Most agriculturally significant crop traits are quantitatively inherited which limits the ease and efficiency of trait dissection. Multi-parent populations overcome the limitations of traditional trait mapping and offer new potential to accurately define the genetic basis of complex crop traits. The increasing popularity and use of nested association mapping (NAM) and multi-parent advanced generation intercross (MAGIC) populations raises questions about the optimal design and allocation of resources in their creation. In this paper we review strategies for the creation of multi-parent populations and describe two complementary in silico studies addressing the design and construction of NAM and MAGIC populations. The first simulates the selection of diverse founder parents and the second the influence of multi-parent crossing schemes (and number of founders) on haplotype creation and diversity. We present and apply two open software resources to simulate alternate strategies for the development of multi-parent populations.
Developments in genomics research are considered to have great potential for improving health caremaking genomics an urgent site for translational efforts.Yet while much emphasis is put on the technical challenges of translation, there is less scholarly attention for the social infrastructures through which novel medical interventions may be delivered to patient populations.Reflecting the idea that cancer is at the frontier of genomic applications in health care, this paper explores how the assessment of familial breast cancer risks was 'translated' into routine health care in Germany, the Netherlands and the United Kingdom.The paper identifies regulation, institutionalization and standardization as key mechanisms of translation that find distinct expression in particular sociocultural contexts and shape both the social and technical making of genomics into routine clinical practice.Translation is therefore an area of social as well as technical concern, and therefore requires collective decisionmaking.
Recounting progress in genomics typically involves detailing a series of milestones from the inception of the Human Genome Project to the present. Eric Lander did just that beautifully in his plenary talk opening the recent International Congress on Human Genetics 2016 in Kyoto. He traced the path from genetics to disease biology as it progressed from identifying disease genes to sequencing genomes, to mapping disease genes, to cataloging common and rare genetic variations to interpreting their clinical significance, to understanding how the genome folds into 3D maps, all of which bespeaks remarkable achievements, and innovation, in science and patient care. Not surprisingly, such regaling of success rarely if ever includes achievements by less resourced countries, because resource limitations for the most part bar contributions of the same magnitude. The challenges faced by researchers in these parts of the world are more readily known than the successes, however large or small. It is for this reason that we bring to your attention remarkable achievements occurring in such areas of the world. In this special issue of the Journal several groups from developing countries from across the globe report their work and perspectives. In ‘Pharmacogenomics for infectious diseases in sub-Saharan Africa successes & opportunities’, Chaudhry and colleagues from South Africa, while addressing both the potential of pharmacogenomics as well as its failure to live up to initial expectations, highlight the fact that international consortia working on pharmacogenomic implementation guidelines have failed to come up with guidelines for the major infectious disorders affecting the developing world such as HIV/AIDS, TB, and malaria. In the globalized world that we live in, international collaboration is the key to success. Limited research infrastructures as well as, poorly developed research and ethics governance mechanisms pose many challenges for both researchers and ethics committees. Roach and colleagues, in their paper ‘Addressing ethical challenges in the genetics sub study of the national eye survey of Trinidad and Tobago’ highlight some of these challenges while demonstrating their novel approaches to developing a culturally appropriate, multifaceted strategy to address these challenges. In today's world the buzzword is genomic medicine. Genomic medicine is dependent on successful implementation of genome sequencing and clinical bioinformatics. At the recent International Congress of Human Genetics 2016 several plenary speakers declared, “Doctors are good, but exomes are better”. Genomic data driven medicine can only be a reality in settings where infrastructure and manpower for genome sequencing and clinical bioinformatics is in place. Helmy and colleagues from Egypt and the UAE provide their perspectives on the challenges faced by the developing world in making genomic medicine a reality due to limited infrastructure for genome sequencing and bioinformatics, and suggest solutions to overcome them, in their article ‘Limited resources of genomic tools in developing countries: challenges and solutions’. Despite significant resource limitations, there are oases of excellence in genomic research in the developing world. These three papers illustrate the breadth of research and depth of success; specifically in forensic genomics, clinical informatics and agrigenomics/bioinformatics. Mohamed and Salama present evidence of the affection of tau normal pattern and pathological aggregates of tau in case of brain hypoxia and suggest therefore that tau protein may be a biomarker for asphyxia in ‘Tau protein as a biomarker for asphyxia: A possible forensic tool.’ Mulder and colleagues from both the Sickle Cell Disease (SCD) community and H3ABioNet report on their recent SCD Ontology workshop that produced the first comprehensive SCD ontology, in ‘Proceedings of a sickle cell disease ontology workshop- towards the first comprehensive ontology for sickle cell disease’. The ontology permits improved data sharing, meta-analyses and further development and curation of databases and clinical informatics. As such it can serve as a model for other disease communities. Tospovirus is severe plant pathogen that damages food crops worldwide. In ‘SeeHaBITaT: a server on bioinformatics applications for tospoviruses and other species’, Habeeb, presents a novel server that enables both control measures and the capacity for other computational research where none had existed. The challenge to take research from bench to bedside is always formidable and all the more so in resourced constrained countries. In their paper ‘Implementation of genomic medicine in Sri Lanka: initial experience and challenges’, Sirisena and colleagues describe how they used clinical exome sequencing and gene panel testing to diagnose three complex cases leading to improved patient care. Such experiences are for most part isolated and therefore there is a need for more widespread equitable implementation of genomic medicine. The final paper by Isaacson Barash ‘Translating translational medicine into global equity: what is needed?’ provides insights about what is needed to achieve widespread equitable implementation of genomic medicine, based on a survey of unmet needs at last fall's Asia Pacific Society of Human Genetics meeting 2015 in Hanoi. To be sure, the successes reported here are significant. And yet, it is still necessary to ask why Genomic Medicine is lagging behind in the less resourced parts of the world. Most developing countries around the world today have large expatriate populations living in the West or affluent countries in the Middle East, working as migrant workers. Often such trained individuals return to their native countries to bring new knowledge and skills to fill the void. Further, increasingly, there is pressure for services available in the West to be made available in developing countries. And yet despite the rapid adoption of IT and increases in global collaborations and data sharing, genomic medicine is not keeping pace outside the West. The national health agenda of most developing countries is shaped by technical assistance given by the World Health Organization (WHO). Sadly, the WHO has been slow to embrace Genomic Medicine and the Human Genetics Program at the WHO has been poorly staffed and poorly funded. The global agenda of the WHO is shaped by resolutions of the World Health Assembly (WHA). Action based on such resolutions received funding, and are implemented through the regional organizations of the WHO. In case of Genomic Medicine, there is no such WHA resolution. The only resolution that comes close to genetics and genomics is the resolution calling on Member States to help redress the limited focus to date on preventing and managing birth defects, especially in low- and middle-income countries. This resolution, made at the 63rd WHA in May 2010, called on Member States to prevent birth defects wherever possible, to implement screening programs, and to provide ongoing support and care to children with birth defects and their families (http://apps.who.int/gb/ebwha/pdf_files/WHA63/A63_R17en.pdf) On the ground in most countries this translated into efforts aimed at strengthening birth defects surveillance (World Health Organization Regional Office for Southeast Asia, 2013). We urge the various international groups that are working on Genomics and Health to now focus their attention on lobbying the WHO for a global plan of action for implementation of genomic medicine with special focus on low- and middle-income countries. This special issue serves to demonstrate that the need, desire and capacity to implement genomic medicine in low- and middle- income countries are there. With the help of the WHO, equitable implementation of genomic medicine is more likely. In conclusion, this special issue captures several translational genetics and genomics success stories from the developing world. The ultimate beneficiaries of this work have to be the people at large. That would happen only in the context of a healthcare workforce that is trained to use genetic and genomic information in their professional practice. That has its own challenges which were highlighted in a previous issue of this journal by de Abrew et al. (2014) Imparting the necessary knowledge, skills and experience on the healthcare workforce to implement genomic medicine is one of the biggest challenges facing the world today and we plan to deal with this fully in another special issue of the journal in the future.
