Strategies For Improving Epistasis Detection And Replication

Genome-wide association studies (GWAS) have been extensively critiqued for their perceived inability to adequately elucidate the genetic underpinnings of complex disease. Of particular concern is “missing heritability,” or the difference between the total estimated heritability of a phenotype and that explained by GWAS-identified loci. There are numerous proposed explanations for this missing heritability, but a frequently ignored and potentially vastly informative alternative explanation is the ubiquity of epistasis underlying complex phenotypes. Given our understanding of how biomolecules interact in networks and pathways, it is not unreasonable to conclude that the effect of variation at individual genetic loci may non-additively depend on and should be analyzed in the context of their interacting partners. It has been recognized for over a century that deviation from expected Mendelian proportions can be explained by the interaction of multiple loci, and the epistatic underpinnings of phenotypes in model organisms have been extensively experimentally quantified. Therefore, the dearth of inspiring single locus GWAS hits for complex human phenotypes (and the inconsistent replication of these between populations) should not be surprising, as one might expect the joint effect of multiple perturbations to interacting partners within a functional biological module to be more important than individual main effects. Current methods for analyzing data from GWAS are not well-equipped to detect epistasis or replicate significant interactions. The multiple testing burden associated with testing each pairwise interaction quickly becomes nearly insurmountable with increasing numbers of loci. Statistical and machine learning approaches that have worked well for other types of high-dimensional data are appealing and may be useful for detecting epistasis, but potentially require tweaks to function appropriately. Biological knowledge may also be leveraged to guide the search for epistasis candidates, but requires context-appropriate application (as, for example, two loci with significant main effects may not have a significant interaction, and vice versa). Rather than renouncing GWAS and the wealth of associated data that has been accumulated as a failure, I propose the development of new techniques and incorporation of diverse data sources to analyze GWAS data in an epistasis-centric framework

Trends in Pharmaceutical and Food Sciences I

Podeu consultar el llibre complet a: https://medwinpublishers.com/OAJPR/OAJPR16000eB001.pdfTrends in Pharmaceutical and Food Sciences I is the first issue of an open access E-book devoted to scientific and technical research that covers the entire spectrum of drug and food research, including medicinal chemistry, pharmacology, drug delivery, microbiology and biochemical studies, as well as relevant developments in nutrition, food safety and analytical innovation. The first chapter, Different techniques to detect G protein coupled receptor heteromers, describes state of the art techniques based in biophysical principles applied to detect oligomeric aggregates formed by G-protein coupled receptors in the cell membrane, and describes how the knowledge generated can be applied to design new compounds for the treatment of neurological and mental diseases. Obesity has become a worldwide problem and it is well known that causes and exacerbates many health problems by promoting profound changes in physiological functions. Chapter 2, Analysis of the role of diet in the appearance of neurodegenerative processes, reviews the consequences of these metabolic alterations while considering their effects in the development of Type 2 Diabetes Mellitus, and their role in the appearance of cognitive impairments such as the sporadic forms of Alzheimer’s disease. The development of new cultivars facing climate change is an issue of great interest for the agrochemical industry and can be approached in different ways. Chapter 3, Arabidopsis Thaliana A Model for the Study of Plant Speciation, reviews different aspects of the plant immune system and the different layers of the plant immune response and signaling. The emerging field in plant research that studies how soil microbiota influences plant basic mechanisms is also discussed. Chagas disease is endemic in Latin America, but recently and due to human migrations, it is becoming a global health problem. In chapter 4, Trypanosoma cruzi infection diagnosis: New insights, challenges and perspectives, a group of experts from several institutions describe the different techniques that can be used for the serological diagnosis of the infection and the characterization of Trypanosoma cruzi, discuss the advantages and drawbacks of each method and propose improvements that would entail important savings for health institutions. Chapter 5, Nutrients, Control of Gene Expression and Metabolic Homeostasis, focuses on the molecular mechanisms that control metabolism by means of regulating gene expression in response to dietary inputs, to design new therapeutic strategies based on nutritional interventions against metabolic diseases. In this context, involvement of FGF21 hormone in the regulation of lipid metabolism during amino acid starvation is described, thus reinforcing its important role as an endocrine factor in coordinating energy homeostasis under a variety of nutritional conditions. This raises the possibility of dietary modulation of circulating levels of FGF21 as an alternative approach to its pharmacological administration. Biodegradable polymeric nanoparticles encapsulating neuroprotective drugs have enormous potential to treat neurodegenerative diseases, including Alzheimer´s disease and glaucoma. Recent advances in the field are described in chapter 6, Polymeric nanoparticles for the treatment of neurodegenerative diseases: Alzheimer’s disease and glaucoma, specifically the preparation of engineered polymeric nanoparticles with attached peptides or antibodies to increase their bioavailability, favoring their transport through the blood brain barrier and the blood retinal barrier, avoiding at the same time possible drug adverse and toxic effects. The last chapter, Pentacyclic triterpenes in table olives: Determination of their composition and bioavailability by LC-M, is a review on the pentacyclic triterpenes contained in table olives, natural compounds of enormous interest due to their beneficial effects on human health, including hepatoprotective, anti-diabetic, antiviral, cardioprotective and antitumor activities. Authors describe a selective and sensitive LC–MS method for the simultaneous determination of the main triterpenic compounds present in Olea europaea L. This opens the possibility to bioavailability studies after consumption of different foods, or administration of plants widely used in traditional medicine, with the aim of studying in depth the beneficial effects of these compounds in human beings. We hope that this new volume will attract the interest of all the scientific community, especially those working in the fields of pharmaceutical, medical, biological, chemical and food sciences

