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  • Computational Methods, Genomics  (140)
  • bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
  • Oxford University Press  (153)
  • Palgrave Macmillan  (12)
  • Cambridge University Press  (7)
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  • 1
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    Equality, Freedom, and Democracy (2021)
    Oxford University Press
    Details
    Publication Date: 2021-02-10
    Description: A democratic regime is assumed to implement freedom and equality as the two critical and most important values. The question we intend to address here is: how and why has the actual implementation of freedom and equality been changing in the 1990–2020 period? Researching this topic, we cannot ignore the impact of the Great Recession since 2008. Thus, in this comparative research, we analyse France, Germany, Italy, Poland, Spain, and the United Kingdom to detect the changes. As expected, the six largest European democracies have been differently affected by the crisis, as they also had different background factors. We address an additional question: what is the impact of the European Union on the two democratic values? Accordingly, we analyse economic inequality, social inequality, and ethnic inequality with the related changing trends and explanations. We also detect and analyse the trend of freedoms, and especially personal dignity, civil rights, and political rights. Thus, the relative decline of equalities and freedoms in the six countries emerge in the different complex facets. We also explore the demand for equalities and freedoms by citizens and the political commitments of party leaders. The other issues we address include how and why, respectively, equalities and freedoms are affected by domestic aspects and the role of external factors, especially the European Union. By connecting equalities and freedoms and drawing the lines of entire research, we show how there are three different paths in the future of democracy: balanced democracy, protest democracy, and unaccountable democracy.
    Keywords: democracy ; equality ; freedom ; great recession ; inter-institutional accountability ; rule of law ; responsiveness ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPB Comparative politics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::1 Geographical Qualifiers::1Q Other geographical groupings, oceans & seas::1QF Political, socio-economic & strategic groupings::1QFE EU (European Union)
    Language: English
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  • 2
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    The Political Regulation Wave (2022)
    Cambridge University Press
    Details
    Publication Date: 2022-08-09
    Description: Why has there been uneven success in reducing air pollution even in the same locality over time? This book offers an innovative theorization of how local political incentives can systematically affect bureaucratic regulation and empirically examines the control of different air pollutants in China and – to a lesser extent – in Mexico.?
    Keywords: political theory ; environmental law and engineering ; China studies ; air pollution studies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCN Environmental economics ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPA Political science & theory
    Language: English
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  • 3
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    Cultural Integration of Immigrants in Europe (2021)
    Oxford University Press
    Details
    Publication Date: 2022-05-13
    Description: The concepts of cultural diversity and cultural identity are at the forefront of the political debate in many western societies. In Europe, the discussion is stimulated by the political pressures associated with immigration flows, which are increasing in many European countries. The imperatives that current immigration trends impose on European democracies bring to light a number of issues that need to be addressed. What are the patterns and dynamics of cultural integration? How do they differ across immigrants of different ethnic groups and religious faiths? How do they differ across host societies? What are the implications and consequences for market outcomes and public policy? Which kind of institutional contexts are more or less likely to accommodate the cultural integration of immigrants? All these questions are crucial for policy makers and await answers. This book aims to provide a stepping stone to the debate. Taking an economic perspective, this edited book presents a current, comparative picture of the process of cultural integration of immigrants across Europe. It documents the main economic debates on the causes and consequences of cultural integration of immigrants, and provides detailed descriptions of the cultural and economic integration process in seven main European countries, including France, Germany, Italy, Spain, Sweden, Switzerland, and the United Kingdom. It also compares the European context with the integration of immigrants in the United States.
    Keywords: immigration ; european models of integration ; economic integration ; integration of immigrants ; cultural integration ; Eastern Europe ; Ethnic group ; Germany ; Second-generation immigrants in the United States ; Switzerland ; bic Book Industry Communication::J Society & social sciences::JF Society & culture: general::JFF Social issues & processes::JFFN Migration, immigration & emigration ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology::JHBD Population & demography ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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  • 4
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    The Economisation of Climate Change (2022)
    Cambridge University Press
    Details
    Publication Date: 2022-08-09
    Description: International economic institutions economise climate change, treating it as an economic rather than environmental issue. This book explores how three such institutions - G20, IMF, OECD - have addressed climate finance and fossil fuel subsidies, and the consequences of the economisation of climate change. Also available as Open Access.
    Keywords: climate change ; environmental policy ; environmental economics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCN Environmental economics ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNP Pollution & threats to the environment::RNPG Climate change ; bic Book Industry Communication::K Economics, finance, business & management::KN Industry & industrial studies::KNB Energy industries & utilities::KNBP Petroleum & oil industries ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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  • 5
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    The Palgrave Handbook of International Energy Economics (2022)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2022-06-21
    Description: This open access handbook is distinguished by its emphasis on international energy, rather than domestic energy policies or international geopolitic aspects. Addressing key topics such as energy production and distribution, renewables and corporate energy structures, alongside global energy trends, regional case studies and emerging areas such as the digitalization of energy and energy transition, this handbook provides a major new contribution to the field of international energy economics. Written by academics, practitioners and policy-makers, this handbook is a valuable and timely addition to the literature on international energy economics. This book was published open access with the support of Eni.
    Keywords: Economics of energy production and distribution ; oil ; gas ; coal ; electricity ; biofuels ; Economics of power generation ; Economics of renewables ; Energy transition ; Energy financing ; International trade in energy ; Corporate energy structures ; Digitalization in Energy ; Cyber-security in energy ; Energy demand for buildings/industry/transportation ; Decarbonization ; Energy subsidies ; Vertical integration in energy ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCN Environmental economics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::T Technology, engineering, agriculture::TH Energy technology & engineering
    Language: English
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  • 6
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    Social Sector in a Decentralized Economy (2022)
    Cambridge University Press
    Details
    Publication Date: 2022-08-09
    Description: This book is an analytical examination of financing and public service delivery challenges in a decentralized framework. In addition, it provides critical insights into the effectiveness of public expenditure, through benefit incidence analysis of education and healthcare services in India.
    Keywords: economics ; policy ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPP Public administration ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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  • 7
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    Governing Failure (2021)
    Cambridge University Press
    Details
    Publication Date: 2023-06-06
    Description: Jacqueline Best argues that the changes in International Monetary Fund, World Bank and donor policies in the 1990s, towards what some have called the 'Post-Washington Consensus,' were driven by an erosion of expert authority and an increasing preoccupation with policy failure. Failures such as the Asian financial crisis and the decades of despair in sub-Saharan Africa led these institutions to develop governance strategies designed to avoid failure: fostering country ownership, developing global standards, managing risk and vulnerability and measuring results. In contrast to the structural adjustment era when policymakers were confident that they had all the answers, the author argues that we are now in an era of provisional governance, in which key actors are aware of the possibility of failure even as they seek to inoculate themselves against it. This book considers the implications of this shift, asking if it is a positive change and whether it is sustainable. This title was made Open Access by libraries from around the world through Knowledge Unlatched.
    Keywords: nongovernmental organisations ; economic assistance ; politics ; development banks ; economic development - finance ; corporate governance ; international devleopment policy ; Conditionality ; Good governance ; Structural adjustment ; World Bank ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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  • 8
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    Hunger and Public Action (2021)
    Oxford University Press
    Details
    Publication Date: 2021-02-10
    Description: This book analyses the role of public action in solving the problem of hunger in the modern world. The study is divided into four parts. The first, making extensive use of the concepts of entitlements and capabilities explores the interaction of nutritional, economic, social, and political elements and their influence on hunger and deprivation. The problem of famine prevention is the main focus of the second part, with special attention given to Africa and India. The third part is devoted to the issue of fighting chronic undernourishment and the lessons to be learnt from the policies of China, India, and some other countries. The last part draws together the main themes and concerns of the earlier chapters, and provides an integrated view of the role of public action in eliminating hunger. The study suggests that there is indeed some space for public action in solving the problem of hunger and deprivation. In the case of famine prevention, social security could provide early warning systems and employment provision plans. To fight endemic deprivation, the authors suggest, among other things, that basic health care, elementary education, and food programmes should be looked at.
    Keywords: capability ; chronic undernourishment ; deprivation ; entitlements ; famine ; hunger ; public action ; social security ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCR Welfare economics
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  • 9
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    Pockets of Effectiveness and the Politics of State-building and Development in Africa (2023)
    Oxford University Press
    Details
    Publication Date: 2023-08-17
    Description: Why do certain parts of the state in Africa work so effectively despite operating in difficult governance contexts? How do 'pockets of bureaucratic effectiveness' emerge and become sustained over time? And what does this tell us about the prospects for state-building and development in Africa? Repeated economic and social crises have demanded that development thinkers and policy actors have had to engage with the critical role that states play in delivering development. Pockets of Effectiveness and the Politics of State-building and Development in Africa shows that politics is the driving factor that shapes how well state agencies perform their roles. It deploys a new conceptual framework – the power domains approach – to explore the shifting fortunes of key state agencies in five countries – Ghana, Kenya, Rwanda, Uganda, and Zambia – over the past three decades. Our original research reveals when, how and why political rulers decide to build effective state agencies and enable them to deliver certain forms of economic development – often through forming strategic coalitions with senior bureaucrats and with international support – and also when this support falters and gives way to a politics of survival. Comparative analysis identifies two potential trajectories towards state-building in Africa, each shaped by different configurations of social and political power. The book critiques the role that international development agencies have played in (mis)shaping the state in Africa and suggests a new strategic agenda for building the state capacities required to deliver sustained development at the current juncture. The book closes with critical commentaries from two leading scholars in the field, to help place our work in context and establish the next steps for research and strategy in this increasingly important area of development theory and practice.
    Keywords: Development studies, Political economy, Public administration, and African Studies ; bic Book Industry Communication::G Reference, information & interdisciplinary subjects::GT Interdisciplinary studies::GTF Development studies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPP Public administration ; bic Book Industry Communication::1 Geographical Qualifiers::1H Africa
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  • 10
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    The Future of Africa (2021)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2024-03-29
    Description: This open access textbook offers a critical introduction to human and economic development prospects in Africa revolving around three questions: where is Africa today, what explains the current state, and, given historical trends and what we know about the world, where do we think the continent will be in 2040? And, a final question: what can we do to create a better tomorrow? It models ambitious progress in health, demographics, agriculture, education, industrialization, technological leapfrogging, increased trade, greater stability, better governance and external support. The book reviews the future of work/jobs, poverty and the impact of climate change. A combined Closing the Gap scenario presents a forecast of what could be possible by 2040. Each chapter suggests which policies might accelerate prospects for each sector. Written in an accessible style, and supported by a range of pedagogical features, this textbook introduces undergraduate and graduate students to the contemporary human and economic development prospects in Africa.
    Keywords: African Politics ; Development Studies ; Political Economy/Economic Systems ; Political Economy and Economic Systems ; Africa ; demographics ; population ; development ; development in Africa ; African Union ; China ; political economy in Africa ; Open access ; Politics & government ; Political economy ; bic Book Industry Communication::J Society & social sciences::JP Politics & government ; bic Book Industry Communication::G Reference, information & interdisciplinary subjects::GT Interdisciplinary studies::GTF Development studies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; thema EDItEUR::J Society and Social Sciences::JP Politics and government ; thema EDItEUR::G Reference, Information and Interdisciplinary subjects::GT Interdisciplinary studies::GTP Development studies ; thema EDItEUR::K Economics, Finance, Business and Management::KC Economics::KCP Political economy
    Language: English
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  • 11
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    Policy Feedback (2022)
    Cambridge University Press
    Details
    Publication Date: 2022-08-09
    Description: This element explores early and more recent contributions of the policy feedback literature to clarify the meaning of this concept and its contribution to both political science and policy studies. This element also discusses the practical implications of policy feedback research through a discussion of its potential impact on policy design.
    Keywords: Public policy ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPP Public administration ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPH Political structure & processes
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  • 12
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    Political Settlements and Development (2022)
    Oxford University Press
    Details
    Publication Date: 2022-09-06
    Description: Few concepts have captured the imagination of the conflict and development communities in recent years as powerfully as the idea of a ‘political settlement’. At its most ambitious, ‘political settlements analysis’ (PSA) promises to explain why conflicts occur and states collapse, the conditions for their successful rehabilitation, different developmental pathways from peace, and how to better fit development policy to country context. Yet despite the meteoric rise of the term and its tremendous promise, not all is well in the world of PSA. Rival definitions of the concept abound; there are disagreements about its scope and the way it should be used; a growing schism between conflict specialists and economists; basic concepts are ambiguous; and little progress has been made on measurement. This book consequently has three main aims. The first is to argue for a revised definition of a political settlement, capable of unifying its diverse strands. The second is to put the concept on a more solid theoretical and scientific footing, providing a method for measuring and categorizing political settlements, using both qualitative case studies and a large-n statistical analysis to illustrate its potential. And the third is to examine the implications of the findings for mainstream social science analysis and for policymakers.
    Keywords: Government Policy, Provision and Effects of Welfare Programmes, Economic Development, Development Planning and Policy, Rent-Seeking, Lobbying, Elections, Legislatures, and Voting Behavior, Bureaucracy, Administrative Processes in Public Organizations, Corruption, Conflict, Conflict Resolution, Alliances, Revolutions, Positive Analysis of Policy Formulation and Implementation, Political Economy ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCS Economic systems & structures
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  • 13
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    The Political Economy of Bank Regulation in Developing Countries (2021)
    Oxford University Press
    Details
    Publication Date: 2021-02-10
    Description: Why do governments in some developing countries implement international standards, while others do not? Focusing on the politics of bank regulation, this book develops a new framework to explain regulatory interdependence between countries in the core and the periphery of the global financial system. Drawing on in-depth analysis of eleven countries across Africa, Asia, and Latin America, it shows how financial globalization generates strong reputational and competitive incentives for developing countries to converge on international standards. Regulatory interdependence is generated by relations between regulators, politicians, and banks within developing countries, and international actors including investors, peer regulators, and international financial institutions. We explain why it is that some configurations of domestic politics and forms of integration into global finance generate convergence with international standards, while other configurations lead to divergence. This book contributes to our understanding of the ways in which governments and firms in the core of global finance powerfully shape regulatory politics in the periphery, and the ways in which peripheral governments and firms manoeuvre within the constraints and opportunities created by financial globalization
    Keywords: Africa ; Asia ; Latin America ; financial globalization ; regulatory interdependence ; international banking standards ; Basel I ; Basel II ; Basel III ; transnational policy networks ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPA Political science & theory ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPB Comparative politics ; bic Book Industry Communication::G Reference, information & interdisciplinary subjects::GT Interdisciplinary studies::GTF Development studies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies
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  • 14
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    The Politics of Inclusive Development: Interrogating the Evidence (2021)
    Oxford University Press
    Details
    Publication Date: 2022-04-28
    Description: It is now widely accepted that politics plays a significant role in shaping the possibilities for inclusive development. However, the specific ways in which this happens across different types and forms of development, and in different contexts, remains poorly understood. This collection provides the state of the art review regarding what is currently known about the politics of inclusive development. Leading academics offer systematic reviews of how politics shapes development across multiple dimensions, including through growth, natural resource governance, poverty reduction, service delivery, social protection, justice systems, the empowerment of marginalized groups, and the role of both traditional and non-traditional donors. The book not only provides a comprehensive update but also a groundbreaking range of new directions for thinking and acting around these issues. The book’s originality thus derives not only from the wide scope of its case-study material, but also from the new conceptual approaches it offers for thinking about the politics of inclusive development, and the innovative and practical suggestions for donors, policymakers, and practitioners that flow from this.