The recent advances in next generation sequencing technologies have made it possible to implement genomic medicine in developing countries such as Sri Lanka where capacity for utilization is limited. This paper aims to describe our initial experience and challenges faced in integrating genomic medicine into routine clinical practice. Using the Illumina MiSeq Next generation sequencing (NGS) platform and an in-house developed bioinformatics pipeline/workflow, we successfully implemented clinical exome sequencing for rare disorders, complex disorders with unusual coexisting phenotypes, and multigene cancer panel testing for inherited cancer syndromes. The advantages of implementing these tests, the challenges for bioinformatics analysis and reporting, the ethical, legal, and social implications of moving from genetic to genomic counseling, and special policy issues related to implementing these tests are further discussed. The implementation of genomic medicine into our routine clinical practice has facilitated improved care for our patients, attesting to the ability of resource limited countries to improve care using advanced genomic technology.
BACKGROUND:The conduct of international collaborative genomics research raises distinct ethical challenges that require special consideration, especially if conducted in settings that are research-naïve or resource-limited. Although there is considerable literature on these issues, there is a dearth of literature chronicling approaches taken to address these issues in the field. Additionally no previous ethical guidelines have been developed to support similar research in Trinidad and Tobago. METHODS:A literature review was undertaken to identify strategies used to address common ethical issues relevant to human genetics and genomics research in research-naïve or resource-limited settings. Strategies identified were combined with novel approaches to develop a culturally appropriate, multifaceted strategy to address potential challenges in the Genetics Substudy of the National Eye Survey of Trinidad and Tobago (GSNESTT). RESULTS:Regarding the protection of study participants, we report a decision to exclude children as participants; the use of a Community Engagement and Sensitization Strategy to increase the genetic literacy of the target population; the involvement of local expertise to ensure cultural sensitivity and to address potential comprehension barriers in informed consent; and an audit of the informed consent process to ensure valid consent. Concerning the regulation of the research, we report on ethics approvals from relevant authorities; a Materials Transfer Agreement to guide sample ownership and export; and a Sample Governance Committee to oversee data use and data access. Finally regarding the protection of the interests of scientists from the host country, we report on capacity building efforts to ensure that local scientists have access to data collected through the project and appropriate recognition of their contributions in future publications. CONCLUSION:This paper outlines an ethical framework for the conduct of population-based genetics and genomics research in Trinidad and Tobago; highlights common issues arising in the field and strategies to address these.
The differences between countries in national income, growth, human development and many other factors are used to classify countries into developed and developing countries. There are several classification systems that use different sets of measures and criteria. The most common classifications are the United Nations (UN) and the World Bank (WB) systems. The UN classification system uses the UN Human Development Index (HDI), an indicator that uses statistic of life expectancy, education, and income per capita for countries' classification. While the WB system uses gross national income (GNI) per capita that is calculated using the World Bank Atlas method. According to the UN and WB classification systems, there are 151 and 134 developing countries, respectively, with 89% overlap between the two systems. Developing countries have limited human development, and limited expenditure in education and research, among several other limitations. The biggest challenge facing genomic researchers and clinicians is limited resources. As a result, genomic tools, specifically genome sequencing technologies, which are rapidly becoming indispensable, are not widely available. In this report, we explore the current status of sequencing technologies in developing countries, describe the associated challenges and emphasize potential solutions.
The recent advances in high-throughput omics technologies have enabled researchers to explore the intricacies of the human microbiome. On the clinical front, the gut microbial community has been the focus of many biomarker-discovery studies. While the recent deluge of high-throughput data in microbiome research has been vastly informative and groundbreaking, we have yet to capture the full potential of omics-based approaches. Realizing the promise of multi-omics data will require integration of disparate omics data, as well as a biologically relevant, mechanistic framework – or metabolic model – on which to overlay these data. Also, a new paradigm for metabolic model evaluation is necessary. Herein, we outline the need for multi-omics data integration, as well as the accompanying challenges. Furthermore, we present a framework for characterizing the ecology of the gut microbiome based on metabolic network modeling.
