Leveraging biochemical reactions to unravel functional impacts of cancer somatic variants affecting protein interaction interfaces [version 3; peer review: 2 approved]

Background: Considering protein mutations in their biological context is essential for understanding their functional impact, interpretation of high-dimensional datasets and development of effective targeted therapies in personalized medicine. Methods: We combined the curated knowledge of biochemical reactions from Reactome with the analysis of interaction-mediating 3D interfaces from Mechismo. In addition, we provided a software tool for users to explore and browse the analysis results in a multi-scale perspective starting from pathways and reactions to protein-protein interactions and protein 3D structures. Results: We analyzed somatic mutations from TCGA, revealing several significantly impacted reactions and pathways in specific cancer types. We found examples of genes not yet listed as oncodrivers, whose rare mutations were predicted to affect cancer processes similarly to known oncodrivers. Some identified processes lack any known oncodrivers, which suggests potentially new cancer-related processes (e.g. complement cascade reactions). Furthermore, we found that mutations perturbing certain processes are significantly associated with distinct phenotypes (i.e. survival time) in specific cancer types (e.g. PIK3CA centered pathways in LGG and UCEC cancer types), suggesting the translational potential of our approach for patient stratification. Our analysis also uncovered several druggable processes (e.g. GPCR signalling pathways) containing enriched reactions, providing support for new off-label therapeutic options. Conclusions: In summary, we have established a multi-scale approach to study genetic variants based on protein-protein interaction 3D structures. Our approach is different from previously published studies in its focus on biochemical reactions and can be applied to other data types (e.g. post-translational modifications) collected for many types of disease

A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection

The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

A crowdsourced analysis to identify ab initio molecular signatures predictive of susceptibility to viral infection

The response to respiratory viruses varies substantially between individuals, and there are currently no known molecular predictors from the early stages of infection. Here we conduct a community-based analysis to determine whether pre- or early post-exposure molecular factors could predict physiologic responses to viral exposure. Using peripheral blood gene expression profiles collected from healthy subjects prior to exposure to one of four respiratory viruses (H1N1, H3N2, Rhinovirus, and RSV), as well as up to 24 h following exposure, we find that it is possible to construct models predictive of symptomatic response using profiles even prior to viral exposure. Analysis of predictive gene features reveal little overlap among models; however, in aggregate, these genes are enriched for common pathways. Heme metabolism, the most significantly enriched pathway, is associated with a higher risk of developing symptoms following viral exposure. This study demonstrates that pre-exposure molecular predictors can be identified and improves our understanding of the mechanisms of response to respiratory viruses

Sequential Requisites Analysis: A New Method for Analyzing Sequential Relationships in Ordinal Data

This paper presents a new method inspired by evolutionary biology for analyzing longer sequences of requisites for the emergence of particular outcome variables across numerous combinations of ordinal variables in social science analysis. The approach involves repeated pairwise investigations of states in a set of variables and identifying what states in the variables that occur before states in all other variables. We illustrate the proposed method by analyzing a set of variables from version 6 of the V-Dem dataset (Coppedge et al. 2015a, b). With a large set of indicators measured over many years, the method makes it possible to explore long, complex sequences across many variables in quantitative datasets. This affords an opportunity, for example, to disentangle the sequential requisites of failing and successful sequences in democratization. For policy purposes this is instrumental: Which components of democracy are most exogenous and least endogenous and therefore the ideal targets for democracy promotion at different stages?This research project was supported by Riksbankens Jubileumsfond, Grant M13-0559:1, PI: Staffan I. Lindberg, V-Dem Institute, University of Gothenburg, Sweden; by Swedish Research Council, Grant C0556201, PIs: Staffan I. Lindberg, V-Dem Institute, University of Gothenburg, Sweden and Jan Teorell, Department of Political Science, Lund University, Sweden; by Knut and Alice Wallenberg Foundation to Wallenberg Academy Fellow Staffan I. Lindberg, Grant 2013.0166, V-Dem Institute, University of Gothenburg, Sweden; as well as by internal grants from the Vice-Chancellor’s office, the Dean of the College of Social Sciences, and the Department of Political Science at University of Gothenburg. We performed simulations and other computational tasks using resources provided by the Notre Dame Center for Research Computing (CRC) through the High Performance Computing section and the Swedish National Infrastructure for Computing (SNIC) at the National Supercomputer Centre in Sweden. We specifically acknowledge the assistance of In-Saeng Suh at CRC and Johan Raber at SNIC in facilitating our use of their respective systems