Cloud-based genomics pipelines for ophthalmology: Reviewed from research to clinical practice

Aim: To familiarize clinicians with clinical genomics, and to describe the potential of cloud computing for enabling the future routine use of genomics in eye hospital settings. Design: Review article exploring the potential for cloud-based genomic pipelines in eye hospitals. Methods: Narrative review of the literature relevant to clinical genomics and cloud computing, using PubMed and Google Scholar. A broad overview of these fields is provided, followed by key examples of their integration. Results: Cloud computing could benefit clinical genomics due to scalability of resources, potentially lower costs, and ease of data sharing between multiple institutions. Challenges include complex pricing of services, costs from mistakes or experimentation, data security, and privacy concerns. Conclusions and future perspectives: Clinical genomics is likely to become more routinely used in clinical practice. Currently this is delivered in highly specialist centers. In the future, cloud computing could enable delivery of clinical genomics services in non-specialist hospital settings, in a fast, cost-effective way, whilst enhancing collaboration between clinical and research teams

Defining the clinical and molecular spectrum of inherited eye diseases in community settings

Inherited eye diseases are an important contributor to the burden of childhood blindness globally. These conditions are often associated with significant phenotypic and genetic heterogeneity and are extremely difficult to study in a general population setting. This thesis details the study of inherited eye diseases in genetically isolated populations including the North American Amish and rural Pakistani and Palestinian communities. Here, an enrichment of disease-causing founder mutations arising from common ancestry, characteristic marriage patterns and geographical isolation, combined with the often large family sizes typical of families in these regions, enables powerful genomic studies to identify pathogenic sequence variants. As well as providing an important opportunity to learn about the genetic causes of inherited eye diseases, these studies also provide desperately required healthcare benefits for the families and populations involved. Chapter 3 describes studies of oculocutaneous albinism (OCA) in 40 Amish and Pakistani families. Results from comprehensive clinical, genomic and functional studies, initiated by a search for the cause of OCA in a number of Amish families, provide strong evidence for the pathogenicity of two common TYR gene variants [p.(Ser192Tyr) and p.(Arg402Gln)] when inherited in cis. These variants were previously considered gene polymorphisms although this has been heavily debated in many studies, and these variants are currently variably reported and even potentially excluded by clinical testing laboratories. The findings reported in this thesis have important diagnostic implications by helping clarify the contribution of these variants to the OCA phenotype, and by promoting the reporting the TYR p.(Ser192Tyr)/p.(Arg402Gln) in cis haplotype as a pathogenic allele. This will likely increase the molecular diagnoses in albinism patients with missing heritability by 25-50%. This chapter also entails a comprehensive investigation involving genetic studies alongside an exhaustive literature review of all published OCA genetic causes in Pakistani families, including cross-referencing with established genomic databases to evidence the likely causality of each gene variant. Chapter 4 entails clinical and genomic findings in four families with phenotypic features highly suggestive of a ciliopathy disorder. Findings include identification of novel SCAPER and BBS5 variants, enabling a more precise definition of the SCAPER clinical phenotype. This work also consolidates an INPP5E c.1879C>T; p.