Are non-protein coding RNAs junk or treasure?: An attempt to explain and reconcile opposing viewpoints of whether the human genome is mostly transcribed into non-functional or functional RNAs.

The human genome project's lasting legacies are the emerging insights into human physiology and disease, and the ascendance of biology as the dominant science of the 21st century. Sequencing revealed that >90% of the human genome is not coding for proteins, as originally thought, but rather is overwhelmingly transcribed into non-protein coding, or non-coding, RNAs (ncRNAs). This discovery initially led to the hypothesis that most genomic DNA is "junk", a term still championed by some geneticists and evolutionary biologists. In contrast, molecular biologists and biochemists studying the vast number of transcripts produced from most of this genome "junk" often surmise that these ncRNAs have biological significance. What gives? This essay contrasts the two opposing, extant viewpoints, aiming to explain their bases, which arise from distinct reference frames of the underlying scientific disciplines. Finally, it aims to reconcile these divergent mindsets in hopes of stimulating synergy between scientific fields.

"Why did I choose genetics?": A survey of current and recent medical genetics and genomics residents provides insight into recruitment efforts.

There is a shortage of clinical geneticists, even with concerted recruitment efforts. Previously, no data had been collected about why young career geneticists chose this specialty. To investigate this question, we carried out a survey of current and recent medical genetics and genomics residents. The goal of this survey was to understand their reasons for pursuing medical genetics and genomics as a specialty. Results demonstrate that, for most, interest in genetics begins in medical school and was largely influenced by mentorship. This suggests that placing greater focus on introducing medical genetics as a clinical specialty and fostering robust mentorship of students in preclinical years may increase recruitment into medical genetics residencies.

Community engagement in genetics and genomics research: a qualitative study of the perspectives of genetics and genomics researchers in Uganda.

BACKGROUND: Generally, there is unanimity about the value of community engagement in health-related research. There is also a growing tendency to view genetics and genomics research (GGR) as a special category of research, the conduct of which including community engagement (CE) as needing additional caution. One of the motivations of this study was to establish how differently if at all, we should think about CE in GGR. AIM: To assess the perspectives of genetics and genomics researchers in Uganda on CE in GGR. METHOD: A cross-sectional qualitative study was conducted at Makerere University and Uganda Virus Research Institute. Twenty-five individuals participated, the majority being male (sixteen). Participants included nineteen genetics and genomics researchers (researchers and research coordinators), two CE officers, three nurses and one nursing counsellor. Data were collected using in-depth interviews and analyzed in a thematic manner using NVivo version 12 Plus. STUDY FINDINGS: Thirteen of the respondents had conducted CE in their GGR in either a geographical and disease-specific community. Some respondents said CE principles are the same and there is no need for special consideration for CE in GGR. Others gave ethical issues in GGR that require special consideration for CE in such research and these were categorized into six themes: GGR is new to communities, Difficulty in communicating GGR by the researchers, Genes are shared in communities, Cultural sensitivities against GGR, Community attitude toward GGR, Some GGR studies take long to end, and Negotiation of research benefits. Special considerations for CE when conducting GGR were suggested and categorized into seven themes: creating awareness of GGR in communities, obtaining both community acceptance and individual consent, CE team composition, involve communities in solving GGR challenges, prolong CE in some GGR, develop guidelines for CE in GGR, and legal considerations on GGR. CONCLUSION: GGR was characterized by special issues that require special CE considerations for such research.