The chances of raising crop productivity to enhance global food security would be greatly improved if we had a complete understanding of all the biological mechanisms that underpinned traits such as crop yield, disease resistance or nutrient and water use efficiency. With more crop genomes emerging all the time, we are nearer having the basic information, at the gene-level, to begin assembling crop gene catalogues and using data from other plant species to understand how the genes function and how their interactions govern crop development and physiology. Unfortunately, the task of creating such a complete knowledge base of gene functions, interaction networks and trait biology is technically challenging because the relevant data are dispersed in myriad databases in a variety of data formats with variable quality and coverage. In this paper we present a general approach for building genome-scale knowledge networks that provide a unified representation of heterogeneous but interconnected datasets to enable effective knowledge mining and gene discovery. We describe the datasets and outline the methods, workflows and tools that we have developed for creating and visualising these networks for the major crop species, wheat and barley. We present the global characteristics of such knowledge networks and with an example linking a seed size phenotype to a barley WRKY transcription factor orthologous to TTG2 from Arabidopsis, we illustrate the value of integrated data in biological knowledge discovery. The software we have developed (www.ondex.org) and the knowledge resources (http://knetminer.rothamsted.ac.uk) we have created are all open-source and provide a first step towards systematic and evidence-based gene discovery in order to facilitate crop improvement.
High throughput approaches such as whole genome sequencing (WGS) and whole exome sequencing (WES) create an unprecedented amount of data providing powerful resources for clinical care and research. Recently, WGS and WES services have been made available by commercial direct-to-consumer (DTC) companies. The DTC offer of genetic testing (GT) has already brought attention to potentially problematic issues such as the adequacy of consumers' informed consent and transparency of companies' research activities. In this study, we analysed the websites of four DTC GT companies offering WGS and/or WES with regard to their policies governing storage and future use of consumers' data and samples. The results are discussed in relation to recommendations and guiding principles such as the "Statement of the European Society of Human Genetics on DTC GT for health-related purposes" (2010) and the "Framework for responsible sharing of genomic and health-related data" (Global Alliance for Genomics and Health, 2014). The analysis reveals that some companies may store and use consumers' samples or sequencing data for unspecified research and share the data with third parties. Moreover, the companies do not provide sufficient or clear information to consumers about this, which can undermine the validity of the consent process. Furthermore, while all companies state that they provide privacy safeguards for data and mention the limitations of these, information about the possibility of re-identification is lacking. Finally, although the companies that may conduct research do include information regarding proprietary claims and commercialisation of the results, it is not clear whether consumers are aware of the consequences of these policies. These results indicate that DTC GT companies still need to improve the transparency regarding handling of consumers' samples and data, including having an explicit and clear consent process for research activities.
Objectives: To explore attitudes of Swiss older adults towards personal genomics (PG).Methods: Using an anonymized voluntary paper-and-pencil survey, data were collected from 151 men and women aged 60-89 years attending the Seniorenuniversitat Zurich, Switzerland (Seniors' University). Analyses were conducted using descriptive and inferential statistics.Results: One third of the respondents were aware of PG, and more than half indicated interest in undergoing PG testing. The primary motivation provided was respondents' interest in finding out about their own disease risk, followed by willingness to contribute to scientific research. Forty-four percent were not interested in undergoing testing because results might be worrisome, or due to concerns about the validity of the results. Only a minority of respondents mentioned privacy-related concerns. Further, 66% were interested in undergoing clinic-based PG motivated by the opportunity to contribute to scientific research (78%) and 75% of all study participants indicated strong preferences to donate genomic data to public research institutions.Conclusion: This study indicates a relatively positive overall attitude towards personal genomic testing among older Swiss adults, a group not typically represented in surveys about personal genomics. Genomic data of older adults can be highly relevant to late life health and maintenance of quality of life. In addition they can be an invaluable source for better understanding of longevity, health and disease. Understanding the attitudes of this population towards genomic analyses, although important, remains under-examined. (c) 2016 The Authors. Published by Elsevier B.V.