(Gln627*) variant, a likely pathogenic founder alteration present in Northern Pakistan, as a cause of MORM syndrome. Chapter 5 documents studies of families with rare and ultra-rare inherited ocular diseases in Pakistani and Palestinian communities. This includes consolidating SDHD dysfunction as a cause of mitochondrial disease through investigations of an extended Palestinian family, facilitating a clearer delineation of the variable ocular (and non-ocular) phenotypical features. Alongside this, the identification of novel and known variants in ALDH1A3, FYCO1, TDRD7, CYP1B1, ATOH7, LRP5, FRMD7 and HPS1 in Pakistani communities contributes to an improved knowledge of the genetic spectrum and frequencies of various forms of inherited eye diseases regionally. The comprehensive OCA and BBS datasets provide notably improved knowledge, as well as a centralised repository, of the genetic spectrum and regional frequencies of the molecular causes of these conditions in the Amish and in Pakistan. Ultimately, these findings will greatly facilitate the establishment of robust cost-effective accurate diagnostic genetic testing, clinical management and counselling efforts. Together the work of this thesis describes data of scientific importance, and highlights the immense value of translational community research studies to deliver clinical benefits locally and globally in the field of inherited eye diseases

Preclinical Animal Modeling in Medicine

The results of preclinical animal research have been successfully implemented in various medical and biological practices. The use of animals in medicine is based on significant anatomical, physiological, and molecular similarities between humans and animals. Particularly, mammals that have vast biological commonalities with humans represent not only a valuable model to explore the mechanisms of varied human diseases, but also to define new diagnostic and treatment strategies. This book covers broad but important aspects of animal modeling for scientific medicine as well as for translational systems and biological sciences. Alternative methods such as cell culture and in vitro experiments that do not require the sacrifice of an animal are encouraged for scientific and medical studies

Discovering Complex Relationships between Drugs and Diseases

Finding the complex semantic relations between existing drugs and new diseases will help in the drug development in a new way. Most of the drugs which have found new uses have been discovered due to serendipity. Hence, the prediction of the uses of drugs for more than one disease should be done in a systematic way by studying the semantic relations between the drugs and diseases and also the other entities involved in the relations. Hence, in order to study the complex semantic relations between drugs and diseases an application was developed that integrates the heterogeneous data in different formats from different public databases which are available online. A high level ontology was also developed to integrate the data and only the fields required for the current study were used. The data was collected from different data sources such as DrugBank, UniProt/SwissProt, GeneCards and OMIM. Most of these data sources are the standard data sources and have been used by National Committee of Biotechnology Information of Nation Institute of Health. The data was parsed and integrated and complex semantic relations were discovered. This is a simple and novel effort which may find uses in development of new drug targets and polypharmacology

The rotterdam study: 2014 objectives and design update

The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods

The landscape of the methodology in drug repurposing using human genomic data:a systematic review