Genetic and clinical characteristics of catecholaminergic polymorphic ventricular tachycardia in a Taiwanese nationwide cohort.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and lethal arrhythmia. Ryanodine receptor 2 (RYR2) mutation accounts for ∼60% of CPVT patients which is inherited in an autosomal dominant pattern. OBJECTIVE: This study aimed to identify CPVT-related mutations and clinical characteristics among Taiwanese CPVT patients and compare to other cohorts worldwide. METHODS: Clinical and genetic data were obtained from the Sudden Arrhythmia Death Syndrome Registry in Taiwan (SADS-TW). Forty clinically diagnosed Taiwanese CPVT patients were included. RESULTS: This is the first nationwide CPVT cohort in Taiwan. Among the 29 Taiwanese patients with CPVT-related gene mutations, 55% had RYR2 mutations, a rate similar to other ethnicities. Three out of 12 RYR2 variants were unreported. Exercise-induced symptoms including syncope and cardiac arrest were more frequent in East Asian cohorts (Taiwanese 79%, Japanese 91%), compared to Caucasian cohorts (59%) (p = 0.002). CONCLUSION: The discovery of diverse RYR2 mutations in the Taiwanese CVPT population demonstrates the importance of genetic testing in different ethnicities.

The Development of Human Genetics at the National Research Centre, Cairo, Egypt: A Story of 50 Years.

This article describes my experiences over more than 50 years in initiating and maintaining research on human genetics and genomics at the National Research Centre in Cairo, Egypt, from its beginnings in a small unit of human genetics to the creation of the Center of Excellence for Human Genetics. This was also the subject of a lecture I gave at the 10th Conference of the African Society of Human Genetics, held in Cairo in November 2017, after which Professor Michèle Ramsay, president of the society, suggested that I write an autobiographical article for the Annual Review of Genomics and Human Genetics. I hope that I succeeded in the difficult assignment of summarizing the efforts of a researcher from a developing country to initiate and maintain the rapidly advancing science of human genetics and genomics in my own country and make contributions to the worldwide scientific community.

Good performance of the criteria of American College of Medical Genetics and Genomics/Association for Molecular Pathology in prediction of pathogenicity of genetic variants causing thoracic aortic aneurysms and dissections.

BACKGROUND: The identification of pathogenic variant in patients with thoracic aortic aneurysms and dissections (TAAD) was previously found to be a significant indicator pointing to earlier need for surgical intervention. In order to evaluate available methods for classifying identified genetic variants we have compared the event-free survival in a cohort of TAAD patients classified as genotype-positive versus genotype-negative by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) criteria or by ClinVar database. METHODS: We analyzed previously unreported cohort of 132 patients tested in the routine clinical setting for genetic variants in a custom panel of 30 genes associated with TAAD or the TruSight Cardio commercial panel of 174 genes associated with cardiac disease. The identified variants were classified using VarSome platform. Kaplan-Meier survival curves were constructed to compare the event-free survival between probands defined as 'genotype-positive' and 'genotype-negative' using different classifications in order to compare their performance. RESULTS: Out of 107 rare variants found, 12 were classified as pathogenic/likely pathogenic by ClinVar, 38 were predicted to be pathogenic/likely pathogenic by ACMG. Variant pathogenicity as assessed by ACMG criteria was a strong predictor of event free survival (event free survival at 50 years 83% vs. 50%, for genotype positive patients vs. reference, respectively, p = 0.00096). The performance of ACMG criteria was similar to that of ClinVar (event free survival at 50 years 87% vs. 50%, for genotype positive patients vs. reference, respectively p = 0.023) but independent from it as shown by analysing variants with no ClinVar record (event free survival at 50 years 80% vs. 50%, p = 0.0039). Variants classified as VUS by ACMG criteria or ClinVar did not affect event-free survival. TAAD specific custom gene panel performed similar to the larger universal cardiac panel. CONCLUSIONS: In our cohort of unrelated TAAD patients ACMG classification tool available at VarSome was useful in assessing pathogenicity of novel genetic variants. Gene panel containing the established genes associated with the highest risk of hereditary TAAD (ACTA1, COL3A1, FBN1, MYH11, SMAD3, TGFB2, TGFBR1, TGFBR2, MYLK) was sufficient to identify prevailing majority of variants most likely to be causative of the disease.

The training of future clinical geneticists: Evaluation and reflection on the ACMG Foundation for Genetic and Genomic Medicine Summer Genetics Scholars Program.