Asphyxial death has been a problem for forensic investigations due to the absence of a validated biomarker for the diagnosis of this event. Recently, research on brain affection by asphyxia raised hopes on the possible use of CNS markers for asphyxia. The cytoskeletal proteins seem to be attractive targets as they are vulnerable to hypoxia and can be affected in asphyxial deaths. Tau, an important cytoskeletal protein, showed affection in many neurodegenerative disorders and recently in some acute incidences like trauma and brain ischemia. In this report we show the affection of the normal pattern of tau and pathological aggregates of tau in the case of brain hypoxia. This may give new clues to asphyxial death investigations.
The purpose of this qualitative study is to elucidate stakeholder perceptions of, and institutional practices related to cell-based therapies and products (CTP) regulation and commercialization in Canada. The development of reproducible, safe and effective CTPs is predicated on regulatory and commercialization environments that enable innovation. Manufacturing processes constitute a critical step for CTP development in this regard. The road from CTP manufacturing to translation in the clinic, however, has yet to be paved. This study aims to fill an empirical gap in the literature by exploring how CTP manufacturing facilities navigate Canadian regulatory and commercialization environments, which together drive the translation of novel CTPs from bench to bedside. Using the multi-level model of practice-driven institutional change proposed by Smets et al., we demonstrate how CTP manufacturing practices are governed by established standards, yet meaningfully shape higher-order regulatory and commercial norms in CTP research and development. We identify four key themes that undergird such processes of innovation: 1) managing regulatory uncertainty, which stems from an inability to classify CTPs within existing regulatory categories for approval and commercialization purposes; 2) building a 'business case' whereby a CTP's market potential is determined in large part by proving its safety and effectiveness; 3) standardizing manufacturing procedures that mobilize CTPs from a research and development phase to a commercialization one; and 4) networking between researchers and regulators to develop responsible commercialization processes that reflect the uniqueness of CTPs as distinct from other biologics and medical devices.
While genomics, and other omics, research is rapidly advancing in the US and Europe, progress has been slower in less resourced countries. The imbalance has given rise to concern about whether the benefits of these advances, namely new and better tests, treatments, risk identification, and prevention strategies, will be shared and available to those living in less resourced reaches of the globe. In effort to give voice to researchers, an informal survey about barriers to advancing translational medicine was administered to attendees of the 11th Asia Pacific Conference on Human Genetics, 2015, Hanoi. The overall goal of the survey was to identify unmet needs and rank their importance. Most attendees completed the survey. Not surprisingly funding is indicated as a major need. Respondents reported that lack of bioinformatics and computational tools, trained data scientists and access to datasets is creating a significant lag behind better resourced regions. Results are intended to inform efforts to create a regional consensus statement of need. Such a regional statement could help funding organizations and policy makers seeking to promote global genomics benefit sharing.
Genomic advancement: Aiming to affirm and improve human life ☆ Challenges to improving human health and well being are both within and outside our control despite the best of scientific advances.While advances continue to offer improved technologies, and thus our ability to not only improve detection and treatment of disease, preventing the roots of illness from taking hold involves environmental and social factors.For example, climate and politics can aid or abet the best of health improvement strategies yielding untoward consequences for those in need who lack substantial control over their access to food and healthcare.In this issue, we present a collection of articles that contribute to our understanding of genomics, ethical and policy factors necessary to improving health.We start with a special section on the genomics of plant breeding and move to translational genomics and health improvement.
