The promise and peril of genomic screening in the general population

Utilization of sequencing to screen the general population for preventable monogenic conditions is receiving substantial attention due to its potential to decrease morbidity and mortality. However, the selection of which variants to return is a serious implementation challenge. Procedures must be investigated to ensure optimal test characteristics and avoidance of harm from false positive test results

Creation and Worldwide Utilisation of New COVID-19 Online Information Hub for Genetics Health Professionals, Patients and Families

The current COVID-19 pandemic has unfortunately resulted in many significant concerns for individuals with genetic disorders and their relatives, regarding the viral infection and, particularly, its specific implications and additional advisable precautions for individuals affected by genetic disorders. To address this, the resulting requirement for guidance and information for the public and for genetics professionals was discussed among colleagues nationally, on the ScotGEN Steering Committee, and internationally on the Education Committee of the European Society of Human Genetics (ESHG). It was agreed that the creation of an online hub of genetics-related COVID-19 information resources would be particularly helpful. The proposed content, divided into a web page for professionals and a page for patients, was discussed with, and approved by, genetics professionals. The hub was created and provided online at www.scotgen.org.uk and linked from the ESHG’s educational website for genetics and genomics, at www.eurogems.org. The new hub provides links, summary information and representative illustrations for a wide range of selected international resources. The resources for professionals include: COVID-19 research related hubs provided by Nature, Science, Frontiers, and PubMed; clinical guidelines; the European Centre for Disease Prevention and Control; the World Health Organisation; and molecular data sources including coronavirus 3D protein structures. The resources for patients and families include links to many accessible sources of support and relevant information. Since the launch of the pages, the website has received visits from over 50 countries worldwide. Several genetics consultants have commented on usefulness, clarity, readability, and ease of navigation. Visits have originated most frequently in the United Kingdom, Kuwait, Hong Kong, Moldova, United States, Philippines, France, and Qatar. More links have been added since the launch of the hub to include additional international public health and academic resources. In conclusion, an up-to-date online hub has been created and made freely available for healthcare professionals, patients, relatives and the public, providing categorised easily navigated links to a range of worldwide resources related to COVID-19. These pages are receiving a rapidly growing number of return visits and the authors continue to maintain and update the pages’ content, incorporating new developments in this field of enormous worldwide importance

Potential Uses and Inherent Challenges of Using Genome-Scale Sequencing to Augment Current Newborn Screening

Since newborn screening (NBS) began in the 1960s, technological advances have enabled its expansion to include an increasing number of disorders. Recent developments now make it possible to sequence an infant’s genome relatively quickly and economically. Clinical application of whole-exome and whole-genome sequencing is expanding at a rapid pace but presents many challenges. Its utility in NBS has yet to be demonstrated and its application in the pediatric population requires examination, not only for potential clinical benefits, but also for the unique ethical challenges it presents

Age-Based Genomic Screening during Childhood: Ethical and Practical Considerations in Public Health Genomics Implementation

Genomic sequencing offers an unprecedented opportunity to detect inherited variants that are implicated in rare Mendelian disorders, yet there are many challenges to overcome before this technology can routinely be applied in the healthy population. The age-based genomic screening (ABGS) approach is a novel alternative to genome-scale sequencing at birth that aims to provide highly actionable genetic information to parents over the course of their child’s routine health care. ABGS utilizes an established metric to identify conditions with high clinical actionability and incorporates information about the age of onset and age of intervention to determine the optimal time to screen for any given condition. Ongoing partnerships with parents and providers are instrumental to the co-creation of educational resources and strategies to address potential implementation barriers. Implementation science frameworks and informative empirical data are used to evaluate strategies to establish this unique clinical application of targeted genomic sequencing. Ultimately, a pilot project conducted in primary care pediatrics clinics will assess patient and implementation outcomes, parent and provider perspectives, and the feasibility of ABGS. A validated, stakeholder-informed, and practical ABGS program will include hundreds of conditions that are actionable during infancy and childhood, setting the stage for a longitudinal implementation that can assess clinical and health economic outcomes

Scientific, institutional and personal rivalries among Soviet geographers in the late Stalin era

Scientific, institutional and personal rivalries between three key centres of geographical research and scholarship (the Academy of Sciences Institute of Geography and the Faculties of Geography at Moscow and Leningrad State Universities) are surveyed for the period from 1945 to the early 1950s. It is argued that the debates and rivalries between members of the three institutions appear to have been motivated by a variety of scientific, ideological, institutional and personal factors, but that genuine scientific disagreements were at least as important as political and ideological factors in influencing the course of the debates and in determining their final outcome

Comparative sequence analysis and tissue localization of members of the SLC6 family of transporters in adult Drosophila melanogaster