PURPOSE: The purpose of the Summer Genetics Scholars Program of the ACMG Foundation for Genetic and Genomic Medicine is to expose medical students to medical genetics and genomics early during school with the aim of increasing the number of physicians pursuing a career in this field. This survey study evaluated the Summer Genetics Scholars Program on the achievement of its goals. METHODS: Former Summer Genetics Scholars who had completed medical school were sent a 13-question survey aimed at evaluating the program and obtaining feedback about their experiences. RESULTS: Of 125 former scholars, 55 completed the survey with 2 additional participants partially completing the survey. The vast majority of former participants report either being very satisfied or satisfied with their experience (96%). CONCLUSION: Whereas most participants found their experience to be beneficial, evaluation of the initial 6 years of the program did not show an increase in the number of students entering residencies in medical genetics and genomics. It likely is too early to assess the program's true influence on entry into the field because data were only available for the first 6 years of the Summer Genetics Scholars Program, and many residents typically choose to complete another primary specialty before medical genetics and genomics.

Clinical impact of whole-genome sequencing in patients with early-onset dementia.

BACKGROUND: In the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation. METHODS: WGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer's disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD. RESULTS: Clinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk. DISCUSSION: WGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.

Impact of the COVID-19 pandemic on medical genetics and genomics training: Perspective from clinical trainees.

We sought to understand how the coronavirus disease 2019 (COVID-19) pandemic has affected the well-being, clinical training, and medical education for clinical trainees in medical genetics and genomics residency and fellowship programs. All clinical genetics trainees in the Accreditation Council for Graduate Medical Education (ACGME)-accredited training programs were invited to complete a survey. 31 out of 174 trainees completed the survey. With regards to well-being, 18 trainees reported increased anxiety, 10 had increased depression, 3 increased financial strain, 13 worsening work-life balance, and 13 worsening physical health. There was increased telehealth utilization in both outpatient (3% before the pandemic vs. 67% during the pandemic) and inpatient clinical encounters (0% vs. 29%). The most commonly reported challenges in telehealth use were inadequate physical examination and technical problems during visits. Twenty trainees believed that the pandemic has negatively impacted overall clinical training while none reported a positive impact. We concluded that the COVID-19 pandemic has negatively impacted most clinical genetics trainees in ACGME-accredited training programs. Telehealth has been increasingly used with some challenges. Further studies are needed on how to optimally integrate what we have learned into the training of medical genetics and genomics in the post-pandemic era.

The Role of Experiments in Monarch Butterfly Conservation: A Review of Recent Studies and Approaches.

Monarch butterflies (Danaus plexippus) (Lepidoptera Danaidae Danaus plexippus (Linnaeus)) are an iconic species of conservation concern due to declines in the overwintering colonies over the past twenty years. Because of this downward trend in overwintering numbers in both California and Mexico, monarchs are currently considered 'warranted-but-precluded' for listing under the Endangered Species Act. Monarchs have a fascinating life history and have become a model system in chemical ecology, migration biology, and host-parasite interactions, but many aspects of monarch biology important for informing conservation practices remain unresolved. In this review, we focus on recent advances using experimental and genetic approaches that inform monarch conservation. In particular, we emphasize three areas of broad importance, which could have an immediate impact on monarch conservation efforts: 1) breeding habitat and host plant use, 2) natural enemies and exotic caterpillar food plants, and 3) the utility of genetic and genomic approaches for understanding monarch biology and informing ongoing conservation efforts. We also suggest future studies in these areas that could improve our understanding of monarch behavior and conservation.

Understanding the classics: the unifying concepts of transgressive segregation, inbreeding depression and heterosis and their central relevance for crop breeding.

