Genomic Innovation Research Articles

Review of national rare disease strategies: innovation driving change

Abstract Background A rare disease affects fewer than 5 in 10,000 people. More than 6,000 known rare diseases affect up to 6% of the European population. A national rare disease strategy sets out a country’s plan to reduce disease burden and improve quality of care for people with rare diseases. This review, requested by the Department of Health in Ireland to inform a new national strategy, described national rare disease strategies in 13 selected countries. Methods Strategies published from 2013 to 2023 were identified via online searches for Austria, Australia, Denmark, England, Finland, France, Germany, Ireland, the Netherlands, Northern Ireland, Portugal, Scotland and Wales. National representatives were contacted to confirm the identified resources. Data were extracted for the domains of: aims, priorities, implementation, governance and funding models. Descriptive analysis and narrative synthesis was undertaken. Results Improving treatment and coordination of care was a common overall aim. Priorities noted in all strategies were: screening and diagnosis; access to healthcare and coordination of services; rare disease research; and patient representation and empowerment. Implementation details varied to reflect the national context and time of strategy development. More recently-developed strategies included more precise actions and greater emphasis on innovations in genomics than older strategies. Strategies were developed, implemented, monitored and evaluated via combinations of newly-established bodies and or existing health authorities. Six countries did not specify a funding model or dedicated budget for strategy implementation. Conclusions National rare disease strategy contents and implementation approaches varied between countries and reflected innovations over time. This review will inform the development of Ireland’s new national rare disease strategy. Key messages • This review provided insights into national rare disease strategies over a 10-year period. • The findings will inform strategy development in Ireland, and are relevant to other countries.

Evolution of translational control and the emergence of genes and open reading frames in human and non-human primate hearts.

Evolutionary innovations can be driven by changes in the rates of RNA translation and the emergence of new genes and small open reading frames (sORFs). In this study, we characterized the transcriptional and translational landscape of the hearts of four primate and two rodent species through integrative ribosome and transcriptomic profiling, including adult left ventricle tissues and induced pluripotent stem cell-derived cardiomyocyte cell cultures. We show here that the translational efficiencies of subunits of the mitochondrial oxidative phosphorylation chain complexes IV and V evolved rapidly across mammalian evolution. Moreover, we discovered hundreds of species-specific and lineage-specific genomic innovations that emerged during primate evolution in the heart, including 551 genes, 504 sORFs and 76 evolutionarily conserved genes displaying human-specific cardiac-enriched expression. Overall, our work describes the evolutionary processes and mechanisms that have shaped cardiac transcription and translation in recent primate evolution and sheds light on how these can contribute to cardiac development and disease.

Lessons from Extremophiles: Functional Adaptations and Genomic Innovations across the Eukaryotic Tree of Life.

From hydrothermal vents, to glaciers, to deserts, research in extreme environments has reshaped our understanding of how and where life can persist. Contained within the genomes of extremophilic organisms are the blueprints for a toolkit to tackle the multitude of challenges of survival in inhospitable environments. As new sequencing technologies have rapidly developed, so too has our understanding of the molecular and genomic mechanisms that have facilitated the success of extremophiles. Although eukaryotic extremophiles remain relatively understudied compared to bacteria and archaea, an increasing number of studies have begun to leverage 'omics tools to shed light on eukaryotic life in harsh conditions. In this perspective paper, we highlight a diverse breadth of research on extremophilic lineages across the eukaryotic tree of life, from microbes to macrobes, that are collectively reshaping our understanding of molecular innovations at life's extremes. These studies are not only advancing our understanding of evolution and biological processes but are also offering a valuable roadmap on how emerging technologies can be applied to identify cellular mechanisms of adaptation to cope with life in stressful conditions, including high and low temperatures, limited water availability, and heavy metal habitats. We shed light on patterns of molecular and organismal adaptation across the eukaryotic tree of life and discuss a few promising research directions, including investigations into the role of horizontal gene transfer in eukaryotic extremophiles and the importance of increasing phylogenetic diversity of model systems.