SUMMARY The SLC6 family comprises proteins that move extracellular neurotransmitters, amino acids and osmolytes across the plasma membrane into the cytosol. In mammals, deletion of SLC6 family members has dramatic physiologic consequences, but in the model organism Drosophila melanogaster, little is known about this family of proteins. Therefore, in this study we carried out an initial analysis of 21 known or putative SLC6 family members from the Drosophila genome. Protein sequences from these genes segregated into either well-defined subfamilies, including the novel insect amino acid transporter subfamily, or into a group of weakly related sequences not affiliated with a recognized subfamily. Reverse transcription-polymerase chain reaction analysis and in situ hybridization showed that seven of these genes are expressed in the CNS. In situ hybridization revealed that two previously cloned SLC6 members, the serotonin and dopamine transporters, were localized to presumptive presynaptic neurons that previously immunolabelled for these transmitters. RNA for CG1732 (the putative GABA transporter) and CG15088 (a member of the novel insect amino acid transporter family) was localized in cells likely to be subtypes of glia, while RNA for CG5226, CG10804 (both members of the orphan neurotransmitter transporter subfamily) and CG5549 (a putative glycine transporter) were expressed broadly throughout the cellular cortex of the CNS. Eight of the 21 sequences were localized outside the CNS in the alimentary canal, Malpighian tubules and reproductive organs. Localization for six sequences was not found or not attempted in the adult fly. We used the Drosophila ortholog of the mammalian vesicular monoamine transporter 2, CG33528, to independently identify monoaminergic neurons in the adult fly. RNA for CG33528 was detected in a limited number of cells in the central brain and in a beaded stripe at the base of the photoreceptors in the position of glia, but not in the photoreceptors themselves. The SLC6 localization observations in conjunction with likely substrates based on phylogenetic inferences are a first step in defining the role of Na/Cl-dependent transporters in Drosophila physiology

Realistic boundary conditions for stochastic simulations of reaction-diffusion processes

Many cellular and subcellular biological processes can be described in terms of diffusing and chemically reacting species (e.g. enzymes). Such reaction-diffusion processes can be mathematically modelled using either deterministic partial-differential equations or stochastic simulation algorithms. The latter provide a more detailed and precise picture, and several stochastic simulation algorithms have been proposed in recent years. Such models typically give the same description of the reaction-diffusion processes far from the boundary of the simulated domain, but the behaviour close to a reactive boundary (e.g. a membrane with receptors) is unfortunately model-dependent. In this paper, we study four different approaches to stochastic modelling of reaction-diffusion problems and show the correct choice of the boundary condition for each model. The reactive boundary is treated as partially reflective, which means that some molecules hitting the boundary are adsorbed (e.g. bound to the receptor) and some molecules are reflected. The probability that the molecule is adsorbed rather than reflected depends on the reactivity of the boundary (e.g. on the rate constant of the adsorbing chemical reaction and on the number of available receptors), and on the stochastic model used. This dependence is derived for each model.Comment: 24 pages, submitted to Physical Biolog

Stochastic modelling of reaction-diffusion processes: algorithms for bimolecular reactions

Several stochastic simulation algorithms (SSAs) have been recently proposed for modelling reaction-diffusion processes in cellular and molecular biology. In this paper, two commonly used SSAs are studied. The first SSA is an on-lattice model described by the reaction-diffusion master equation. The second SSA is an off-lattice model based on the simulation of Brownian motion of individual molecules and their reactive collisions. In both cases, it is shown that the commonly used implementation of bimolecular reactions (i.e. the reactions of the form A + B -> C, or A + A -> C) might lead to incorrect results. Improvements of both SSAs are suggested which overcome the difficulties highlighted. In particular, a formula is presented for the smallest possible compartment size (lattice spacing) which can be correctly implemented in the first model. This implementation uses a new formula for the rate of bimolecular reactions per compartment (lattice site).Comment: 33 pages, submitted to Physical Biolog

Supporting Parental Decisions About Genomic Sequencing for Newborn Screening: The NC NEXUS Decision Aid

Advances in genomic sequencing technology have raised fundamental challenges to the traditional ways genomic information is communicated. These challenges will become increasingly complex and will affect a much larger population in the future if genomics is incorporated into standard newborn screening practice. Clinicians, public health officials, and other stakeholders will need to agree on the types of information that they should seek and communicate to parents. Currently, few evidence-based and validated tools are available to support parental informed decision-making. These tools will be necessary as genomics is integrated into clinical practice and public health systems. In this article we describe how the North Carolina Newborn Exome Sequencing for Universal Screening study is addressing the need to support parents in making informed decisions about the use of genomic testing in newborn screening. We outline the context for newborn screening and justify the need for parental decision support. We also describe the process of decision aid development and the data sources, processes, and best practices being used in development. By the end of the study, we will have an evidenced-based process and validated tools to support parental informed decision-making about the use of genomic sequencing in newborn screening. Data from the study will help answer important questions about which genomic information ought to be sought and communicated when testing newborns