    Keywords: citizenship ; transnational ; politics ; recognition ; inclusive development ; political settlement ; accumulation ; China ; Economic growth ; Ethnic group ; Welfare ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCB Macroeconomics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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  • 15
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    Reviving Classical Liberalism Against Populism (2024)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2024-03-14
    Description: This open access book by Nils Karlson explores the strategies used by left- and right-wing populists to make populism intelligible, recognizable, and contestable. It presents a synthesized explanatory model for how populists promote autocratization through the deliberate polarization of society. It traces the ideational roots of the core populist ideas and shows that these ideas form a collectivistic identity politics. Karlson argues that to fight back requires the revival of liberalism itself by defending and developing the liberal institutions, the liberal spirit, liberal narratives, and liberal statecraft.  The book also presents and discusses an extensive list of counterstrategies against populism.  Written within the tradition of political theory and institutional economics, this book uses a wide variety of sources, including results and analyses from social psychology, ethics, law, and history.
    Keywords: Classical Liberalism ; Populism ; Liberalism ; Liberal ; statecraft ; liberal politics ; identity politics ; political theory ; institutional economics ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPA Political science & theory ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology ; bic Book Industry Communication::J Society & social sciences::JP Politics & government
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  • 16
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    Made in Africa: (2021)
    Oxford University Press
    Details
    Publication Date: 2021-02-10
    Description: This book presents the findings of original field research into the design, practice, and varied outcomes of industrial policy in three sectors in Ethiopia, covering export-oriented and import-substitution industries. The three sectors are cement, leather and leather products, and floriculture. Given that there is a single industrial strategy, why do its outcomes vary across sectors? To what extent is this a function of the specific market and political economy features of each sector? The book examines industrial structures and associated global value chains to demonstrate the challenges faced by African firms in international markets. Part of the book’s relevance is the light it throws on the whole question of industrial policy in low-income countries, the subject of renewed discussion among development economists and organizations in recent years. The findings are also discussed in the light of the history of, and the history of thought about, industrialization. Insights for researchers and policymakers emerge from the analysis of failures and successes in the three industrial sectors. The book also challenges prevailing wisdom on how much and what kind of state intervention is required to support transformational industrial policy in Africa. Among other things, the book highlights the significance for policy design of maximizing linkage effects, backward and forward, from particular industries and activities.
    Keywords: development economics & emerging economies ; economics of industrial organisation ; political economy ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCD Economics of industrial organisation ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
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  • 17
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    Reviving Classical Liberalism Against Populism (2024)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2024-01-16
    Description: This open access book by Nils Karlson explores the strategies used by left- and right-wing populists to make populism intelligible, recognizable, and contestable. It presents a synthesized explanatory model for how populists promote autocratization through the deliberate polarization of society. It traces the ideational roots of the core populist ideas and shows that these ideas form a collectivistic identity politics. Karlson argues that to fight back requires the revival of liberalism itself by defending and developing the liberal institutions, the liberal spirit, liberal narratives, and liberal statecraft.  The book also presents and discusses an extensive list of counterstrategies against populism.  Written within the tradition of political theory and institutional economics, this book uses a wide variety of sources, including results and analyses from social psychology, ethics, law, and history.
    Keywords: Classical Liberalism ; Populism ; Liberalism ; Liberal ; statecraft ; liberal politics ; identity politics ; political theory ; institutional economics ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPA Political science & theory ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology
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  • 18
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    Dumbing Down (2022)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2022-03-16
    Description: This open access book examines the challenges and issues caused by a move to a marketized education system in Sweden. Observing the introduction of the school voucher system and a postmodern social constructivist view of knowledge, the move away from objective knowledge is identified as the core reason for Sweden’s current education crisis. The impact of declining education standards on the labor market is also discussed. This book highlights the issues seen in Sweden and suggests policies that can improve education in the rest of the Western world as well. It will be relevant to students and researchers interested in education and labor economics.
    Keywords: Swedish Educational System ; Educational Performance in Swedish Schools ; Marketized Education ; Test Results and National Economic Performance ; Dysfunctional work environment ; Fragmentation of the Swedish School System ; Open Access ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCF Labour economics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
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  • 19
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    Consequences of the Global Financial Crisis (2021)
    Oxford University Press
    Details
    Publication Date: 2024-03-29
    Description: The Global Financial Crisis (GFC) is the most serious economic crisis since the Great Depression. Many books have explored its causes, but this book systematically explores its consequences. The focus is primarily on the policy and political consequences of the GFC. This book asks how governments responded to the challenge and what the political consequences of the combination of the GFC itself and policy responses to it have been. Based on workshops held in the United States and the United Kingdom, it brings together leading academics to consider the divergent ways in which particular countries have responded in different ways to the crisis, including China, France, the United Kingdom, and the United States. Part of what is happening is a structural shift in economic power from east to west, but China has its fragilities while Germany offers an example of a largely successful Western model. The book also assesses attempts to develop global economic governance and to reform financial regulation and looks critically at the role of credit rating agencies. Unlike earlier crises, no new paradigm has emerged to challenge existing ways of thinking, meaning that neoliberalism has emerged relatively unscathed. The crisis has lacked a coherent and innovative intellectual response and has been characterized by remarkable policy stability.
    Keywords: neoliberalism ; structural change ; financial regulation ; global financial crisis ; China ; International Monetary Fund ; Non-commercial activity ; United States ; bic Book Industry Communication::J Society & social sciences::JP Politics & government ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::K Economics, finance, business & management::KJ Business & management ; thema EDItEUR::J Society and Social Sciences::JP Politics and government ; thema EDItEUR::K Economics, Finance, Business and Management::KC Economics::KCP Political economy ; thema EDItEUR::K Economics, Finance, Business and Management::KJ Business and Management
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  • 20
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    The Politics of Distributing Social Transfers (2022)
    Oxford University Press
    Details
    Publication Date: 2022-09-06
    Description: This book provides a systematic analysis of the political processes shaping the distribution of social transfers in six countries in sub-Saharan Africa and South Asia. In doing so, the book addresses a notable gap in recent research on social protection concerning the politics of implementation. While considerable attention has been devoted to debating the merits of different policy designs and the political factors shaping the adoption and diffusion of different policy models, ultimately the ability of any social transfer programme to deliver on its promises is dependent on the effective implementation and distribution of social transfers in line with intended objectives. The chapters in this book examine international and sub-national variation in programme implementation in Bangladesh, Ethiopia, Ghana, Kenya, Nepal, and Rwanda, drawing on a common analytical framework that highlights the importance of state capacity and reach, rooted in histories of state formation, and contemporary political competition in shaping the distribution of social transfers. Comparative analysis of the case studies supports the view that variation in the capacity and reach of the state within countries is a centrally important factor shaping the effectiveness and impartiality of distribution. Yet state capacity alone is insufficient. Rather, political competition and power relations shape how this capacity is actually deployed in practice. As such, the book underscores the inherently political nature of implementation and questions common technocratic efforts to improve implementation by de-politicizing the social protection policy process.
    Keywords: social protection, social transfer, policy implementation, political economy, power relations, state capacity, Africa, South Asia ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::J Society & social sciences::JF Society & culture: general::JFF Social issues & processes ; bic Book Industry Communication::G Reference, information & interdisciplinary subjects::GT Interdisciplinary studies::GTF Development studies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies
    Language: English
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    New Sources of Development Finance (2021)
    Oxford University Press
    Details
    Publication Date: 2021-02-10
    Description: "As their Millennium Development Goals, world leaders have pledged by 2015 to halve the number of people living in extreme poverty and hunger, to achieve universal primary education, to reduce child mortality, to halt the spread of HIV/AIDS, and to halve the number of people without safe drinking water. Achieving these goals requires a large increase in the flow of financial resources to developing countries – double the present development assistance from abroad. In examining innovative ways to secure these resources, this book, which is part of the UNU–WIDER Studies in Development Economics series, sets out a framework for the economic analysis of different sources of funding and applying the tools of modern public economics to identify the key issues. It examines the role of new sources of overseas aid, considers the fiscal architecture and the lessons that can be learned from federal fiscal systems, asks how far increased transfers impose a burden on donors, and investigates how far the raising of resources can be separated from their use. In turn, the book examines global environmental taxes (such as a carbon tax), the taxation of currency transactions (the Tobin tax), a development‐focused allocation of Special Drawing Rights by the International Monetary Fund (IMF), the UK Government proposal for an International Finance Facility, increased private donations for development purposes, a global lottery (or premium bond), and increased remittances by emigrants. In each case, it considers the feasibility of the proposal and the resources that it can realistically raise, and offers new perspectives and insights into these new and controversial proposals. "
    Keywords: child mortality reduction ; development economics ; allocation of Special Drawing Rights by IMF ; development assistance ; development finance ; economic analysis ; environmental taxes ; federal fiscal systems ; funding ; global lottery ; global premium bond ; HIV/AIDS spread prevention ; hunger reduction ; International Finance Facility ; Millennium Development Goals ; poverty alleviation ; private donations ; remittances by emigrants ; safe drinking water ; sources of funding ; sources of overseas aid ; Special Drawing Rights ; taxation of currency transactions ; Tobin tax ; universal primary education ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCL International economics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::K Economics, finance, business & management::KF Finance & accounting::KFF Finance::KFFD Public finance::KFFD1 Taxation
    Language: English
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    Ageing and Health (2022)
    Cambridge University Press
    Details
    Publication Date: 2022-08-09
    Description: Ageing societies can be healthy and productive- if they get the politics right. This book argues that the population ageing crisis can be solved through policies that reduce inequalities between and within generations. It then explores the political coalitions needed to support policymaking that avoids pitting generations against each other.
    Keywords: economics of ageing ; politics of ageing ; healthy ageing ; ageing crisis ; health policy ; health systems ; healthcare management ; public policy ; public finance ; intergenerational justice ; welfare state ; pensions ; pension policy ; public health ; bic Book Industry Communication::K Economics, finance, business & management ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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    Making Global Policy (2022)
    Cambridge University Press
    Details
    Publication Date: 2022-08-09
    Description: This Element goes beyond traditional texts which focus on public policy as an activity of states to outline how global policy making has driven many global and regional transformations over the past quarter-century. This title is also available as Open Access on Cambridge Core.
    Keywords: public policy ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPP Public administration ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPA Political science & theory ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPS International relations::JPSN International institutions ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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    Determinants of Financial Development (2021)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2023-03-20
    Description: "As the world has witnessed the worst financial crisis and climate crisis of our age, during the period of 2007-2009, the issues surrounding the emergence and development of financial markets and carbon markets is becoming an increasingly significant area of research and debate worldwide. By engaging with recently developed methods of research and new areas of practice, this book investigates the political, economic, policy and geographic determinants of the development of financial markets. The volume examines the causality between financial development and aggregate private investment from an economic perspective. It also explores the consequences of political liberalization, focusing on the impact of institutional improvement on financial development. It studies what stimulates governments to initiate reforms aimed at boosting financial development, and analyses the determinants of carbon markets in developing countries from a geographic point of view. This book is essential reading for all interested in economic and financial development, climate change, environmental economics, and applied econometrics. "
    Keywords: reform ; financiele markten ; carbon ; development ; financial markets ; koolstof ; ontwikkeling ; hervorming ; crisis ; Democracy ; Dependent and independent variables ; Estimator ; Gross domestic product ; Long run and short run ; P-value ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCB Macroeconomics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCN Environmental economics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::K Economics, finance, business & management::KF Finance & accounting::KFF Finance::KFFK Banking
    Language: English
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    When Can Oil Economies Be Deemed Sustainable? (2020)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2021-12-24
    Description: This open access book questions the stereotype depicting all Gulf (GCC) economies as not sustainable, and starts a critical discussion of what these economies and polities should do to guarantee themselves a relatively stable future. Volatile international oil markets and the acceleration of the energy transition has challenged the notion that oil revenues are sufficient to sustain oil economies in the near to medium term. But what is the meaning of economic sustainability? The book discusses the multiple dimensions of the concept: economic diversification, continuing value of resources, taxation and fiscal development, labor market sustainability, sustainable income distribution, environmental sustainability, political order (democracy or authoritarianism) and sustainability, regional integration. The overarching message in this book is that we should move on from the simplistic branding of the Gulf economies as unsustainable and tackle the details of which adaptations they might need to undertake.
    Keywords: International Political Economy ; Sustainable Development ; Natural Resource and Energy Economics ; Energy Policy, Economics and Management ; Middle Eastern Politics ; Middle Eastern and North African Economics ; International Relations ; Environmental Social Sciences ; Environmental Economics ; Economy-wide Country Studies ; Open Access ; Sustainability of GCC Development ; New Global Oil Order ; Economic sustainability in resource-rich states ; Gulf Economic Diversification and Sustainable Development ; Political Economy of Diversification ; Economic Transformation vs. Diversification ; Oil and Economic Diversification ; Fiscal dimensions of Economic Sustainability ; Labour Market dimensions of Economic Sustainability ; Hydrocarbon Endowment in the Gulf Region ; Normalizing the Saudi Economy ; Inclusive Growth in the Gulf Region ; Saudi Private Sector’s Contribution to Fiscal Sustainability ; Economic Sustainability and the Energy Transition ; Economic Diversification in the MENA ; Peak Oil and the Energy Transition in the MENA ; Economic Diversification Through Energy Sector Reform ; Energy Pricing Reform in the Gulf Region ; Climate Strategy for Producer Countries ; Political economy ; Sustainability ; Environmental economics ; Energy technology & engineering ; Energy industries & utilities ; Politics & government ; Middle East ; Economics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RN The environment::RNU Sustainability ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCN Environmental economics ; bic Book Industry Communication::T Technology, engineering, agriculture::TH Energy technology & engineering ; bic Book Industry Communication::J Society & social sciences::JP Politics & government ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics
    Language: English
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    Governing Social Protection in the Long Term (2021)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2021-02-10
    Description: This open access book examines the comparative evolution of social protection in Australia and New Zealand from 1890 to the present day, focusing on the relationship between employment relations and social policy. Utilising longstanding and more recent developments in historical institutionalist methodology, Ramia investigates the relationship between these two policy domains in the context of social protection theory. He argues that treating employment relations as dynamic, and as inextricably intertwined with changes in the welfare state over time, allows for more accurate portrayal of similarity and difference in social protection. The book will be of most interest to researchers, advanced undergraduate and postgraduate students in social policy, employment relations, public policy, social and political history, and comparative politics.