To return or not to return the results of genomics research: that has been the question at the crux of an ongoing debate spawned by the increasingly rapid evolution of genomics.1 Like many debates, this one arises from conflicting perspectives on broader concerns: for example, the purported distinction between research and patient care, the relationship between health care institutions and the communities they serve, and the role of patient- and research-participant-engagement in such debates (and in their resolution). In 2012, Geisinger began to lay the groundwork for a significant expansion of the MyCode Community Health Initiative, a research platform comprised not only of a biobank established five years earlier but also of the clinical data collected in the electronic health records of the biobank's patient–participants and of the investigations made possible by these resources. Advances in genomic knowledge, coupled with steady decreases in sequencing costs, supplied the immediate context for this effort, which also entailed extensive internal discussion and patient–participant engagement focused on the ethical question, should Geisinger return clinically actionable results of genomics research to MyCode's patient–participants whose sequenced genomes yield such results? In convening the internal discussions, the aim was to enlist organizational leaders, clinicians, and investigators in a process of ethical analysis and reflection for the purpose of identifying what obligations, if any, Geisinger has toward its patient–participants with regard to the return of results. Through engagement with the patient–participants, nearly 100 of whom were convened through focus groups described below, the aim was to solicit their views on the very same question.2 After the focus groups, the views of the engaged participants were clear: they overwhelmingly favored the return of results. Additional discussions were then held with leadership, researchers and Geisinger's Institutional Review Board (IRB) and ultimately, Geisinger did indeed decide to return genomic results to that subset of MyCode participants whose sequenced genomes are found to contain one or more of the genetic variants on a defined list (based in part on the March 2013 clinical testing recommendations of the American College of Medical Genetics and Genomics3) and to integrate those clinically actionable results in genetically informed plans of care for these patient–participants. Soon after this decision, in early 2014, Geisinger announced an ambitious collaboration in genomics discovery with the Tarrytown, NY-based Regeneron Pharmaceuticals and embarked upon the anticipated expansion of MyCode—the current goal of which is to increase the ranks of patient–participants to at least 250,000 over five years. Against the backdrop of President Obama's recently announced Precision Medicine Initiative (PMI), which calls for the development of a one-million-participant cohort, Geisinger hopes to become a funded member of the PMI consortium and is considering a many-fold increase in the size of MyCode, inspired, in large measure, by rapid growth in the number of consented participants.4 Here we describe the development of the ethical rationale for returning genomic results to patient–participants in the MyCode Community Health Initiative with special attention to the aforementioned internal discussions, reflections and focus groups through which the institution sought to engage patient–participants.
Aim: Identify solutions to the most important policy barriers to the clinical adoption of next-generation sequencing. Materials & methods: Four-round modified policy Delphi with a multistakeholder panel of 48 experts. The panel deliberated policy solutions to (previously reported) challenges deemed most important to address. Results: The group advocated using consensus panels to promote consistency in payer policies and to standardize test reporting, and favored making genomic data-sharing a condition of regulatory clearance, certification, or accreditation processes. They were split on the role of US FDA. Conclusion: Panelists found common ground on solutions for health plan coverage policy consistency, data-sharing, and standardizing reporting, but were sharply divided on the role of the FDA in mitigating risks to patients.
The use of mitochondrial transfer as a clinic procedure is drawing closer to reality. Here we provide a detailed overview of mitochondrial transfer techniques - both established and recent - including pronuclear, spindle, ooplasmic and blastomere transfer. Reasons as to why some techniques are more suitable for the prevention of mitochondrial DNA disease than others, as well as the advantages and disadvantages of each methodology, are discussed. The possible clinical introduction of these techniques has raised concerns about the adverse effects they may have on resultant embryos and offspring. Success rates of each technique, embryo viability and developmental consequences post mitochondrial transfer are addressed through analysis of evidence obtained from both animal and human studies. Counterarguments against potential mitochondrial-nuclear genome incompatibility are also provided. Additional clinical applications of mitochondrial transfer techniques are discussed. These include the rescue or enhancement of fertility in women of advanced maternal age or those suffering from diabetes. An alternative to using mitochondrial DNA transfer for germ line therapies is the therapeutic use of somatic cell nuclear transfer for the generation of personalised stem cells. Although ethically challenging, this method could offer patients already suffering from mitochondrial DNA diseases a novel treatment option.