40th Anniversary Virtual Issues: Genomic Innovations in Extremophiles

40th Anniversary Virtual Issues: Genomic Innovations in Extremophiles

Establishing African genomics and bioinformatics programs through annual regional workshops.

The African BioGenome Project (AfricaBP) Open Institute for Genomics and Bioinformatics aims to overcome barriers to capacity building through its distributed African regional workshops and prioritizes the exchange of grassroots knowledge and innovation in biodiversity genomics and bioinformatics. In 2023, we implemented 28 workshops on biodiversity genomics and bioinformatics, covering 11 African countries across the 5 African geographical regions. These regional workshops trained 408 African scientists in hands-on molecular biology, genomics and bioinformatics techniques as well as the ethical, legal and social issues associated with acquiring genetic resources. Here, we discuss the implementation of transformative strategies, such as expanding the regional workshop model of AfricaBP to involve multiple countries, institutions and partners, including the proposed creation of an African digital database with sequence information relating to both biodiversity and agriculture. This will ultimately help create a critical mass of skilled genomics and bioinformatics scientists across Africa.

Conotruncal Heart Defects: A Narrative Review of Molecular Genetics, Genomics Research and Innovation.

Congenital heart defects (CHDs) are most prevalent cardiac defects that occur at birth, leading to significant neonatal mortality and morbidity, especially in the developing nations. Among the CHDs, conotruncal heart defects (CTDs) are particularly noteworthy, comprising a significant portion of congenital cardiac anomalies. While advances in imaging and surgical techniques have improved the diagnosis, prognosis, and management of CTDs, their molecular genetics and genomic substrates remain incompletely understood. This expert review covers the recent advances from January 2016 onward and examines the complexities surrounding the genetic etiologies, prevalence, embryology, diagnosis, and clinical management of CTDs. We also emphasize the known copy number variants and single nucleotide variants associated with CTDs, along with the current planetary health research efforts aimed at CTDs in large cohort studies. In all, this comprehensive narrative review of molecular genetics and genomics research and innovation on CTDs draws from and highlights selected works from around the world and offers new ideas for advances in CTD diagnosis, precision medicine interventions, and accurate assessment of prognosis and recurrence risks.

An Evolving Paradigm in Borderline Resectable and Locally Advanced Pancreatic Cancer: Current Strategies and Opportunities for the Future

Pancreatic ductal adenocarcinoma (PDAC), a cancer of the gastrointestinal tract, has been increasing in incidence, with an estimated doubling worldwide over the past two decades. Despite increases in awareness and innovations in genomics and drug discovery, 5-year survival remains low, at only 10%. This is in part owing to the majority of patients being diagnosed at the advanced stage of the disease, in addition to chemotherapy recalcitrant disease. Surgical resection is necessary for a potential cure, however, this is only possible for the 10% of patients who present with resectable disease and potentially for those with borderline resectable disease. Locally advanced pancreatic cancer accounts for approximately 30% of those with PDAC and most of those patients are often precluded from curative intent surgery due to major vascular invasion and local infiltration into peri-pancreatic soft tissue. In cases of locally advanced disease, induction chemotherapy is often used, identifying the subgroup of patients more suited for local treatments and those who may later develop metastases. The treatment regimens used for patients with locally advanced PDAC are often extrapolated from trials involving patients with metastatic disease. In some cases, responses to neoadjuvant therapy have allowed for surgical resection, albeit these aggressive resections were associated with significant morbidity. There is growing interest in identifying the optimal neoadjuvant treatment for patients with borderline resectable pancreatic cancer (BRPC) and locally advanced PDAC (LAPC) in an effort to improve outcomes. Here we review therapeutic strategies for borderline resectable and locally advanced PDAC, with a focus on novel systemic therapy regimens, chemoradiation, and different radiation modalities.

CRISPR/Cas9 gene targeting plus nanopore DNA sequencing with the plasmid pBR322 in the classroom.