    Keywords: Social Policy ; Sociology of Work ; Political Sociology ; social harm ; the free market ; employment and welfare ; labour market ; industrial relations ; Open access ; Political economy ; Social & ethical issues ; Sociology: work & labour ; Sociology ; Politics & government ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology::JHBL Sociology: work & labour ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology
    Language: English
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    Transnational Solidarity in Times of Crises (2021)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2021-02-10
    Description: This open access collection is devoted to an in-depth, qualitative analysis of practices of cross-national solidarity in response to the current political and social crises, from citizens’ initiatives to networks of cooperation among civil society actors. The book analyses existing informal groups at the grassroots, furthering transnational solidarity in three thematic areas: disability, unemployment and immigration. Contributions assess how civic groups respond to the various crises affecting Europe, especially the economic and refugee crises, presenting new findings from a systematic comparative study conducted in eight European countries (Denmark, France, Germany, Greece, Italy, Poland, Switzerland, and the UK). The research will be of interest to scholars, students, journalists, policy-makers and activists interested in civil society, social movements, charitable actions, altruism and solidarity, as well as European studies and the socio-economic challenges of current European crises.
    Keywords: Political Sociology ; Social Sciences, general ; Migration ; Social Policy ; Sociology of Organizations and Occupations ; Sociology of Migration ; European Studies ; Social movements ; Activism ; volunteering ; Disability ; Unemployment ; Immigration ; Open Access ; Sociology ; Politics & government ; Society & Social Sciences ; Migration, immigration & emigration ; Political economy ; Social & ethical issues ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology ; bic Book Industry Communication::J Society & social sciences ; bic Book Industry Communication::J Society & social sciences::JF Society & culture: general::JFF Social issues & processes::JFFN Migration, immigration & emigration ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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    Deals and Development (2021)
    Oxford University Press
    Details
    Publication Date: 2024-03-29
    Description: "International financial crises have plagued the world in recent decades, including the Latin American debt crisis of the 1980s, the East Asian crisis of the late twentieth century, and the global financial crisis of 2007-09. One of the basic problems faced during these crises is the lack of adequate preventive mechanisms, as well as insufficient instruments to finance countries in crisis and to overcome their over-indebtedness. Resetting the International Monetary (Non)System provides an analysis of the global monetary system and the necessary reforms that it should undergo to play an active role in the twenty-first century and proposes a comprehensive yet evolutionary reform of the system. Criticising the ad hoc framework- a ""(non)system""- that has evolved following the breakdown of the Bretton Woods arrangement in the early 1970's, Resetting the International Monetary (Non)System places a special focus on the asymmetries that emerging and developing countries face, analysing the controversial management of crises by the International Monetary Fund and proposing a consistent set of reform proposals to design a better system of international monetary cooperation. Policy orientated and structured to deal in a sequential way with the issues involved, it suggests provision of international liquidity through a system that mixes the multicurrency arrangement with a more active use of the IMF's Special Drawing Rights; stronger mechanisms of macroeconomic policy cooperation, including greater cooperation in exchange rate management and freedom to manage capital flows; additional automatic balance-of-payments financing facilities and the complementary use of swap and regional arrangements; a multilateral sovereign debt workout mechanism; and major reforms of the system's governance."
    Keywords: economics ; monetary economics ; Ghana ; Gross domestic product ; Liberia ; Malaysia ; Thailand ; Uganda ; bic Book Industry Communication::J Society & social sciences::JP Politics & government ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCG Economic growth ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; thema EDItEUR::J Society and Social Sciences::JP Politics and government ; thema EDItEUR::K Economics, Finance, Business and Management::KC Economics ; thema EDItEUR::K Economics, Finance, Business and Management::KC Economics::KCG Economic growth ; thema EDItEUR::K Economics, Finance, Business and Management::KC Economics::KCM Development economics and emerging economies ; thema EDItEUR::K Economics, Finance, Business and Management::KC Economics::KCP Political economy
    Language: English
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    A City Cannot Be a Work of Art (2023)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2023-11-16
    Description: This open access book connects Jane Jacobs's celebrated urban analysis to her ideas on economics and social theory. While Jacobs is a legend in the field of urbanism and famous for challenging and profoundly influencing urban planning and design, her theoretical contributions – although central to her criticisms of and proposals for public policy – are frequently overlooked even by her most enthusiastic admirers. This book argues that Jacobs’s insight that “a city cannot be a work of art” underlies both her ideas on planning and her understanding of economic development and social cooperation. It shows how the theory of the market process and Jacobs’s theory of urban processes are useful complements – an example of what economists and urbanists can learn from each other. This Jacobs-cum-market-process perspective offers new theoretical, historical, and policy analyses of cities, more realistic and coherent than standard accounts by either economists or urbanists.
    Keywords: social theory ; spontaneous order ; entrepreneurship ; Jane Jacobs ; urban design ; urbanism ; diversity ; innovation ; living city ; economic development ; social capital ; social networks ; action space ; urban planning ; bic Book Industry Communication::R Earth sciences, geography, environment, planning::RG Geography::RGC Human geography ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology::JHBA Social theory ; bic Book Industry Communication::J Society & social sciences::JP Politics & government::JPP Public administration ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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    Remittances as Social Practices and Agents of Change (2023)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2023-11-17
    Description: This open access book explores the transformative effects of remittances. Remittances are conceptualized as flows of money, objects, ideas, traditions, and symbolic capital, mapping out a cross-border space in which people live, work, and communicate with multiple belongings. By doing so, they effect social change both in places of origin and destination. However, their power to improve individual living conditions and community infrastructure mainly results from global inequality. Hence, we challenge the remittance mantra and go beyond the migration-development-nexus by revealing dependencies and frictions in remittance relations. Remittances are thus scrutinized in their effects on both social cohesion and social rupture. By highlighting the transformative effects of remittance in the context of conflict, climate change, and the postcolonial, we shed light on the future of transnational society. Presenting empirical case studies from Ghana, Burkina Faso, Sri Lanka, New Zealand, Turkey, Lebanon, USA, Japan, and various European countries, as well as historical North America and the Habsburg Empire, we explore remittance relations from a range of disciplines including anthropology, sociology, history, design, architecture, governance, and peace studies.
    Keywords: transnationalism ; migration ; economy ; political economy ; charity ; financial remittances ; gift ; exchange ; cultural exchange ; bic Book Industry Communication::J Society & social sciences::JF Society & culture: general::JFF Social issues & processes::JFFN Migration, immigration & emigration ; bic Book Industry Communication::J Society & social sciences::JH Sociology & anthropology::JHB Sociology ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies
    Language: English
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    How Nations Learn (2021)
    Oxford University Press
    Details
    Publication Date: 2021-02-10
    Description: Authored by eminent scholars, the volume aims to generate interest and debate among policymakers, practitioners, and researchers on the complexity of learning and catch-up, particularly for twenty-first century late-late developers. The volume explores technological learning at the firm level, policy learning by the state, and the cumulative and multifaceted nature of the learning process, which encompasses learning by doing, by experiment, emulation, innovation, and leapfrogging. Why is catch-up rare? And why have some nations succeeded while others failed? What are the prospects for successful learning and catch-up in the twenty-first century? These are pertinent questions that require further research and in-depth analysis. The World Bank estimates that out of the 101 middle-income economies in 1960, only thirteen became high income by 2008. This volume examines how nations learn by reviewing key structural and contingent factors that contribute to dynamic learning and catch-up. Rejecting both the one-size-fits-all approach and the agnosticism that all nations are unique and different, the volume uses historical as well as firm-level, industry-level, and country-level evidence and experiences to identify the sources and drivers of successful learning and catch-up and the lessons for late-latecomer countries. Building on the latecomer-advantage perspective, the volume shows that what is critical for dynamic learning and catch-up is not learning per se but the intensity of learning, robust industrial policies, and the pace and direction of learning. Equally important are the passion to learn, long-term strategic vision, and understanding the context in which successful learning occurs.
    Keywords: catch-up ; technological learning ; industrial policy ; latecomers ; intensity of learning ; policy learning ; emualation ; innovation ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCG Economic growth ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCM Development economics & emerging economies ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy ; bic Book Industry Communication::K Economics, finance, business & management::KN Industry & industrial studies
    Language: English
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    The Japanese Banking Crisis (2021)
    Springer Nature | Palgrave Macmillan
    Details
    Publication Date: 2021-02-10
    Description: This open access book provides a readable narrative of the bubbles and the banking crisis Japan experienced during the two decades between the late 1980s and the early 2000s. Japan, which was a leading competitor in the world’s manufacturing sector, tried to transform itself into an economy with domestic demand-led mature growth, but the ensuing bubbles and crisis instead made the country suffer from chronicle deflation and stagnation. The book analyses why the Japanese authorities could not avoid making choices that led to this outcome. The chapters are based on the lectures to regulators from emerging economies delivered at the Global Financial Partnership Center of the Financial Services Agency of Japan.
    Keywords: Macroeconomics/Monetary Economics//Financial Economics ; Development Finance ; Economic History ; Political Economy/Economic Systems ; Macroeconomics and Monetary Economics ; Political Economy and Economic Systems ; Japanese banking crisis ; Financial Stability ; Banking Regulation in Japan ; Financial Crisis Management in Japan ; Japanese Economy ; Macro-prudential Policy ; Japanese financial cycle of 1986-2003 ; Open Access ; Macroeconomics ; Monetary economics ; Finance ; Development economics & emerging economies ; Political economy ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCB Macroeconomics ; bic Book Industry Communication::K Economics, finance, business & management::KF Finance & accounting::KFF Finance ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCZ Economic history ; bic Book Industry Communication::K Economics, finance, business & management::KC Economics::KCP Political economy
    Language: English
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    A low-latency, big database system and browser for storage, querying and visualization of 3D genomic data (2015)
    Oxford University Press
    Details
    Publication Date: 2015-09-19
    Description: Recent releases of genome three-dimensional (3D) structures have the potential to transform our understanding of genomes. Nonetheless, the storage technology and visualization tools need to evolve to offer to the scientific community fast and convenient access to these data. We introduce simultaneously a database system to store and query 3D genomic data ( 3DBG ), and a 3D genome browser to visualize and explore 3D genome structures ( 3DGB ). We benchmark 3DBG against state-of-the-art systems and demonstrate that it is faster than previous solutions, and importantly gracefully scales with the size of data. We also illustrate the usefulness of our 3D genome Web browser to explore human genome structures. The 3D genome browser is available at http://3dgb.cs.mcgill.ca/ .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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    Analysis of strand-specific RNA-seq data using machine learning reveals the structures of transcription units in Clostridium thermocellum (2015)
    Oxford University Press
    Details
    Publication Date: 2015-05-29
    Description: Identification of transcription units (TUs) encoded in a bacterial genome is essential to elucidation of transcriptional regulation of the organism. To gain a detailed understanding of the dynamically composed TU structures, we have used four strand-specific RNA-seq (ssRNA-seq) datasets collected under two experimental conditions to derive the genomic TU organization of Clostridium thermocellum using a machine-learning approach. Our method accurately predicted the genomic boundaries of individual TUs based on two sets of parameters measuring the RNA-seq expression patterns across the genome: expression-level continuity and variance. A total of 2590 distinct TUs are predicted based on the four RNA-seq datasets. Among the predicted TUs, 44% have multiple genes. We assessed our prediction method on an independent set of RNA-seq data with longer reads. The evaluation confirmed the high quality of the predicted TUs. Functional enrichment analyses on a selected subset of the predicted TUs revealed interesting biology. To demonstrate the generality of the prediction method, we have also applied the method to RNA-seq data collected on Escherichia coli and achieved high prediction accuracies. The TU prediction program named SeqTU is publicly available at https://code.google.com/p/seqtu/ . We expect that the predicted TUs can serve as the baseline information for studying transcriptional and post-transcriptional regulation in C. thermocellum and other bacteria.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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    A thesaurus of genetic variation for interrogation of repetitive genomic regions (2015)
    Oxford University Press
    Details
    Publication Date: 2015-05-29
    Description: Detecting genetic variation is one of the main applications of high-throughput sequencing, but is still challenging wherever aligning short reads poses ambiguities. Current state-of-the-art variant calling approaches avoid such regions, arguing that it is necessary to sacrifice detection sensitivity to limit false discovery. We developed a method that links candidate variant positions within repetitive genomic regions into clusters. The technique relies on a resource, a thesaurus of genetic variation, that enumerates genomic regions with similar sequence. The resource is computationally intensive to generate, but once compiled can be applied efficiently to annotate and prioritize variants in repetitive regions. We show that thesaurus annotation can reduce the rate of false variant calls due to mappability by up to three orders of magnitude. We apply the technique to whole genome datasets and establish that called variants in low mappability regions annotated using the thesaurus can be experimentally validated. We then extend the analysis to a large panel of exomes to show that the annotation technique opens possibilities to study variation in hereto hidden and under-studied parts of the genome.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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    A new molecular signature method for prediction of driver cancer pathways from transcriptional data (2016)
    Oxford University Press
    Details
    Publication Date: 2016-06-21
    Description: Assigning cancer patients to the most effective treatments requires an understanding of the molecular basis of their disease. While DNA-based molecular profiling approaches have flourished over the past several years to transform our understanding of driver pathways across a broad range of tumors, a systematic characterization of key driver pathways based on RNA data has not been undertaken. Here we introduce a new approach for predicting the status of driver cancer pathways based on signature functions derived from RNA sequencing data. To identify the driver cancer pathways of interest, we mined DNA variant data from TCGA and nominated driver alterations in seven major cancer pathways in breast, ovarian and colon cancer tumors. The activation status of these driver pathways were then characterized using RNA sequencing data by constructing classification signature functions in training datasets and then testing the accuracy of the signatures in test datasets. The signature functions differentiate well tumors with nominated pathway activation from tumors with no signs of activation: average AUC equals to 0.83. Our results confirm that driver genomic alterations are distinctively displayed at the transcriptional level and that the transcriptional signatures can generally provide an alternative to DNA sequencing methods in detecting specific driver pathways.
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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    DanQ: a hybrid convolutional and recurrent deep neural network for quantifying the function of DNA sequences (2016)
    Oxford University Press
    Details
    Publication Date: 2016-06-21
    Description: Modeling the properties and functions of DNA sequences is an important, but challenging task in the broad field of genomics. This task is particularly difficult for non-coding DNA, the vast majority of which is still poorly understood in terms of function. A powerful predictive model for the function of non-coding DNA can have enormous benefit for both basic science and translational research because over 98% of the human genome is non-coding and 93% of disease-associated variants lie in these regions. To address this need, we propose DanQ, a novel hybrid convolutional and bi-directional long short-term memory recurrent neural network framework for predicting non-coding function de novo from sequence. In the DanQ model, the convolution layer captures regulatory motifs, while the recurrent layer captures long-term dependencies between the motifs in order to learn a regulatory ‘grammar’ to improve predictions. DanQ improves considerably upon other models across several metrics. For some regulatory markers, DanQ can achieve over a 50% relative improvement in the area under the precision-recall curve metric compared to related models. We have made the source code available at the github repository http://github.com/uci-cbcl/DanQ .