The process of drug development is expensive and time-consuming. In contrast, drug repurposing can be introduced to clinical practice more quickly and at a reduced cost. Over the last decade, there has been a significant expansion of large biobanks that link genomic data to electronic health record (EHR) data, public availability of various databases containing biological and clinical information, and rapid development of novel methodologies and algorithms in integrating different sources of data. This review aims to provide a thorough summary of different strategies that utilize genomic data to seek drug-repositioning opportunities. We searched MEDLINE and EMBASE databases to identify eligible studies up until 1st May 2023, with a total of 102 studies finally included after two-step parallel screening. We summarized commonly used strategies for drug repurposing, including Mendelian randomization, multi-omic-based and network-based studies, and illustrated each strategy with examples, as well as the data sources implemented. By leveraging existing knowledge and infrastructure to expedite the drug discovery process and reduce costs, drug repurposing potentially identifies new therapeutic uses for approved drugs in a more efficient and targeted manner. However, technical challenges when integrating different types of data and biased or incomplete understanding of drug interactions are important hindrances that cannot be disregarded in the pursuit of identifying novel therapeutic applications. This review offers an overview of drug repurposing methodologies, providing valuable insights and guiding future directions for advancing drug repurposing studies

Investigating disease mechanisms in autosomal dominant optic atrophy with retinal ganglion cells derived from induced pluripotent stem cells

Dominant Optic Atrophy (DOA) is the most common inherited optic neuropathy in the UK, characterised by the preferential loss of retinal ganglion cells (RGCs) and progressive blindness. 60-70 % of DOA patients harbour mutations in the OPA1 gene, encoding a mitochondrial protein that regulates mitochondrial morphology, bioenergetics and mitochondrial DNA (mtDNA) quality. Currently, DOA has no therapeutic options and the mechanisms driving RGC degeneration are poorly understood. In this study, a biobank of induced pluripotent stem cells iPSCs (iPSCs) encompassing the clinical and genetic DOA spectrum was created using patient-derived OPA1 mutant fibroblast cell lines, and CRISPR/Cas9 gene editing to generate isogenic cell lines. RGC differentiation was optimized and characterised in 2D and 3D in vitro methods, demonstrating expression of RGC-associated genes including BRN3B and ISL1. OPA1 mutant iPSCs showed no differentiation deficit compared to wild-type control cell lines, exhibiting comparable expression of all relevant markers. 2D-RGCs demonstrated enrichment of neuronal associated markers, including ELAVL3 and TAU, when compared to 3D retinal organoids. Phenotypic analysis demonstrated significant deficits in respiration, ATP production and increased mtDNA mutation in fibroblasts, iPSCs and 2D-RGCs compared to isogenic controls. Characterisation of mitochondrial stress through induction of stress associated gene expression demonstrated significant levels of upregulation in iPSCs, however, 3D- and 2D-RGCs exhibited fewer upregulated genes indicating that mitochondrial stress may be a cell type specific response. Importantly, correction of patient-derived iPSCs restored mitochondrial homeostasis, demonstrating that restoration of WT OPA1 expression is able to mitigate mutant associated phenotypes. Thus, an OPA1 mutant iPSC biobank has been established encompassing the clinical disease spectrum, enabling effective in vitro modelling to establish RGC specific disease mechanisms. OPA1 mutant RGCs demonstrate significant reductions in mitochondrial homeostasis, including reduced bioenergetic output and mtDNA quality. This work provides a platform for further investigation of OPA1-mediated disease mechanisms and therapeutic design

Pacific Symposium on Biocomputing 2023

The Pacific Symposium on Biocomputing (PSB) 2023 is an international, multidisciplinary conference for the presentation and discussion of current research in the theory and application of computational methods in problems of biological significance. Presentations are rigorously peer reviewed and are published in an archival proceedings volume. PSB 2023 will be held on January 3-7, 2023 in Kohala Coast, Hawaii. Tutorials and workshops will be offered prior to the start of the conference.PSB 2023 will bring together top researchers from the US, the Asian Pacific nations, and around the world to exchange research results and address open issues in all aspects of computational biology. It is a forum for the presentation of work in databases, algorithms, interfaces, visualization, modeling, and other computational methods, as applied to biological problems, with emphasis on applications in data-rich areas of molecular biology.The PSB has been designed to be responsive to the need for critical mass in sub-disciplines within biocomputing. For that reason, it is the only meeting whose sessions are defined dynamically each year in response to specific proposals. PSB sessions are organized by leaders of research in biocomputing's 'hot topics.' In this way, the meeting provides an early forum for serious examination of emerging methods and approaches in this rapidly changing field