVSA), and EGDMA on prepared hydrogels was investigated. All formulations showed higher swelling at high pHs and vice versa. Formulations containing higher content of AA and EGDMA show reduced swelling, but one with higher content of PVSA showed increased swelling. Hydrogel network was characterized by determining structural parameters and loaded with isosorbide mononitrate. FTIR confirmed absence of drug polymer interaction while DSC and TGA demonstrated molecular dispersion of drug in a thermally stable polymeric network. All the hydrogel formulations exhibited a pH dependent release of isosorbide mononitrate which was found to be directly proportional to pH of the medium and PVSA content and inversely proportional to the AA contents. Drug release data were fitted to various kinetics models. Results indicated that release of isosorbide mononitrate from poly(AA-co-VSA) hydrogels was non-Fickian and that the mechanism was diffusion-controlled
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