    Keywords: Computational Methods, Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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    Phylogeny-aware identification and correction of taxonomically mislabeled sequences (2016)
    Oxford University Press
    Details
    Publication Date: 2016-06-21
    Description: Molecular sequences in public databases are mostly annotated by the submitting authors without further validation. This procedure can generate erroneous taxonomic sequence labels. Mislabeled sequences are hard to identify, and they can induce downstream errors because new sequences are typically annotated using existing ones. Furthermore, taxonomic mislabelings in reference sequence databases can bias metagenetic studies which rely on the taxonomy. Despite significant efforts to improve the quality of taxonomic annotations, the curation rate is low because of the labor-intensive manual curation process. Here, we present SATIVA, a phylogeny-aware method to automatically identify taxonomically mislabeled sequences (‘mislabels’) using statistical models of evolution. We use the Evolutionary Placement Algorithm (EPA) to detect and score sequences whose taxonomic annotation is not supported by the underlying phylogenetic signal, and automatically propose a corrected taxonomic classification for those. Using simulated data, we show that our method attains high accuracy for identification (96.9% sensitivity/91.7% precision) as well as correction (94.9% sensitivity/89.9% precision) of mislabels. Furthermore, an analysis of four widely used microbial 16S reference databases (Greengenes, LTP, RDP and SILVA) indicates that they currently contain between 0.2% and 2.5% mislabels. Finally, we use SATIVA to perform an in-depth evaluation of alternative taxonomies for Cyanobacteria. SATIVA is freely available at https://github.com/amkozlov/sativa .
    Keywords: Computational Methods, Genomics
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    iGEMS: an integrated model for identification of alternative exon usage events (2016)
    Oxford University Press
    Details
    Publication Date: 2016-06-21
    Description: DNA microarrays and RNAseq are complementary methods for studying RNA molecules. Current computational methods to determine alternative exon usage (AEU) using such data require impractical visual inspection and still yield high false-positive rates. Integrated Gene and Exon Model of Splicing (iGEMS) adapts a gene-level residuals model with a gene size adjusted false discovery rate and exon-level analysis to circumvent these limitations. iGEMS was applied to two new DNA microarray datasets, including the high coverage Human Transcriptome Arrays 2.0 and performance was validated using RT-qPCR. First, AEU was studied in adipocytes treated with ( n = 9) or without ( n = 8) the anti-diabetes drug, rosiglitazone. iGEMS identified 555 genes with AEU, and robust verification by RT-qPCR (~90%). Second, in a three-way human tissue comparison (muscle, adipose and blood, n = 41) iGEMS identified 4421 genes with at least one AEU event, with excellent RT-qPCR verification (95%, n = 22). Importantly, iGEMS identified a variety of AEU events, including 3'UTR extension, as well as exon inclusion/exclusion impacting on protein kinase and extracellular matrix domains. In conclusion, iGEMS is a robust method for identification of AEU while the variety of exon usage between human tissues is 5–10 times more prevalent than reported by the Genotype-Tissue Expression consortium using RNA sequencing.
    Keywords: Computational Methods, Genomics
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    TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data (2016)
    Oxford University Press
    Details
    Publication Date: 2016-05-06
    Description: The Cancer Genome Atlas (TCGA) research network has made public a large collection of clinical and molecular phenotypes of more than 10 000 tumor patients across 33 different tumor types. Using this cohort, TCGA has published over 20 marker papers detailing the genomic and epigenomic alterations associated with these tumor types. Although many important discoveries have been made by TCGA's research network, opportunities still exist to implement novel methods, thereby elucidating new biological pathways and diagnostic markers. However, mining the TCGA data presents several bioinformatics challenges, such as data retrieval and integration with clinical data and other molecular data types (e.g. RNA and DNA methylation). We developed an R/Bioconductor package called TCGAbiolinks to address these challenges and offer bioinformatics solutions by using a guided workflow to allow users to query, download and perform integrative analyses of TCGA data. We combined methods from computer science and statistics into the pipeline and incorporated methodologies developed in previous TCGA marker studies and in our own group. Using four different TCGA tumor types (Kidney, Brain, Breast and Colon) as examples, we provide case studies to illustrate examples of reproducibility, integrative analysis and utilization of different Bioconductor packages to advance and accelerate novel discoveries.
    Keywords: Computational Methods, Genomics
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    Robust detection of alternative splicing in a population of single cells (2016)
    Oxford University Press
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    Publication Date: 2016-05-06
    Description: Single cell RNA-seq experiments provide valuable insight into cellular heterogeneity but suffer from low coverage, 3' bias and technical noise. These unique properties of single cell RNA-seq data make study of alternative splicing difficult, and thus most single cell studies have restricted analysis of transcriptome variation to the gene level. To address these limitations, we developed SingleSplice, which uses a statistical model to detect genes whose isoform usage shows biological variation significantly exceeding technical noise in a population of single cells. Importantly, SingleSplice is tailored to the unique demands of single cell analysis, detecting isoform usage differences without attempting to infer expression levels for full-length transcripts. Using data from spike-in transcripts, we found that our approach detects variation in isoform usage among single cells with high sensitivity and specificity. We also applied SingleSplice to data from mouse embryonic stem cells and discovered a set of genes that show significant biological variation in isoform usage across the set of cells. A subset of these isoform differences are linked to cell cycle stage, suggesting a novel connection between alternative splicing and the cell cycle.
    Keywords: Computational Methods, Genomics
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    CARGO: effective format-free compressed storage of genomic information (2016)
    Oxford University Press
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    Publication Date: 2016-07-09
    Description: The recent super-exponential growth in the amount of sequencing data generated worldwide has put techniques for compressed storage into the focus. Most available solutions, however, are strictly tied to specific bioinformatics formats, sometimes inheriting from them suboptimal design choices; this hinders flexible and effective data sharing. Here, we present CARGO (Compressed ARchiving for GenOmics), a high-level framework to automatically generate software systems optimized for the compressed storage of arbitrary types of large genomic data collections. Straightforward applications of our approach to FASTQ and SAM archives require a few lines of code, produce solutions that match and sometimes outperform specialized format-tailored compressors and scale well to multi-TB datasets. All CARGO software components can be freely downloaded for academic and non-commercial use from http://bio-cargo.sourceforge.net .
    Keywords: Computational Methods, Genomics
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    InPhaDel: integrative shotgun and proximity-ligation sequencing to phase deletions with single nucleotide polymorphisms (2016)
    Oxford University Press
    Details
    Publication Date: 2016-07-09
    Description: Phasing of single nucleotide (SNV), and structural variations into chromosome-wide haplotypes in humans has been challenging, and required either trio sequencing or restricting phasing to population-based haplotypes. Selvaraj et al . demonstrated single individual SNV phasing is possible with proximity ligated (HiC) sequencing. Here, we demonstrate HiC can phase structural variants into phased scaffolds of SNVs. Since HiC data is noisy, and SV calling is challenging, we applied a range of supervised classification techniques, including Support Vector Machines and Random Forest, to phase deletions. Our approach was demonstrated on deletion calls and phasings on the NA12878 human genome. We used three NA12878 chromosomes and simulated chromosomes to train model parameters. The remaining NA12878 chromosomes withheld from training were used to evaluate phasing accuracy. Random Forest had the highest accuracy and correctly phased 86% of the deletions with allele-specific read evidence. Allele-specific read evidence was found for 76% of the deletions. HiC provides significant read evidence for accurately phasing 33% of the deletions. Also, eight of eight top ranked deletions phased by only HiC were validated using long range polymerase chain reaction and Sanger. Thus, deletions from a single individual can be accurately phased using a combination of shotgun and proximity ligation sequencing. InPhaDel software is available at: http://l337x911.github.io/inphadel/.
    Keywords: Computational Methods, Genomics
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    Redundans: an assembly pipeline for highly heterozygous genomes (2016)
    Oxford University Press
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    Publication Date: 2016-07-09
    Description: Many genomes display high levels of heterozygosity (i.e. presence of different alleles at the same loci in homologous chromosomes), being those of hybrid organisms an extreme such case. The assembly of highly heterozygous genomes from short sequencing reads is a challenging task because it is difficult to accurately recover the different haplotypes. When confronted with highly heterozygous genomes, the standard assembly process tends to collapse homozygous regions and reports heterozygous regions in alternative contigs. The boundaries between homozygous and heterozygous regions result in multiple assembly paths that are hard to resolve, which leads to highly fragmented assemblies with a total size larger than expected. This, in turn, causes numerous problems in downstream analyses such as fragmented gene models, wrong gene copy number, or broken synteny. To circumvent these caveats we have developed a pipeline that specifically deals with the assembly of heterozygous genomes by introducing a step to recognise and selectively remove alternative heterozygous contigs. We tested our pipeline on simulated and naturally-occurring heterozygous genomes and compared its accuracy to other existing tools. Our method is freely available at https://github.com/Gabaldonlab/redundans .
    Keywords: Computational Methods, Genomics
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    Graph-based modeling of tandem repeats improves global multiple sequence alignment (2013)
    Oxford University Press
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    Publication Date: 2013-09-26
    Description: Tandem repeats (TRs) are often present in proteins with crucial functions, responsible for resistance, pathogenicity and associated with infectious or neurodegenerative diseases. This motivates numerous studies of TRs and their evolution, requiring accurate multiple sequence alignment. TRs may be lost or inserted at any position of a TR region by replication slippage or recombination, but current methods assume fixed unit boundaries, and yet are of high complexity. We present a new global graph-based alignment method that does not restrict TR unit indels by unit boundaries. TR indels are modeled separately and penalized using the phylogeny-aware alignment algorithm. This ensures enhanced accuracy of reconstructed alignments, disentangling TRs and measuring indel events and rates in a biologically meaningful way. Our method detects not only duplication events but also all changes in TR regions owing to recombination, strand slippage and other events inserting or deleting TR units. We evaluate our method by simulation incorporating TR evolution, by either sampling TRs from a profile hidden Markov model or by mimicking strand slippage with duplications. The new method is illustrated on a family of type III effectors, a pathogenicity determinant in agriculturally important bacteria Ralstonia solanacearum. We show that TR indel rate variation contributes to the diversification of this protein family.
    Keywords: Computational Methods, Genomics
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    Meander: visually exploring the structural variome using space-filling curves (2013)
    Oxford University Press
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    Publication Date: 2013-06-08
    Description: The introduction of next generation sequencing methods in genome studies has made it possible to shift research from a gene-centric approach to a genome wide view. Although methods and tools to detect single nucleotide polymorphisms are becoming more mature, methods to identify and visualize structural variation (SV) are still in their infancy. Most genome browsers can only compare a given sequence to a reference genome; therefore, direct comparison of multiple individuals still remains a challenge. Therefore, the implementation of efficient approaches to explore and visualize SVs and directly compare two or more individuals is desirable. In this article, we present a visualization approach that uses space-filling Hilbert curves to explore SVs based on both read-depth and pair-end information. An interactive open-source Java application, called Meander , implements the proposed methodology, and its functionality is demonstrated using two cases. With Meander , users can explore variations at different levels of resolution and simultaneously compare up to four different individuals against a common reference. The application was developed using Java version 1.6 and Processing.org and can be run on any platform. It can be found at http://homes.esat.kuleuven.be/~bioiuser/meander .
    Keywords: Computational Methods, Genomics
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    Following the footprints of polymorphic inversions on SNP data: from detection to association tests (2015)
    Oxford University Press
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    Publication Date: 2015-05-03
    Description: Inversion polymorphisms have important phenotypic and evolutionary consequences in humans. Two different methodologies have been used to infer inversions from SNP dense data, enabling the use of large cohorts for their study. One approach relies on the differences in linkage disequilibrium across breakpoints; the other one captures the internal haplotype groups that tag the inversion status of chromosomes. In this article, we assessed the convergence of the two methods in the detection of 20 human inversions that have been reported in the literature. The methods converged in four inversions including inv-8p23, for which we studied its association with low-BMI in American children. Using a novel haplotype tagging method with control on inversion ancestry, we computed the frequency of inv-8p23 in two American cohorts and observed inversion haplotype admixture. Accounting for haplotype ancestry, we found that the European inverted allele in children carries a recessive risk of underweight, validated in an independent Spanish cohort (combined: OR= 2.00, P = 0.001). While the footprints of inversions on SNP data are complex, we show that systematic analyses, such as convergence of different methods and controlling for ancestry, can reveal the contribution of inversions to the ancestral composition of populations and to the heritability of human disease.
    Keywords: Computational Methods, Genomics
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    Reconstructing genome-scale metabolic models with merlin (2015)
    Oxford University Press
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    Publication Date: 2015-05-03
    Description: The Metabolic Models Reconstruction Using Genome-Scale Information ( merlin ) tool is a user-friendly Java application that aids the reconstruction of genome-scale metabolic models for any organism that has its genome sequenced. It performs the major steps of the reconstruction process, including the functional genomic annotation of the whole genome and subsequent construction of the portfolio of reactions. Moreover, merlin includes tools for the identification and annotation of genes encoding transport proteins, generating the transport reactions for those carriers. It also performs the compartmentalisation of the model, predicting the organelle localisation of the proteins encoded in the genome and thus the localisation of the metabolites involved in the reactions promoted by such enzymes. The gene-proteins-reactions (GPR) associations are automatically generated and included in the model. Finally, merlin expedites the transition from genomic data to draft metabolic models reconstructions exported in the SBML standard format, allowing the user to have a preliminary view of the biochemical network, which can be manually curated within the environment provided by merlin .
    Keywords: Computational Methods, Genomics
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    Inferential modeling of 3D chromatin structure (2015)
    Oxford University Press
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    Publication Date: 2015-05-03
    Description: For eukaryotic cells, the biological processes involving regulatory DNA elements play an important role in cell cycle. Understanding 3D spatial arrangements of chromosomes and revealing long-range chromatin interactions are critical to decipher these biological processes. In recent years, chromosome conformation capture (3C) related techniques have been developed to measure the interaction frequencies between long-range genome loci, which have provided a great opportunity to decode the 3D organization of the genome. In this paper, we develop a new Bayesian framework to derive the 3D architecture of a chromosome from 3C-based data. By modeling each chromosome as a polymer chain, we define the conformational energy based on our current knowledge on polymer physics and use it as prior information in the Bayesian framework. We also propose an expectation-maximization (EM) based algorithm to estimate the unknown parameters of the Bayesian model and infer an ensemble of chromatin structures based on interaction frequency data. We have validated our Bayesian inference approach through cross-validation and verified the computed chromatin conformations using the geometric constraints derived from fluorescence in situ hybridization (FISH) experiments. We have further confirmed the inferred chromatin structures using the known genetic interactions derived from other studies in the literature. Our test results have indicated that our Bayesian framework can compute an accurate ensemble of 3D chromatin conformations that best interpret the distance constraints derived from 3C-based data and also agree with other sources of geometric constraints derived from experimental evidence in the previous studies. The source code of our approach can be found in https://github.com/wangsy11/InfMod3DGen .