Transgressive segregation and heterosis are the reasons that plant breeding works. Molecular explanations for both phenomena have been suggested and play a contributing role. However, it is often overlooked by molecular genetic researchers that transgressive segregation and heterosis are most simply explained by dispersion of favorable alleles. Therefore, advances in molecular biology will deliver the most impact on plant breeding when integrated with sources of heritable trait variation - and this will be best achieved within a quantitative genetics framework. An example of the power of quantitative approaches is the implementation of genomic selection, which has recently revolutionized animal breeding. Genomic selection is now being applied to both hybrid and inbred crops and is likely to be the major source of improvement in plant breeding practice over the next decade. Breeders' ability to efficiently apply genomic selection methodologies is due to recent technology advances in genotyping and sequencing. Furthermore, targeted integration of additional molecular data (such as gene expression, gene copy number and methylation status) into genomic prediction models may increase their performance. In this review, we discuss and contextualize a suite of established quantitative genetics themes relating to hybrid vigour, transgressive segregation and their central relevance to plant breeding, with the aim of informing crop researchers outside of the quantitative genetics discipline of their relevance and importance to crop improvement. Better understanding between molecular and quantitative disciplines will increase the potential for further improvements in plant breeding methodologies and so help underpin future food security.

Organoids: a promising new in vitro platform in livestock and veterinary research.

Organoids are self-organizing, self-renewing three-dimensional cellular structures that resemble organs in structure and function. They can be derived from adult stem cells, embryonic stem cells, or induced pluripotent stem cells. They contain most of the relevant cell types with a topology and cell-to-cell interactions resembling that of the in vivo tissue. The widespread and increasing adoption of organoid-based technologies in human biomedical research is testament to their enormous potential in basic, translational- and applied-research. In a similar fashion there appear to be ample possibilities for research applications of organoids from livestock and companion animals. Furthermore, organoids as in vitro models offer a great possibility to reduce the use of experimental animals. Here, we provide an overview of studies on organoids in livestock and companion animal species, with focus on the methods developed for organoids from a variety of tissues/organs from various animal species and on the applications in veterinary research. Current limitations, and ongoing research to address these limitations, are discussed. Further, we elaborate on a number of fields of research in animal nutrition, host-microbe interactions, animal breeding and genomics, and animal biotechnology, in which organoids may have great potential as an in vitro research tool.

A scoping review of genetics and genomics research ethics policies and guidelines for Africa.

BACKGROUND: Genetics and genomics research (GGR) is increasingly being conducted around the world; yet, researchers and research oversight entities in many countries have struggled with ethical challenges. A range of ethics and regulatory issues need to be addressed through comprehensive policy frameworks that integrate with local environments. While important efforts have been made to enhance understanding and awareness of ethical dimensions of GGR in Africa, including through the H3Africa initiative, there remains a need for in-depth policy review, at a country-level, to inform and stimulate local policy development and revision on the continent. METHODS: To identify and characterize existing ethics-related guidelines and laws applicable to GGR across much of Africa, we conducted a scoping review of English language policy documents identified through databases, repositories, and web searches. Thirty-six documents were included and coded using a framework that contained a range of themes across five analytical categories: (1) respect, (2) beneficence, (3) justice, (4) independent oversight, and (5) bans and prohibitions. Data analysis software (NVivo 12) was used to organize, code, and tabulate information according to document characteristics and topics. Illustrative examples of policy requirements were selected for inclusion. RESULTS: Documents that met inclusion criteria spanned 20 years; published between 1996 and 2018, with the majority (58%) published after 2009. About two-thirds were denoted as "guidelines," and slightly more than half were non-exclusive to GGR. Very few (six) country-level documents identified were specific to GGR. Requirements related to the principle of "respect" appeared most often across all documents, relative to other principles and processes. The most commonly stated ban was on reproductive cloning. Other prohibitions applied to germline editing, undue inducements in research, sample use for commercial purposes, employee mandatory DNA testing, fetal sex selection, stem cell use, eugenics, and research without public health benefits. CONCLUSIONS: Enforceable policies that are indispensable to the ethical conduct and review of GGR are either deficient or missing in many African countries. Existing international, GGR-specific ethics guidelines can be used to inform GGR policy development at a country-level, in conjunction with insight from country specific ethics committees and other local stakeholders.

Integrating Genomic Professional Skills Into Nursing Practice: Results From a Large Cohort of Israeli Nurses.