    Keywords: Computational Methods, Genomics
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    Integrating motif, DNA accessibility and gene expression data to build regulatory maps in an organism (2015)
    Oxford University Press
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    Publication Date: 2015-05-03
    Description: Characterization of cell type specific regulatory networks and elements is a major challenge in genomics, and emerging strategies frequently employ high-throughput genome-wide assays of transcription factor (TF) to DNA binding, histone modifications or chromatin state. However, these experiments remain too difficult/expensive for many laboratories to apply comprehensively to their system of interest. Here, we explore the potential of elucidating regulatory systems in varied cell types using computational techniques that rely on only data of gene expression, low-resolution chromatin accessibility, and TF–DNA binding specificities (‘motifs’). We show that static computational motif scans overlaid with chromatin accessibility data reasonably approximate experimentally measured TF–DNA binding. We demonstrate that predicted binding profiles and expression patterns of hundreds of TFs are sufficient to identify major regulators of ~200 spatiotemporal expression domains in the Drosophila embryo. We are then able to learn reliable statistical models of enhancer activity for over 70 expression domains and apply those models to annotate domain specific enhancers genome-wide. Throughout this work, we apply our motif and accessibility based approach to comprehensively characterize the regulatory network of fruitfly embryonic development and show that the accuracy of our computational method compares favorably to approaches that rely on data from many experimental assays.
    Keywords: Computational Methods, Genomics
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    FOAM (Functional Ontology Assignments for Metagenomes): a Hidden Markov Model (HMM) database with environmental focus (2014)
    Oxford University Press
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    Publication Date: 2014-11-07
    Description: A new functional gene database, FOAM (Functional Ontology Assignments for Metagenomes), was developed to screen environmental metagenomic sequence datasets. FOAM provides a new functional ontology dedicated to classify gene functions relevant to environmental microorganisms based on Hidden Markov Models (HMMs). Sets of aligned protein sequences (i.e. ‘profiles’) were tailored to a large group of target KEGG Orthologs (KOs) from which HMMs were trained. The alignments were checked and curated to make them specific to the targeted KO. Within this process, sequence profiles were enriched with the most abundant sequences available to maximize the yield of accurate classifier models. An associated functional ontology was built to describe the functional groups and hierarchy. FOAM allows the user to select the target search space before HMM-based comparison steps and to easily organize the results into different functional categories and subcategories. FOAM is publicly available at http://portal.nersc.gov/project/m1317/FOAM/ .
    Keywords: Computational Methods, Genomics
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    A statistical framework for revealing signaling pathways perturbed by DNA variants (2015)
    Oxford University Press
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    Publication Date: 2015-06-24
    Description: Much of the inter-individual variation in gene expression is triggered via perturbations of signaling networks by DNA variants. We present a novel probabilistic approach for identifying the particular pathways by which DNA variants perturb the signaling network. Our procedure, called PINE, relies on a systematic integration of established biological knowledge of signaling networks with data on transcriptional responses to various experimental conditions. Unlike previous approaches, PINE provides statistical aspects that are critical for prioritizing hypotheses for followup experiments. Using simulated data, we show that higher accuracy is attained with PINE than with existing methods. We used PINE to analyze transcriptional responses of immune dendritic cells to several pathogenic stimulations. PINE identified statistically significant genetic perturbations in the pathogen-sensing signaling network, suggesting previously uncharacterized regulatory mechanisms for functional DNA variants.
    Keywords: Computational Methods, Genomics
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    Why weight? Modelling sample and observational level variability improves power in RNA-seq analyses (2015)
    Oxford University Press
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    Publication Date: 2015-08-29
    Description: Variations in sample quality are frequently encountered in small RNA-sequencing experiments, and pose a major challenge in a differential expression analysis. Removal of high variation samples reduces noise, but at a cost of reducing power, thus limiting our ability to detect biologically meaningful changes. Similarly, retaining these samples in the analysis may not reveal any statistically significant changes due to the higher noise level. A compromise is to use all available data, but to down-weight the observations from more variable samples. We describe a statistical approach that facilitates this by modelling heterogeneity at both the sample and observational levels as part of the differential expression analysis. At the sample level this is achieved by fitting a log-linear variance model that includes common sample-specific or group-specific parameters that are shared between genes. The estimated sample variance factors are then converted to weights and combined with observational level weights obtained from the mean–variance relationship of the log-counts-per-million using ‘voom’. A comprehensive analysis involving both simulations and experimental RNA-sequencing data demonstrates that this strategy leads to a universally more powerful analysis and fewer false discoveries when compared to conventional approaches. This methodology has wide application and is implemented in the open-source ‘limma’ package.
    Keywords: Computational Methods, Genomics
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    RAX2: a genome-wide detection method of condition-associated transcription variation (2015)
    Oxford University Press
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    Publication Date: 2015-08-29
    Description: Most mammalian genes have mRNA variants due to alternative promoter usage, alternative splicing, and alternative cleavage and polyadenylation. Expression of alternative RNA isoforms has been found to be associated with tumorigenesis, proliferation and differentiation. Detection of condition-associated transcription variation requires association methods. Traditional association methods such as Pearson chi-square test and Fisher Exact test are single test methods and do not work on count data with replicates. Although the Cochran Mantel Haenszel (CMH) approach can handle replicated count data, our simulations showed that multiple CMH tests still had very low power. To identify condition-associated variation of transcription, we here proposed a ranking analysis of chi-squares (RAX2) for large-scale association analysis. RAX2 is a nonparametric method and has accurate and conservative estimation of FDR profile. Simulations demonstrated that RAX2 performs well in finding condition-associated transcription variants. We applied RAX2 to primary T-cell transcriptomic data and identified 1610 (16.3%) tags associated in transcription with immune stimulation at FDR 〈 0.05. Most of these tags also had differential expression. Analysis of two and three tags within genes revealed that under immune stimulation short RNA isoforms were preferably used.
    Keywords: Computational Methods, Genomics
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    Unique transposon landscapes are pervasive across Drosophila melanogaster genomes (2015)
    Oxford University Press
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    Publication Date: 2015-12-16
    Description: To understand how transposon landscapes (TLs) vary across animal genomes, we describe a new method called the Transposon Insertion and Depletion AnaLyzer (TIDAL) and a database of 〉300 TLs in Drosophila melanogaster (TIDAL-Fly). Our analysis reveals pervasive TL diversity across cell lines and fly strains, even for identically named sub-strains from different laboratories such as the ISO1 strain used for the reference genome sequence. On average, 〉500 novel insertions exist in every lab strain, inbred strains of the Drosophila Genetic Reference Panel (DGRP), and fly isolates in the Drosophila Genome Nexus (DGN). A minority (〈25%) of transposon families comprise the majority (〉70%) of TL diversity across fly strains. A sharp contrast between insertion and depletion patterns indicates that many transposons are unique to the ISO1 reference genome sequence. Although TL diversity from fly strains reaches asymptotic limits with increasing sequencing depth, rampant TL diversity causes unsaturated detection of TLs in pools of flies. Finally, we show novel transposon insertions negatively correlate with Piwi-interacting RNA (piRNA) levels for most transposon families, except for the highly-abundant roo retrotransposon. Our study provides a useful resource for Drosophila geneticists to understand how transposons create extensive genomic diversity in fly cell lines and strains.
    Keywords: Computational Methods, Genomics
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    Mixed Integer Linear Programming based machine learning approach identifies regulators of telomerase in yeast (2016)
    Oxford University Press
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    Publication Date: 2016-06-03
    Description: Understanding telomere length maintenance mechanisms is central in cancer biology as their dysregulation is one of the hallmarks for immortalization of cancer cells. Important for this well-balanced control is the transcriptional regulation of the telomerase genes. We integrated Mixed Integer Linear Programming models into a comparative machine learning based approach to identify regulatory interactions that best explain the discrepancy of telomerase transcript levels in yeast mutants with deleted regulators showing aberrant telomere length, when compared to mutants with normal telomere length. We uncover novel regulators of telomerase expression, several of which affect histone levels or modifications. In particular, our results point to the transcription factors Sum1, Hst1 and Srb2 as being important for the regulation of EST1 transcription, and we validated the effect of Sum1 experimentally. We compiled our machine learning method leading to a user friendly package for R which can straightforwardly be applied to similar problems integrating gene regulator binding information and expression profiles of samples of e.g. different phenotypes, diseases or treatments.
    Keywords: Computational Methods, Genomics
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    f-divergence cutoff index to simultaneously identify differential expression in the integrated transcriptome and proteome (2016)
    Oxford University Press
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    Publication Date: 2016-06-03
    Description: The ability to integrate ‘omics’ (i.e. transcriptomics and proteomics) is becoming increasingly important to the understanding of regulatory mechanisms. There are currently no tools available to identify differentially expressed genes (DEGs) across different ‘omics’ data types or multi-dimensional data including time courses. We present fCI (f-divergence Cut-out Index), a model capable of simultaneously identifying DEGs from continuous and discrete transcriptomic, proteomic and integrated proteogenomic data. We show that fCI can be used across multiple diverse sets of data and can unambiguously find genes that show functional modulation, developmental changes or misregulation. Applying fCI to several proteogenomics datasets, we identified a number of important genes that showed distinctive regulation patterns. The package fCI is available at R Bioconductor and http://software.steenlab.org/fCI/ .
    Keywords: Computational Methods, Genomics
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    CLASS2: accurate and efficient splice variant annotation from RNA-seq reads (2016)
    Oxford University Press
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    Publication Date: 2016-06-03
    Description: Next generation sequencing of cellular RNA is making it possible to characterize genes and alternative splicing in unprecedented detail. However, designing bioinformatics tools to accurately capture splicing variation has proven difficult. Current programs can find major isoforms of a gene but miss lower abundance variants, or are sensitive but imprecise. CLASS2 is a novel open source tool for accurate genome-guided transcriptome assembly from RNA-seq reads based on the model of splice graph. An extension of our program CLASS, CLASS2 jointly optimizes read patterns and the number of supporting reads to score and prioritize transcripts, implemented in a novel, scalable and efficient dynamic programming algorithm. When compared against reference programs, CLASS2 had the best overall accuracy and could detect up to twice as many splicing events with precision similar to the best reference program. Notably, it was the only tool to produce consistently reliable transcript models for a wide range of applications and sequencing strategies, including ribosomal RNA-depleted samples. Lightweight and multi-threaded, CLASS2 requires 〈3GB RAM and can analyze a 350 million read set within hours, and can be widely applied to transcriptomics studies ranging from clinical RNA sequencing, to alternative splicing analyses, and to the annotation of new genomes.
    Keywords: Computational Methods, Genomics
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    FACETS: allele-specific copy number and clonal heterogeneity analysis tool for high-throughput DNA sequencing (2016)
    Oxford University Press
    Details
    Publication Date: 2016-09-20
    Description: Allele-specific copy number analysis (ASCN) from next generation sequencing (NGS) data can greatly extend the utility of NGS beyond the identification of mutations to precisely annotate the genome for the detection of homozygous/heterozygous deletions, copy-neutral loss-of-heterozygosity (LOH), allele-specific gains/amplifications. In addition, as targeted gene panels are increasingly used in clinical sequencing studies for the detection of ‘actionable’ mutations and copy number alterations to guide treatment decisions, accurate, tumor purity-, ploidy- and clonal heterogeneity-adjusted integer copy number calls are greatly needed to more reliably interpret NGS-based cancer gene copy number data in the context of clinical sequencing. We developed FACETS, an ASCN tool and open-source software with a broad application to whole genome, whole-exome, as well as targeted panel sequencing platforms. It is a fully integrated stand-alone pipeline that includes sequencing BAM file post-processing, joint segmentation of total- and allele-specific read counts, and integer copy number calls corrected for tumor purity, ploidy and clonal heterogeneity, with comprehensive output and integrated visualization. We demonstrate the application of FACETS using The Cancer Genome Atlas (TCGA) whole-exome sequencing of lung adenocarcinoma samples. We also demonstrate its application to a clinical sequencing platform based on a targeted gene panel.
    Keywords: Computational Methods, Genomics
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    A genome-wide approach for detecting novel insertion-deletion variants of mid-range size (2016)
    Oxford University Press
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    Publication Date: 2016-09-03
    Description: We present SWAN, a statistical framework for robust detection of genomic structural variants in next-generation sequencing data and an analysis of mid-range size insertion and deletions (〈10 Kb) for whole genome analysis and DNA mixtures. To identify these mid-range size events, SWAN collectively uses information from read-pair, read-depth and one end mapped reads through statistical likelihoods based on Poisson field models. SWAN also uses soft-clip/split read remapping to supplement the likelihood analysis and determine variant boundaries. The accuracy of SWAN is demonstrated by in silico spike-ins and by identification of known variants in the NA12878 genome. We used SWAN to identify a series of novel set of mid-range insertion/deletion detection that were confirmed by targeted deep re-sequencing. An R package implementation of SWAN is open source and freely available.
    Keywords: Computational Methods, Genomics
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    Comprehensive analysis of high-throughput screens with HiTSeekR (2016)
    Oxford University Press
    Details
    Publication Date: 2016-08-20
    Description: High-throughput screening (HTS) is an indispensable tool for drug (target) discovery that currently lacks user-friendly software tools for the robust identification of putative hits from HTS experiments and for the interpretation of these findings in the context of systems biology. We developed HiTSeekR as a one-stop solution for chemical compound screens, siRNA knock-down and CRISPR/Cas9 knock-out screens, as well as microRNA inhibitor and -mimics screens. We chose three use cases that demonstrate the potential of HiTSeekR to fully exploit HTS screening data in quite heterogeneous contexts to generate novel hypotheses for follow-up experiments: (i) a genome-wide RNAi screen to uncover modulators of TNFα, (ii) a combined siRNA and miRNA mimics screen on vorinostat resistance and (iii) a small compound screen on KRAS synthetic lethality. HiTSeekR is publicly available at http://hitseekr.compbio.sdu.dk . It is the first approach to close the gap between raw data processing, network enrichment and wet lab target generation for various HTS screen types.
    Keywords: Computational Methods, Genomics
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    An ensemble strategy that significantly improves de novo assembly of microbial genomes from metagenomic next-generation sequencing data (2015)
    Oxford University Press
    Details
    Publication Date: 2015-04-21
    Description: Next-generation sequencing (NGS) approaches rapidly produce millions to billions of short reads, which allow pathogen detection and discovery in human clinical, animal and environmental samples. A major limitation of sequence homology-based identification for highly divergent microorganisms is the short length of reads generated by most highly parallel sequencing technologies. Short reads require a high level of sequence similarities to annotated genes to confidently predict gene function or homology. Such recognition of highly divergent homologues can be improved by reference-free ( de novo ) assembly of short overlapping sequence reads into larger contigs. We describe an ensemble strategy that integrates the sequential use of various de Bruijn graph and overlap-layout-consensus assemblers with a novel partitioned sub-assembly approach. We also proposed new quality metrics that are suitable for evaluating metagenome de novo assembly. We demonstrate that this new ensemble strategy tested using in silico spike-in, clinical and environmental NGS datasets achieved significantly better contigs than current approaches.
    Keywords: Computational Methods, Genomics
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    Distinguishing between productive and abortive promoters using a random forest classifier in Mycoplasma pneumoniae (2015)
    Oxford University Press
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    Publication Date: 2015-04-21
    Description: Distinguishing between promoter-like sequences in bacteria that belong to true or abortive promoters, or to those that do not initiate transcription at all, is one of the important challenges in transcriptomics. To address this problem, we have studied the genome-reduced bacterium Mycoplasma pneumoniae , for which the RNAs associated with transcriptional start sites have been recently experimentally identified. We determined the contribution to transcription events of different genomic features: the –10, extended –10 and –35 boxes, the UP element, the bases surrounding the –10 box and the nearest-neighbor free energy of the promoter region. Using a random forest classifier and the aforementioned features transformed into scores, we could distinguish between true, abortive promoters and non-promoters with good –10 box sequences. The methods used in this characterization of promoters can be extended to other bacteria and have important applications for promoter design in bacterial genome engineering.
    Keywords: Computational Methods, Genomics
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    Pathway analysis from lists of microRNAs: common pitfalls and alternative strategy (2015)
    Oxford University Press
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    Publication Date: 2015-04-21
    Description: MicroRNAs (miRNAs) are involved in the regulation of gene expression at a post-transcriptional level. As such, monitoring miRNA expression has been increasingly used to assess their role in regulatory mechanisms of biological processes. In large scale studies, once miRNAs of interest have been identified, the target genes they regulate are often inferred using algorithms or databases. A pathway analysis is then often performed in order to generate hypotheses about the relevant biological functions controlled by the miRNA signature. Here we show that the method widely used in scientific literature to identify these pathways is biased and leads to inaccurate results. In addition to describing the bias and its origin we present an alternative strategy to identify potential biological functions specifically impacted by a miRNA signature. More generally, our study exemplifies the crucial need of relevant negative controls when developing, and using, bioinformatics methods.
    Keywords: Computational Methods, Genomics
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    svaseq: removing batch effects and other unwanted noise from sequencing data (2014)
    Oxford University Press
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    Publication Date: 2014-11-28
    Description: It is now known that unwanted noise and unmodeled artifacts such as batch effects can dramatically reduce the accuracy of statistical inference in genomic experiments. These sources of noise must be modeled and removed to accurately measure biological variability and to obtain correct statistical inference when performing high-throughput genomic analysis. We introduced surrogate variable analysis (sva) for estimating these artifacts by (i) identifying the part of the genomic data only affected by artifacts and (ii) estimating the artifacts with principal components or singular vectors of the subset of the data matrix. The resulting estimates of artifacts can be used in subsequent analyses as adjustment factors to correct analyses. Here I describe a version of the sva approach specifically created for count data or FPKMs from sequencing experiments based on appropriate data transformation. I also describe the addition of supervised sva (ssva) for using control probes to identify the part of the genomic data only affected by artifacts. I present a comparison between these versions of sva and other methods for batch effect estimation on simulated data, real count-based data and FPKM-based data. These updates are available through the sva Bioconductor package and I have made fully reproducible analysis using these methods available from: https://github.com/jtleek/svaseq .
    Keywords: Computational Methods, Genomics
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    Insyght: navigating amongst abundant homologues, syntenies and gene functional annotations in bacteria, it's that symbol! (2014)
    Oxford University Press
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    Publication Date: 2014-11-28
    Description: High-throughput techniques have considerably increased the potential of comparative genomics whilst simultaneously posing many new challenges. One of those challenges involves efficiently mining the large amount of data produced and exploring the landscape of both conserved and idiosyncratic genomic regions across multiple genomes. Domains of application of these analyses are diverse: identification of evolutionary events, inference of gene functions, detection of niche-specific genes or phylogenetic profiling. Insyght is a comparative genomic visualization tool that combines three complementary displays: (i) a table for thoroughly browsing amongst homologues, (ii) a comparator of orthologue functional annotations and (iii) a genomic organization view designed to improve the legibility of rearrangements and distinctive loci. The latter display combines symbolic and proportional graphical paradigms. Synchronized navigation across multiple species and interoperability between the views are core features of Insyght. A gene filter mechanism is provided that helps the user to build a biologically relevant gene set according to multiple criteria such as presence/absence of homologues and/or various annotations. We illustrate the use of Insyght with scenarios. Currently, only Bacteria and Archaea are supported. A public instance is available at http://genome.jouy.inra.fr/Insyght . The tool is freely downloadable for private data set analysis.
    Keywords: Computational Methods, Genomics
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    iPro54-PseKNC: a sequence-based predictor for identifying sigma-54 promoters in prokaryote with pseudo k-tuple nucleotide composition (2014)
    Oxford University Press
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    Publication Date: 2014-11-28
    Description: The 54 promoters are unique in prokaryotic genome and responsible for transcripting carbon and nitrogen-related genes. With the avalanche of genome sequences generated in the postgenomic age, it is highly desired to develop automated methods for rapidly and effectively identifying the 54 promoters. Here, a predictor called ‘ iPro54-PseKNC ’ was developed. In the predictor, the samples of DNA sequences were formulated by a novel feature vector called ‘pseudo k -tuple nucleotide composition’, which was further optimized by the incremental feature selection procedure. The performance of iPro54-PseKNC was examined by the rigorous jackknife cross-validation tests on a stringent benchmark data set. As a user-friendly web-server, iPro54-PseKNC is freely accessible at http://lin.uestc.edu.cn/server/iPro54-PseKNC . For the convenience of the vast majority of experimental scientists, a step-by-step protocol guide was provided on how to use the web-server to get the desired results without the need to follow the complicated mathematics that were presented in this paper just for its integrity. Meanwhile, we also discovered through an in-depth statistical analysis that the distribution of distances between the transcription start sites and the translation initiation sites were governed by the gamma distribution, which may provide a fundamental physical principle for studying the 54 promoters.
    Keywords: Computational Methods, Genomics
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    Binding site discovery from nucleic acid sequences by discriminative learning of hidden Markov models (2014)
    Oxford University Press
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    Publication Date: 2014-11-28
    Description: We present a discriminative learning method for pattern discovery of binding sites in nucleic acid sequences based on hidden Markov models. Sets of positive and negative example sequences are mined for sequence motifs whose occurrence frequency varies between the sets. The method offers several objective functions, but we concentrate on mutual information of condition and motif occurrence. We perform a systematic comparison of our method and numerous published motif-finding tools. Our method achieves the highest motif discovery performance, while being faster than most published methods. We present case studies of data from various technologies, including ChIP-Seq, RIP-Chip and PAR-CLIP, of embryonic stem cell transcription factors and of RNA-binding proteins, demonstrating practicality and utility of the method. For the alternative splicing factor RBM10, our analysis finds motifs known to be splicing-relevant. The motif discovery method is implemented in the free software package Discrover. It is applicable to genome- and transcriptome-scale data, makes use of available repeat experiments and aside from binary contrasts also more complex data configurations can be utilized.
    Keywords: Computational Methods, Genomics
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    Spatial localization of co-regulated genes exceeds genomic gene clustering in the Saccharomyces cerevisiae genome (2013)
    Oxford University Press
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    Publication Date: 2013-02-20
    Description: While it has been long recognized that genes are not randomly positioned along the genome, the degree to which its 3D structure influences the arrangement of genes has remained elusive. In particular, several lines of evidence suggest that actively transcribed genes are spatially co-localized, forming transcription factories; however, a generalized systematic test has hitherto not been described. Here we reveal transcription factories using a rigorous definition of genomic structure based on Saccharomyces cerevisiae chromosome conformation capture data, coupled with an experimental design controlling for the primary gene order. We develop a data-driven method for the interpolation and the embedding of such datasets and introduce statistics that enable the comparison of the spatial and genomic densities of genes. Combining these, we report evidence that co-regulated genes are clustered in space, beyond their observed clustering in the context of gene order along the genome and show this phenomenon is significant for 64 out of 117 transcription factors. Furthermore, we show that those transcription factors with high spatially co-localized targets are expressed higher than those whose targets are not spatially clustered. Collectively, our results support the notion that, at a given time, the physical density of genes is intimately related to regulatory activity.
    Keywords: Computational Methods, Genomics
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    PanOCT: automated clustering of orthologs using conserved gene neighborhood for pan-genomic analysis of bacterial strains and closely related species (2012)
    Oxford University Press
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    Publication Date: 2012-12-14
    Description: Pan-genome ortholog clustering tool ( PanOCT ) is a tool for pan-genomic analysis of closely related prokaryotic species or strains. PanOCT uses conserved gene neighborhood information to separate recently diverged paralogs into orthologous clusters where homology-only clustering methods cannot. The results from PanOCT and three commonly used graph-based ortholog-finding programs were compared using a set of four publicly available strains of the same bacterial species. All four methods agreed on ~70% of the clusters and ~86% of the proteins. The clusters that did not agree were inspected for evidence of correctness resulting in 85 high-confidence manually curated clusters that were used to compare all four methods.
    Keywords: Computational Methods, Genomics
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    A novel ab initio identification system of transcriptional regulation motifs in genome DNA sequences based on direct comparison scheme of signal/noise distributions (2012)
    Oxford University Press
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    Publication Date: 2012-10-10
    Description: A novel ab initio parameter-tuning-free system to identify transcriptional factor (TF) binding motifs (TFBMs) in genome DNA sequences was developed. It is based on the comparison of two types of frequency distributions with respect to the TFBM candidates in the target DNA sequences and the non-candidates in the background sequence, with the latter generated by utilizing the intergenic sequences. For benchmark tests, we used DNA sequence datasets extracted by ChIP-on-chip and ChIP-seq techniques and identified 65 yeast and four mammalian TFBMs, with the latter including gaps. The accuracy of our system was compared with those of other available programs (i.e. MEME, Weeder, BioProspector, MDscan and DME) and was the best among them, even without tuning of the parameter set for each TFBM and pre-treatment/editing of the target DNA sequences. Moreover, with respect to some TFs for which the identified motifs are inconsistent with those in the references, our results were revealed to be correct, by comparing them with other existing experimental data. Thus, our identification system does not need any other biological information except for gene positions, and is also expected to be applicable to genome DNA sequences to identify unknown TFBMs as well as known ones.
    Keywords: Computational Methods, Genomics
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    Identification of new microRNA-regulated genes by conserved targeting in plant species (2012)
    Oxford University Press
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    Publication Date: 2012-10-10
    Description: MicroRNAs (miRNAs) are major regulators of gene expression in multicellular organisms. They recognize their targets by sequence complementarity and guide them to cleavage or translational arrest. It is generally accepted that plant miRNAs have extensive complementarity to their targets and their prediction usually relies on the use of empirical parameters deduced from known miRNA–target interactions. Here, we developed a strategy to identify miRNA targets which is mainly based on the conservation of the potential regulation in different species. We applied the approach to expressed sequence tags datasets from angiosperms. Using this strategy, we predicted many new interactions and experimentally validated previously unknown miRNA targets in Arabidopsis thaliana . Newly identified targets that are broadly conserved include auxin regulators, transcription factors and transporters. Some of them might participate in the same pathways as the targets known before, suggesting that some miRNAs might control different aspects of a biological process. Furthermore, this approach can be used to identify targets present in a specific group of species, and, as a proof of principle, we analyzed Solanaceae -specific targets. The presented strategy can be used alone or in combination with other approaches to find miRNA targets in plants.
    Keywords: Computational Methods, Genomics
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    Use of ChIP-Seq data for the design of a multiple promoter-alignment method (2012)
    Oxford University Press
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    Publication Date: 2012-04-15
    Description: We address the challenge of regulatory sequence alignment with a new method, Pro-Coffee, a multiple aligner specifically designed for homologous promoter regions. Pro-Coffee uses a dinucleotide substitution matrix estimated on alignments of functional binding sites from TRANSFAC. We designed a validation framework using several thousand families of orthologous promoters. This dataset was used to evaluate the accuracy for predicting true human orthologs among their paralogs. We found that whereas other methods achieve on average 73.5% accuracy, and 77.6% when trained on that same dataset, the figure goes up to 80.4% for Pro-Coffee. We then applied a novel validation procedure based on multi-species ChIP-seq data. Trained and untrained methods were tested for their capacity to correctly align experimentally detected binding sites. Whereas the average number of correctly aligned sites for two transcription factors is 284 for default methods and 316 for trained methods, Pro-Coffee achieves 331, 16.5% above the default average. We find a high correlation between a method's performance when classifying orthologs and its ability to correctly align proven binding sites. Not only has this interesting biological consequences, it also allows us to conclude that any method that is trained on the ortholog data set will result in functionally more informative alignments.
    Keywords: Computational Methods, Genomics
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    MCScanX: a toolkit for detection and evolutionary analysis of gene synteny and collinearity (2012)
    Oxford University Press
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    Publication Date: 2012-04-15
    Description: MCScan is an algorithm able to scan multiple genomes or subgenomes in order to identify putative homologous chromosomal regions, and align these regions using genes as anchors. The MCScanX toolkit implements an adjusted MCScan algorithm for detection of synteny and collinearity that extends the original software by incorporating 14 utility programs for visualization of results and additional downstream analyses. Applications of MCScanX to several sequenced plant genomes and gene families are shown as examples. MCScanX can be used to effectively analyze chromosome structural changes, and reveal the history of gene family expansions that might contribute to the adaptation of lineages and taxa. An integrated view of various modes of gene duplication can supplement the traditional gene tree analysis in specific families. The source code and documentation of MCScanX are freely available at http://chibba.pgml.uga.edu/mcscan2/ .
    Keywords: Computational Methods, Genomics
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    LARVA: an integrative framework for large-scale analysis of recurrent variants in noncoding annotations (2015)
    Oxford University Press
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    Publication Date: 2015-09-30
    Description: In cancer research, background models for mutation rates have been extensively calibrated in coding regions, leading to the identification of many driver genes, recurrently mutated more than expected. Noncoding regions are also associated with disease; however, background models for them have not been investigated in as much detail. This is partially due to limited noncoding functional annotation. Also, great mutation heterogeneity and potential correlations between neighboring sites give rise to substantial overdispersion in mutation count, resulting in problematic background rate estimation. Here, we address these issues with a new computational framework called LARVA. It integrates variants with a comprehensive set of noncoding functional elements, modeling the mutation counts of the elements with a β-binomial distribution to handle overdispersion. LARVA, moreover, uses regional genomic features such as replication timing to better estimate local mutation rates and mutational hotspots. We demonstrate LARVA's effectiveness on 760 whole-genome tumor sequences, showing that it identifies well-known noncoding drivers, such as mutations in the TERT promoter. Furthermore, LARVA highlights several novel highly mutated regulatory sites that could potentially be noncoding drivers. We make LARVA available as a software tool and release our highly mutated annotations as an online resource ( larva.gersteinlab.org ).
    Keywords: Computational Methods, Genomics
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    Beegle: from literature mining to disease-gene discovery (2016)
    Oxford University Press
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    Publication Date: 2016-01-30
    Description: Disease-gene identification is a challenging process that has multiple applications within functional genomics and personalized medicine. Typically, this process involves both finding genes known to be associated with the disease (through literature search) and carrying out preliminary experiments or screens (e.g. linkage or association studies, copy number analyses, expression profiling) to determine a set of promising candidates for experimental validation. This requires extensive time and monetary resources. We describe Beegle , an online search and discovery engine that attempts to simplify this process by automating the typical approaches. It starts by mining the literature to quickly extract a set of genes known to be linked with a given query, then it integrates the learning methodology of Endeavour (a gene prioritization tool) to train a genomic model and rank a set of candidate genes to generate novel hypotheses. In a realistic evaluation setup, Beegle has an average recall of 84% in the top 100 returned genes as a search engine, which improves the discovery engine by 12.6% in the top 5% prioritized genes. Beegle is publicly available at http://beegle.esat.kuleuven.be/ .