PURPOSE: To explore the association of genomic knowledge, self-epistemic authority (SEA; i.e., subjective perception of knowledge expertise), perceived importance of genomics in nursing, and the integration of genomic skills into nursing practice. DESIGN: A cross-sectional study of nurses working in pediatric, obstetric, and internal wards of two medical centers in Israel between February and October 2018. METHODS: Participants completed anonymous questionnaires about genomic knowledge, SEA, perceived importance of genomics, and the performance of genomic skills in nursing practice. Associations between variables were analyzed using Pearson correlations, and a hierarchical regression model was used to determine which variables explained the performance of genomic practices among participants. FINDINGS: Altogether 423 nurses participated in the study. The mean genomic knowledge was low (55.05 ± 14.82%). Nurses reported a low integration of genomic skills in their practice (M = 1.90, SD = 0.71), although their overall perceived importance of genomics was positive (M = 2.88, SD = 0.68). Positive correlations were found between SEA and the integration of genomic skills in nursing practice. Obstetric nurses had more genomic knowledge, more positive perceptions about genomics, and performed more genomic skills in their nursing practice. CONCLUSIONS: Although nurses realized the importance of genomics to their practice, and genomics is part of the Israeli nursing core curriculum, we found disappointingly low levels of knowledge and performance of genomic skills in nursing practice. CLINICAL RELEVANCE: The results call for action to establish ongoing education programs in genomics for nurses, which would lead to the inclusion of genomic skills into routine nursing practice, and prepare nurses for providing personalized medicine.

Phosphoproteomic analysis identifies phospho-Threonine-17 site of phospholamban important in low molecular weight isoform of fibroblast growth factor 2-induced protection against post-ischemic cardiac dysfunction.

RATIONALE: Among its many biological roles, fibroblast growth factor 2 (FGF2) protects the heart from dysfunction and damage associated with an ischemic attack. Our laboratory demonstrated that its protection against myocardial dysfunction occurs by the low molecular weight (LMW) isoform of FGF2, while the high molecular weight (HMW) isoforms are associated with a worsening in post-ischemic recovery of cardiac function. LMW FGF2-mediated cardioprotection is facilitated by activation of multiple kinases, including PKCalpha, PKCepsilon, and ERK, and inhibition of p38 and JNK. OBJECTIVE: Yet, the substrates of those kinases associated with LMW FGF2-induced cardioprotection against myocardial dysfunction remain to be elucidated. METHODS AND RESULTS: To identify substrates in LMW FGF2 improvement of post-ischemic cardiac function, mouse hearts expressing only LMW FGF2 were subjected to ischemia-reperfusion (I/R) injury and analyzed by a mass spectrometry (MS)-based quantitative phosphoproteomic strategy. MS analysis identified 50 phosphorylation sites from 7 sarcoendoplasmic reticulum (SR) proteins that were significantly altered in I/R-treated hearts only expressing LMW FGF2 compared to those hearts lacking FGF2. One of those phosphorylated SR proteins identified was phospholamban (PLB), which exhibited rapid, increased phosphorylation at Threonine-17 (Thr17) after I/R in hearts expressing only LMW FGF2; this was further validated using Selected Reaction Monitoring-based MS workflow. To demonstrate a mechanistic role of phospho-Thr17 PLB in LMW FGF2-mediated cardioprotection, hearts only expressing LMW FGF2 and those expressing only LMW FGF2 with a mutant PLB lacking phosphorylatable Thr17 (Thr17Ala PLB) were subjected to I/R. Hearts only expressing LMW FGF2 showed significantly improved recovery of cardiac function following I/R (p < 0.05), and this functional improvement was significantly abrogated in hearts expressing LMW FGF2 and Thr17Ala PLB (p < 0.05). CONCLUSION: The findings indicate that LMW FGF2 modulates intracellular calcium handling/cycling via regulatory changes in SR proteins essential for recovery from I/R injury, and thereby protects the heart from post-ischemic cardiac dysfunction.