    Keywords: Computational Methods, Genomics
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    A computational method for studying the relation between alternative splicing and DNA methylation (2016)
    Oxford University Press
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    Publication Date: 2016-01-30
    Description: Alternative splicing is an important mechanism in eukaryotes that expands the transcriptome and proteome significantly. It plays an important role in a number of biological processes. Understanding its regulation is hence an important challenge. Recently, increasing evidence has been collected that supports an involvement of intragenic DNA methylation in the regulation of alternative splicing. The exact mechanisms of regulation, however, are largely unknown, and speculated to be complex: different methylation profiles might exist, each of which could be associated with a different regulation mechanism. We present a computational technique that is able to determine such stable methylation patterns and allows to correlate these patterns with inclusion propensity of exons. Pattern detection is based on dynamic time warping (DTW) of methylation profiles, a sophisticated similarity measure for signals that can be non-trivially transformed. We design a flexible self-organizing map approach to pattern grouping. Exemplary application on available data sets indicates that stable patterns which correlate non-trivially with exon inclusion do indeed exist. To improve the reliability of these predictions, further studies on larger data sets will be required. We have thus taken great care that our software runs efficiently on modern hardware, so that it can support future studies on large-scale data sets.
    Keywords: Computational Methods, Genomics
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    BubbleTree: an intuitive visualization to elucidate tumoral aneuploidy and clonality using next generation sequencing data (2016)
    Oxford University Press
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    Publication Date: 2016-03-01
    Description: Tumors are characterized by properties of genetic instability, heterogeneity, and significant oligoclonality. Elucidating this intratumoral heterogeneity is challenging but important. In this study, we propose a framework, BubbleTree, to characterize the tumor clonality using next generation sequencing (NGS) data. BubbleTree simultaneously elucidates the complexity of a tumor biopsy, estimating cancerous cell purity, tumor ploidy, allele-specific copy number, and clonality and represents this in an intuitive graph. We further developed a three-step heuristic method to automate the interpretation of the BubbleTree graph, using a divide-and-conquer strategy. In this study, we demonstrated the performance of BubbleTree with comparisons to similar commonly used tools such as THetA2, ABSOLUTE, AbsCN-seq and ASCAT, using both simulated and patient-derived data. BubbleTree outperformed these tools, particularly in identifying tumor subclonal populations and polyploidy. We further demonstrated BubbleTree's utility in tracking clonality changes from patients’ primary to metastatic tumor and dating somatic single nucleotide and copy number variants along the tumor clonal evolution. Overall, the BubbleTree graph and corresponding model is a powerful approach to provide a comprehensive spectrum of the heterogeneous tumor karyotype in human tumors. BubbleTree is R-based and freely available to the research community ( https://www.bioconductor.org/packages/release/bioc/html/BubbleTree.html ).
    Keywords: Computational Methods, Genomics
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    Discovery and characterization of Alu repeat sequences via precise local read assembly (2015)
    Oxford University Press
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    Publication Date: 2015-12-02
    Description: Alu insertions have contributed to 〉11% of the human genome and ~30–35 Alu subfamilies remain actively mobile, yet the characterization of polymorphic Alu insertions from short-read data remains a challenge. We build on existing computational methods to combine Alu detection and de novo assembly of WGS data as a means to reconstruct the full sequence of insertion events from Illumina paired end reads. Comparison with published calls obtained using PacBio long-reads indicates a false discovery rate below 5%, at the cost of reduced sensitivity due to the colocation of reference and non-reference repeats. We generate a highly accurate call set of 1614 completely assembled Alu variants from 53 samples from the Human Genome Diversity Project (HGDP) panel. We utilize the reconstructed alternative insertion haplotypes to genotype 1010 fully assembled insertions, obtaining 〉99% agreement with genotypes obtained by PCR. In our assembled sequences, we find evidence of premature insertion mechanisms and observe 5' truncation in 16% of Alu Ya5 and Alu Yb8 insertions. The sites of truncation coincide with stem-loop structures and SRP9/14 binding sites in the Alu RNA, implicating L1 ORF2p pausing in the generation of 5' truncations. Additionally, we identified variable Alu J and Alu S elements that likely arose due to non-retrotransposition mechanisms.
    Keywords: Computational Methods, Genomics
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    A mostly traditional approach improves alignment of bisulfite-converted DNA (2012)
    Oxford University Press
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    Publication Date: 2012-07-22
    Description: Cytosines in genomic DNA are sometimes methylated. This affects many biological processes and diseases. The standard way of measuring methylation is to use bisulfite, which converts unmethylated cytosines to thymines, then sequence the DNA and compare it to a reference genome sequence. We describe a method for the critical step of aligning the DNA reads to the correct genomic locations. Our method builds on classic alignment techniques, including likelihood-ratio scores and spaced seeds. In a realistic benchmark, our method has a better combination of sensitivity, specificity and speed than nine other high-throughput bisulfite aligners. This study enables more accurate and rational analysis of DNA methylation. It also illustrates how to adapt general-purpose alignment methods to a special case with distorted base patterns: this should be informative for other special cases such as ancient DNA and AT-rich genomes.
    Keywords: Computational Methods, Genomics
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    PhiSpy: a novel algorithm for finding prophages in bacterial genomes that combines similarity- and composition-based strategies (2012)
    Oxford University Press
    Details
    Publication Date: 2012-09-13
    Description: Prophages are phages in lysogeny that are integrated into, and replicated as part of, the host bacterial genome. These mobile elements can have tremendous impact on their bacterial hosts’ genomes and phenotypes, which may lead to strain emergence and diversification, increased virulence or antibiotic resistance. However, finding prophages in microbial genomes remains a problem with no definitive solution. The majority of existing tools rely on detecting genomic regions enriched in protein-coding genes with known phage homologs, which hinders the de novo discovery of phage regions. In this study, a weighted phage detection algorithm, PhiSpy was developed based on seven distinctive characteristics of prophages, i.e. protein length, transcription strand directionality, customized AT and GC skew, the abundance of unique phage words, phage insertion points and the similarity of phage proteins. The first five characteristics are capable of identifying prophages without any sequence similarity with known phage genes. PhiSpy locates prophages by ranking genomic regions enriched in distinctive phage traits, which leads to the successful prediction of 94% of prophages in 50 complete bacterial genomes with a 6% false-negative rate and a 0.66% false-positive rate.
    Keywords: Computational Methods, Genomics
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    Exploiting mid-range DNA patterns for sequence classification: binary abstraction Markov models (2012)
    Oxford University Press
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    Publication Date: 2012-06-06
    Description: Messenger RNA sequences possess specific nucleotide patterns distinguishing them from non-coding genomic sequences. In this study, we explore the utilization of modified Markov models to analyze sequences up to 44 bp, far beyond the 8-bp limit of conventional Markov models, for exon/intron discrimination. In order to analyze nucleotide sequences of this length, their information content is first reduced by conversion into shorter binary patterns via the application of numerous abstraction schemes. After the conversion of genomic sequences to binary strings, homogenous Markov models trained on the binary sequences are used to discriminate between exons and introns. We term this approach the Binary Abstraction Markov Model (BAMM). High-quality abstraction schemes for exon/intron discrimination are selected using optimization algorithms on supercomputers. The best MM classifiers are then combined using support vector machines into a single classifier. With this approach, over 95% classification accuracy is achieved without taking reading frame into account. With further development, the BAMM approach can be applied to sequences lacking the genetic code such as ncRNAs and 5'-untranslated regions.
    Keywords: Computational Methods, Genomics
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    New methods for finding common insertion sites and co-occurring common insertion sites in transposon- and virus-based genetic screens (2012)
    Oxford University Press
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    Publication Date: 2012-05-13
    Description: Insertional mutagenesis screens in mice are used to identify individual genes that drive tumor formation. In these screens, candidate cancer genes are identified if their genomic location is proximal to a common insertion site (CIS) defined by high rates of transposon or retroviral insertions in a given genomic window. In this article, we describe a new method for defining CISs based on a Poisson distribution, the Poisson Regression Insertion Model, and show that this new method is an improvement over previously described methods. We also describe a modification of the method that can identify pairs and higher orders of co-occurring common insertion sites. We apply these methods to two data sets, one generated in a transposon-based screen for gastrointestinal tract cancer genes and another based on the set of retroviral insertions in the Retroviral Tagged Cancer Gene Database. We show that the new methods identify more relevant candidate genes and candidate gene pairs than found using previous methods. Identification of the biologically relevant set of mutations that occur in a single cell and cause tumor progression will aid in the rational design of single and combinatorial therapies in the upcoming age of personalized cancer therapy.
    Keywords: Computational Methods, Genomics
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    Isoform-level gene signature improves prognostic stratification and accurately classifies glioblastoma subtypes (2014)
    Oxford University Press
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    Publication Date: 2014-05-01
    Description: Molecular stratification of tumors is essential for developing personalized therapies. Although patient stratification strategies have been successful; computational methods to accurately translate the gene-signature from high-throughput platform to a clinically adaptable low-dimensional platform are currently lacking. Here, we describe PIGExClass (platform-independent isoform-level gene-expression based classification-system), a novel computational approach to derive and then transfer gene-signatures from one analytical platform to another. We applied PIGExClass to design a reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) based molecular-subtyping assay for glioblastoma multiforme (GBM), the most aggressive primary brain tumors. Unsupervised clustering of TCGA (the Cancer Genome Altas Consortium) GBM samples, based on isoform-level gene-expression profiles, recaptured the four known molecular subgroups but switched the subtype for 19% of the samples, resulting in significant ( P = 0.0103) survival differences among the refined subgroups. PIGExClass derived four-class classifier, which requires only 121 transcript-variants, assigns GBM patients’ molecular subtype with 92% accuracy. This classifier was translated to an RT-qPCR assay and validated in an independent cohort of 206 GBM samples. Our results demonstrate the efficacy of PIGExClass in the design of clinically adaptable molecular subtyping assay and have implications for developing robust diagnostic assays for cancer patient stratification.
    Keywords: Computational Methods, Genomics
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    fourSig: a method for determining chromosomal interactions in 4C-Seq data (2014)
    Oxford University Press
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    Publication Date: 2014-05-01
    Description: The ability to correlate chromosome conformation and gene expression gives a great deal of information regarding the strategies used by a cell to properly regulate gene activity. 4C-Seq is a relatively new and increasingly popular technology where the set of genomic interactions generated by a single point in the genome can be determined. 4C-Seq experiments generate large, complicated data sets and it is imperative that signal is properly distinguished from noise. Currently, there are a limited number of methods for analyzing 4C-Seq data. Here, we present a new method, fourSig , which in addition to being precise and simple to use also includes a new feature that prioritizes detected interactions. Our results demonstrate the efficacy of fourSig with previously published and novel 4C-Seq data sets and show that our significance prioritization correlates with the ability to reproducibly detect interactions among replicates.
    Keywords: Computational Methods, Genomics
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    High-resolution functional annotation of human transcriptome: predicting isoform functions by a novel multiple instance-based label propagation method (2014)
    Oxford University Press
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    Publication Date: 2014-04-03
    Description: Alternative transcript processing is an important mechanism for generating functional diversity in genes. However, little is known about the precise functions of individual isoforms. In fact, proteins (translated from transcript isoforms), not genes, are the function carriers. By integrating multiple human RNA-seq data sets, we carried out the first systematic prediction of isoform functions, enabling high-resolution functional annotation of human transcriptome. Unlike gene function prediction, isoform function prediction faces a unique challenge: the lack of the training data—all known functional annotations are at the gene level. To address this challenge, we modelled the gene–isoform relationships as multiple instance data and developed a novel label propagation method to predict functions. Our method achieved an average area under the receiver operating characteristic curve of 0.67 and assigned functions to 15 572 isoforms. Interestingly, we observed that different functions have different sensitivities to alternative isoform processing, and that the function diversity of isoforms from the same gene is positively correlated with their tissue expression diversity. Finally, we surveyed the literature to validate our predictions for a number of apoptotic genes. Strikingly, for the famous ‘TP53’ gene, we not only accurately identified the apoptosis regulation function of its five isoforms, but also correctly predicted the precise direction of the regulation.
    Keywords: Computational Methods, Genomics
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    Efficient large-scale protein sequence comparison and gene matching to identify orthologs and co-orthologs (2012)
    Oxford University Press
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    Publication Date: 2012-03-29
    Description: Broadly, computational approaches for ortholog assignment is a three steps process: (i) identify all putative homologs between the genomes, (ii) identify gene anchors and (iii) link anchors to identify best gene matches given their order and context. In this article, we engineer two methods to improve two important aspects of this pipeline [specifically steps (ii) and (iii)]. First, computing sequence similarity data [step (i)] is a computationally intensive task for large sequence sets, creating a bottleneck in the ortholog assignment pipeline. We have designed a fast and highly scalable sort-join method (afree) based on k -mer counts to rapidly compare all pairs of sequences in a large protein sequence set to identify putative homologs. Second, availability of complex genomes containing large gene families with prevalence of complex evolutionary events, such as duplications, has made the task of assigning orthologs and co-orthologs difficult. Here, we have developed an iterative graph matching strategy where at each iteration the best gene assignments are identified resulting in a set of orthologs and co-orthologs. We find that the afree algorithm is faster than existing methods and maintains high accuracy in identifying similar genes. The iterative graph matching strategy also showed high accuracy in identifying complex gene relationships. Standalone afree available from http://vbc.med.monash.edu.au/~kmahmood/afree . EGM2, complete ortholog assignment pipeline (including afree and the iterative graph matching method) available from http://vbc.med.monash.edu.au/~kmahmood/EGM2 .
    Keywords: Computational Methods, Genomics
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    The allele distribution in next-generation sequencing data sets is accurately described as the result of a stochastic branching process (2012)
    Oxford University Press
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    Publication Date: 2012-03-29
    Description: With the availability of next-generation sequencing (NGS) technology, it is expected that sequence variants may be called on a genomic scale. Here, we demonstrate that a deeper understanding of the distribution of the variant call frequencies at heterozygous loci in NGS data sets is a prerequisite for sensitive variant detection. We model the crucial steps in an NGS protocol as a stochastic branching process and derive a mathematical framework for the expected distribution of alleles at heterozygous loci before measurement that is sequencing. We confirm our theoretical results by analyzing technical replicates of human exome data and demonstrate that the variance of allele frequencies at heterozygous loci is higher than expected by a simple binomial distribution. Due to this high variance, mutation callers relying on binomial distributed priors are less sensitive for heterozygous variants that deviate strongly from the expected mean frequency. Our results also indicate that error rates can be reduced to a greater degree by technical replicates than by increasing sequencing depth.
    Keywords: Computational Methods, Genomics
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    Unsupervised discovery of microbial population structure within metagenomes using nucleotide base composition (2012)
    Oxford University Press
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    Publication Date: 2012-03-14
    Description: An approach to infer the unknown microbial population structure within a metagenome is to cluster nucleotide sequences based on common patterns in base composition, otherwise referred to as binning. When functional roles are assigned to the identified populations, a deeper understanding of microbial communities can be attained, more so than gene-centric approaches that explore overall functionality. In this study, we propose an unsupervised, model-based binning method with two clustering tiers, which uses a novel transformation of the oligonucleotide frequency-derived error gradient and GC content to generate coarse groups at the first tier of clustering; and tetranucleotide frequency to refine these groups at the secondary clustering tier. The proposed method has a demonstrated improvement over PhyloPythia, S-GSOM, TACOA and TaxSOM on all three benchmarks that were used for evaluation in this study. The proposed method is then applied to a pyrosequenced metagenomic library of mud volcano sediment sampled in southwestern Taiwan, with the inferred population structure validated against complementary sequencing of 16S ribosomal RNA marker genes. Finally, the proposed method was further validated against four publicly available metagenomes, including a highly complex Antarctic whale-fall bone sample, which was previously assumed to be too complex for binning prior to functional analysis.
    Keywords: Computational Methods, Genomics
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    NTRFinder: a software tool to find nested tandem repeats (2012)
    Oxford University Press
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    Publication Date: 2012-02-17
    Description: We introduce the software tool NTRFinder to search for a complex repetitive structure in DNA we call a nested tandem repeat (NTR). An NTR is a recurrence of two or more distinct tandem motifs interspersed with each other. We propose that NTRs can be used as phylogenetic and population markers. We have tested our algorithm on both real and simulated data, and present some real NTRs of interest. NTRFinder can be downloaded from http://www.maths.otago.ac.nz/~aamatroud/ .
    Keywords: Computational Methods, Genomics
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    sPARTA: a parallelized pipeline for integrated analysis of plant miRNA and cleaved mRNA data sets, including new miRNA target-identification software (2014)
    Oxford University Press
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    Publication Date: 2014-10-10
    Description: Parallel analysis of RNA ends (PARE) is a technique utilizing high-throughput sequencing to profile uncapped, mRNA cleavage or decay products on a genome-wide basis. Tools currently available to validate miRNA targets using PARE data employ only annotated genes, whereas important targets may be found in unannotated genomic regions. To handle such cases and to scale to the growing availability of PARE data and genomes, we developed a new tool, ‘ sPARTA ’ (small RNA-PARE target analyzer) that utilizes a built-in, plant-focused target prediction module (aka ‘ miRferno ’). sPARTA not only exhibits an unprecedented gain in speed but also it shows greater predictive power by validating more targets, compared to a popular alternative. In addition, the novel ‘seed-free’ mode, optimized to find targets irrespective of complementarity in the seed-region, identifies novel intergenic targets. To fully capitalize on the novelty and strengths of sPARTA , we developed a web resource, ‘ comPARE ’, for plant miRNA target analysis; this facilitates the systematic identification and analysis of miRNA-target interactions across multiple species, integrated with visualization tools. This collation of high-throughput small RNA and PARE datasets from different genomes further facilitates re-evaluation of existing miRNA annotations, resulting in a ‘cleaner’ set of microRNAs.
    Keywords: Computational Methods, Genomics
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    A statistical model of ChIA-PET data for accurate detection of chromatin 3D interactions (2014)
    Oxford University Press
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    Publication Date: 2014-10-10
    Description: Identification of three-dimensional (3D) interactions between regulatory elements across the genome is crucial to unravel the complex regulatory machinery that orchestrates proliferation and differentiation of cells. ChIA-PET is a novel method to identify such interactions, where physical contacts between regions bound by a specific protein are quantified using next-generation sequencing. However, determining the significance of the observed interaction frequencies in such datasets is challenging, and few methods have been proposed. Despite the fact that regions that are close in linear genomic distance have a much higher tendency to interact by chance, no methods to date are capable of taking such dependency into account. Here, we propose a statistical model taking into account the genomic distance relationship, as well as the general propensity of anchors to be involved in contacts overall. Using both real and simulated data, we show that the previously proposed statistical test, based on Fisher's exact test, leads to invalid results when data are dependent on genomic distance. We also evaluate our method on previously validated cell-line specific and constitutive 3D interactions, and show that relevant interactions are significant, while avoiding over-estimating the significance of short nearby interactions.
    Keywords: Computational Methods, Genomics
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    COMET: adaptive context-based modeling for ultrafast HIV-1 subtype identification (2014)
    Oxford University Press
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    Publication Date: 2014-10-10
    Description: Viral sequence classification has wide applications in clinical, epidemiological, structural and functional categorization studies. Most existing approaches rely on an initial alignment step followed by classification based on phylogenetic or statistical algorithms. Here we present an ultrafast alignment-free subtyping tool for human immunodeficiency virus type one (HIV-1) adapted from Prediction by Partial Matching compression. This tool, named COMET, was compared to the widely used phylogeny-based REGA and SCUEAL tools using synthetic and clinical HIV data sets (1 090 698 and 10 625 sequences, respectively). COMET's sensitivity and specificity were comparable to or higher than the two other subtyping tools on both data sets for known subtypes. COMET also excelled in detecting and identifying new recombinant forms, a frequent feature of the HIV epidemic. Runtime comparisons showed that COMET was almost as fast as USEARCH. This study demonstrates the advantages of alignment-free classification of viral sequences, which feature high rates of variation, recombination and insertions/deletions. COMET is free to use via an online interface.
    Keywords: Computational Methods, Genomics
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    Large-scale modeling of condition-specific gene regulatory networks by information integration and inference (2014)
    Oxford University Press
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    Publication Date: 2014-11-28
    Description: Understanding how regulatory networks globally coordinate the response of a cell to changing conditions, such as perturbations by shifting environments, is an elementary challenge in systems biology which has yet to be met. Genome-wide gene expression measurements are high dimensional as these are reflecting the condition-specific interplay of thousands of cellular components. The integration of prior biological knowledge into the modeling process of systems-wide gene regulation enables the large-scale interpretation of gene expression signals in the context of known regulatory relations. We developed COGERE ( http://mips.helmholtz-muenchen.de/cogere ), a method for the inference of condition-specific gene regulatory networks in human and mouse. We integrated existing knowledge of regulatory interactions from multiple sources to a comprehensive model of prior information. COGERE infers condition-specific regulation by evaluating the mutual dependency between regulator (transcription factor or miRNA) and target gene expression using prior information. This dependency is scored by the non-parametric, nonlinear correlation coefficient 2 (eta squared) that is derived by a two-way analysis of variance. We show that COGERE significantly outperforms alternative methods in predicting condition-specific gene regulatory networks on simulated data sets. Furthermore, by inferring the cancer-specific gene regulatory network from the NCI-60 expression study, we demonstrate the utility of COGERE to promote hypothesis-driven clinical research.
    Keywords: Computational Methods, Genomics
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    ptRNApred: computational identification and classification of post-transcriptional RNA (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Non-coding RNAs (ncRNAs) are known to play important functional roles in the cell. However, their identification and recognition in genomic sequences remains challenging. In silico methods, such as classification tools, offer a fast and reliable way for such screening and multiple classifiers have already been developed to predict well-defined subfamilies of RNA. So far, however, out of all the ncRNAs, only tRNA, miRNA and snoRNA can be predicted with a satisfying sensitivity and specificity. We here present ptRNApred , a tool to detect and classify subclasses of non-coding RNA that are involved in the regulation of post-transcriptional modifications or DNA replication, which we here call post-transcriptional RNA (ptRNA). It (i) detects RNA sequences coding for post-transcriptional RNA from the genomic sequence with an overall sensitivity of 91% and a specificity of 94% and (ii) predicts ptRNA-subclasses that exist in eukaryotes: snRNA, snoRNA, RNase P, RNase MRP, Y RNA or telomerase RNA. AVAILABILITY: The ptRNApred software is open for public use on http://www.ptrnapred.org/ .
    Keywords: Computational Methods, Genomics
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    The eSNV-detect: a computational system to identify expressed single nucleotide variants from transcriptome sequencing data (2014)
    Oxford University Press
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    Publication Date: 2014-12-17
    Description: Rapid development of next generation sequencing technology has enabled the identification of genomic alterations from short sequencing reads. There are a number of software pipelines available for calling single nucleotide variants from genomic DNA but, no comprehensive pipelines to identify, annotate and prioritize expressed SNVs (eSNVs) from non-directional paired-end RNA-Seq data. We have developed the eSNV-Detect, a novel computational system, which utilizes data from multiple aligners to call, even at low read depths, and rank variants from RNA-Seq. Multi-platform comparisons with the eSNV-Detect variant candidates were performed. The method was first applied to RNA-Seq from a lymphoblastoid cell-line, achieving 99.7% precision and 91.0% sensitivity in the expressed SNPs for the matching HumanOmni2.5 BeadChip data. Comparison of RNA-Seq eSNV candidates from 25 ER+ breast tumors from The Cancer Genome Atlas (TCGA) project with whole exome coding data showed 90.6–96.8% precision and 91.6–95.7% sensitivity. Contrasting single-cell mRNA-Seq variants with matching traditional multicellular RNA-Seq data for the MD-MB231 breast cancer cell-line delineated variant heterogeneity among the single-cells. Further, Sanger sequencing validation was performed for an ER+ breast tumor with paired normal adjacent tissue validating 29 out of 31 candidate eSNVs. The source code and user manuals of the eSNV-Detect pipeline for Sun Grid Engine and virtual machine are available at http://bioinformaticstools.mayo.edu/research/esnv-detect/ .
    Keywords: Computational Methods, Genomics
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    Conditional mutual inclusive information enables accurate quantification of associations in gene regulatory networks (2015)
    Oxford University Press
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    Publication Date: 2015-03-14
    Description: Mutual information (MI), a quantity describing the nonlinear dependence between two random variables, has been widely used to construct gene regulatory networks (GRNs). Despite its good performance, MI cannot separate the direct regulations from indirect ones among genes. Although the conditional mutual information (CMI) is able to identify the direct regulations, it generally underestimates the regulation strength, i.e. it may result in false negatives when inferring gene regulations. In this work, to overcome the problems, we propose a novel concept, namely conditional mutual inclusive information (CMI2), to describe the regulations between genes. Furthermore, with CMI2, we develop a new approach, namely CMI2NI (CMI2-based network inference), for reverse-engineering GRNs. In CMI2NI, CMI2 is used to quantify the mutual information between two genes given a third one through calculating the Kullback–Leibler divergence between the postulated distributions of including and excluding the edge between the two genes. The benchmark results on the GRNs from DREAM challenge as well as the SOS DNA repair network in Escherichia coli demonstrate the superior performance of CMI2NI. Specifically, even for gene expression data with small sample size, CMI2NI can not only infer the correct topology of the regulation networks but also accurately quantify the regulation strength between genes. As a case study, CMI2NI was also used to reconstruct cancer-specific GRNs using gene expression data from The Cancer Genome Atlas (TCGA). CMI2NI is freely accessible at http://www.comp-sysbio.org/cmi2ni .
    Keywords: Computational Methods, Genomics
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    CODEX: a normalization and copy number variation detection method for whole exome sequencing (2015)
    Oxford University Press
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    Publication Date: 2015-04-02
    Description: High-throughput sequencing of DNA coding regions has become a common way of assaying genomic variation in the study of human diseases. Copy number variation (CNV) is an important type of genomic variation, but detecting and characterizing CNV from exome sequencing is challenging due to the high level of biases and artifacts. We propose CODEX, a normalization and CNV calling procedure for whole exome sequencing data. The Poisson latent factor model in CODEX includes terms that specifically remove biases due to GC content, exon capture and amplification efficiency, and latent systemic artifacts. CODEX also includes a Poisson likelihood-based recursive segmentation procedure that explicitly models the count-based exome sequencing data. CODEX is compared to existing methods on a population analysis of HapMap samples from the 1000 Genomes Project, and shown to be more accurate on three microarray-based validation data sets. We further evaluate performance on 222 neuroblastoma samples with matched normals and focus on a well-studied rare somatic CNV within the ATRX gene. We show that the cross-sample normalization procedure of CODEX removes more noise than normalizing the tumor against the matched normal and that the segmentation procedure performs well in detecting CNVs with nested structures.
    Keywords: Computational Methods, Genomics
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    Hunting complex differential gene interaction patterns across molecular contexts (2014)
    Oxford University Press
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    Publication Date: 2014-04-15
    Description: Heterogeneity in genetic networks across different signaling molecular contexts can suggest molecular regulatory mechanisms. Here we describe a comparative chi-square analysis (CP 2 ) method, considerably more flexible and effective than other alternatives, to screen large gene expression data sets for conserved and differential interactions. CP 2 decomposes interactions across conditions to assess homogeneity and heterogeneity. Theoretically, we prove an asymptotic chi-square null distribution for the interaction heterogeneity statistic. Empirically, on synthetic yeast cell cycle data, CP 2 achieved much higher statistical power in detecting differential networks than alternative approaches. We applied CP 2 to Drosophila melanogaster wing gene expression arrays collected under normal conditions, and conditions with overexpressed E2F and Cabut, two transcription factor complexes that promote ectopic cell cycling. The resulting differential networks suggest a mechanism by which E2F and Cabut regulate distinct gene interactions, while still sharing a small core network. Thus, CP 2 is sensitive in detecting network rewiring, useful in comparing related biological systems.
    Keywords: Computational Methods, Genomics
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    DNA motif elucidation using belief propagation (2013)
    Oxford University Press
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    Publication Date: 2013-09-06
    Description: Protein-binding microarray (PBM) is a high-throughout platform that can measure the DNA-binding preference of a protein in a comprehensive and unbiased manner. A typical PBM experiment can measure binding signal intensities of a protein to all the possible DNA k-mers (k = 8 ~10); such comprehensive binding affinity data usually need to be reduced and represented as motif models before they can be further analyzed and applied. Since proteins can often bind to DNA in multiple modes, one of the major challenges is to decompose the comprehensive affinity data into multimodal motif representations. Here, we describe a new algorithm that uses Hidden Markov Models (HMMs) and can derive precise and multimodal motifs using belief propagations. We describe an HMM-based approach using belief propagations (kmerHMM), which accepts and preprocesses PBM probe raw data into median-binding intensities of individual k-mers. The k-mers are ranked and aligned for training an HMM as the underlying motif representation. Multiple motifs are then extracted from the HMM using belief propagations. Comparisons of kmerHMM with other leading methods on several data sets demonstrated its effectiveness and uniqueness. Especially, it achieved the best performance on more than half of the data sets. In addition, the multiple binding modes derived by kmerHMM are biologically meaningful and will be useful in interpreting other genome-wide data such as those generated from ChIP-seq. The executables and source codes are available at the authors’ websites: e.g. http://www.cs.toronto.edu/~wkc/kmerHMM .
    Keywords: Computational Methods, Genomics
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