Expanding Access to Large-Scale Genomic Data While Promoting Privacy: A Game Theoretic Approach.

Emerging scientific endeavors are creating big data repositories of data from millions of individuals. Sharing data in a privacy-respecting manner could lead to important discoveries, but high-profile demonstrations show that links between de-identified genomic data and named persons can sometimes be reestablished. Such re-identification attacks have focused on worst-case scenarios and spurred the adoption of data-sharing practices that unnecessarily impede research. To mitigate concerns, organizations have traditionally relied upon legal deterrents, like data use agreements, and are considering suppressing or adding noise to genomic variants. In this report, we use a game theoretic lens to develop more effective, quantifiable protections for genomic data sharing. This is a fundamentally different approach because it accounts for adversarial behavior and capabilities and tailors protections to anticipated recipients with reasonable resources, not adversaries with unlimited means. We demonstrate this approach via a new public resource with genomic summary data from over 8,000 individuals-the Sequence and Phenotype Integration Exchange (SPHINX)-and show that risks can be balanced against utility more effectively than with traditional approaches. We further show the generalizability of this framework by applying it to other genomic data collection and sharing endeavors. Recognizing that such models are dependent on a variety of parameters, we perform extensive sensitivity analyses to show that our findings are robust to their fluctuations.

Rice yield formation under high day and night temperatures-A prerequisite to ensure future food security.

Increasing temperatures resulting from climate change dramatically impact rice crop production in Asia. Depending on the specific stage of rice development, heat stress reduces tiller/panicle number, decreases grain number per plant and lower grain weight, thus negatively impacting yield formation. Hence improving rice crop tolerance to heat stress in terms of sustaining yield stability under high day temperature (HDT), high night temperature (HNT), or combined high day and night temperature (HDNT) will bolster future food security. In this review article, we highlight the phenological alterations caused by heat and the underlying molecular-physiological and genetic mechanisms operating under different types of heat conditions (HDT, HNT, and HDNT) to understand heat tolerance. Based on our synthesis of HDT, HNT, and HDNT effects on rice yield components, we outline future breeding strategies to contribute to sustained food security under climate change.

Genetics of Marine Organisms Associated with Human Health.

Marine habitats harbour a large variety of organisms that belong to diverse taxa; from bacteria and unicellular eukaryotes to fungi, animals, and plants. Although we have only started to understand the diversity and structure of marine communities, it is clear that numerous marine species have or might have an impact on human health. Some are a source of natural products with potential or actual medical applications, others are toxic and harmful to humans, and some are used in biomedical research to help understand the molecular basis of human diseases. New molecular genetics and genomic methods provide powerful and ever more indispensable tools for studying marine organisms and all aspects of their influence on human health. Herein, we present work using the latest research, which mostly uses genomics, to tackle the questions related with the topic of the issue.

A Computational Framework Based on Ensemble Deep Neural Networks for Essential Genes Identification.

Essential genes contain key information of genomes that could be the key to a comprehensive understanding of life and evolution. Because of their importance, studies of essential genes have been considered a crucial problem in computational biology. Computational methods for identifying essential genes have become increasingly popular to reduce the cost and time-consumption of traditional experiments. A few models have addressed this problem, but performance is still not satisfactory because of high dimensional features and the use of traditional machine learning algorithms. Thus, there is a need to create a novel model to improve the predictive performance of this problem from DNA sequence features. This study took advantage of a natural language processing (NLP) model in learning biological sequences by treating them as natural language words. To learn the NLP features, a supervised learning model was consequentially employed by an ensemble deep neural network. Our proposed method could identify essential genes with sensitivity, specificity, accuracy, Matthews correlation coefficient (MCC), and area under the receiver operating characteristic curve (AUC) values of 60.2%, 84.6%, 76.3%, 0.449, and 0.814, respectively. The overall performance outperformed the single models without ensemble, as well as the state-of-the-art predictors on the same benchmark dataset. This indicated the effectiveness of the proposed method in determining essential genes, in particular, and other sequencing problems, in general.