Both nanopore-based DNA sequencing and CRISPR/Cas-based gene editing represent groundbreaking innovations in molecular biology and genomics, offering unprecedented insights into and tools for working with genetic information. For students, reading, editing, and even writing DNA will be part of their everyday life. We have developed a laboratory procedure that includes (i) the biosynthesis of a guide RNA for, (ii) targeting Cas9 to specifically linearize the pBR322 plasmid, and (iii) the identification of the cutting site through nanopore DNA sequencing. The protocol is intentionally kept simple and requires neither living organisms nor biosafety laboratories. We divided the experimental procedures into separate activities to facilitate customization. Assuming access to a well-equipped molecular biology laboratory, an initial investment of approximately $2,700 is necessary. The material costs for each experiment group amount to around $130. Furthermore, we have developed a freely accessible website (https://dnalesen.hs-mittweida.de) for sequence read analysis and visualization, lowering the required computational skills to a minimum. For those with strong computational skills, we provide instructions for terminal-based data processing. With the presented activities, we aim to provide a hands-on experiment that engages students in modern molecular genetics and motivates them to discuss potential implications. The complete experiment can be accomplished within half a day and has been successfully implemented by us at high schools, in teacher training, and at universities. Our tip is to combine CRISPR/Cas gene targeting with nanopore-based DNA sequencing. As a tool, we provide a website that facilitates sequence data analysis and visualization.

Comparative genomics of Ascetosporea gives new insight into the evolutionary basis for animal parasitism in Rhizaria

BackgroundAscetosporea (Endomyxa, Rhizaria) is a group of unicellular parasites infecting aquatic invertebrates. They are increasingly being recognized as widespread and important in marine environments, causing large annual losses in invertebrate aquaculture. Despite their importance, little molecular data of Ascetosporea exist, with only two genome assemblies published to date. Accordingly, the evolutionary origin of these parasites is unclear, including their phylogenetic position and the genomic adaptations that accompanied the transition from a free-living lifestyle to parasitism. Here, we sequenced and assembled three new ascetosporean genomes, as well as the genome of a closely related amphizoic species, to investigate the phylogeny, origin, and genomic adaptations to parasitism in Ascetosporea.ResultsUsing a phylogenomic approach, we confirm the monophyly of Ascetosporea and show that Paramyxida group with Mikrocytida, with Haplosporida being sister to both groups. We report that the genomes of these parasites are relatively small (12–36 Mb) and gene-sparse (~ 2300–5200 genes), while containing surprisingly high amounts of non-coding sequence (~ 70–90% of the genomes). Performing gene-tree aware ancestral reconstruction of gene families, we demonstrate extensive gene losses at the origin of parasitism in Ascetosporea, primarily of metabolic functions, and little gene gain except on terminal branches. Finally, we highlight some functional gene classes that have undergone expansions during evolution of the group.ConclusionsWe present important new genomic information from a lineage of enigmatic but important parasites of invertebrates and illuminate some of the genomic innovations accompanying the evolutionary transition to parasitism in this lineage. Our results and data provide a genetic basis for the development of control measures against these parasites.

Revealing the Satellite DNA Content in Ancistrus sp. (Siluriformes: Loricariidae) by Genomic and Bioinformatic Analysis

Introduction: Eukaryotic genomes are composed of simple, repetitive sequences, including satellite DNAs (satDNA), which are noncoding sequences arranged in tandem arrays. These sequences play a crucial role in genomic functions and innovations, influencing processes such as the maintenance of nuclear material, the formation of heterochromatin and the differentiation of sex chromosomes. In this genomic era, advances in next-generation sequencing and bioinformatics tools have facilitated the exhaustive cataloging of repetitive elements in genomes, particularly in non-model species. This study focuses on the satDNA content of Ancistrus sp., a diverse species of fish from the Loricariidae family. The genus Ancistrus shows significant karyotypic evolution, with extensive variability from the ancestral diploid number. Methods: By means of bioinformatic approaches, 40 satDNA families in Ancistrus sp., constituting 5.19% of the genome were identified. Analysis of the abundance and divergence landscape revealed diverse profiles, indicating recent amplification and homogenization of these satDNA sequences. Results: The most abundant satellite, AnSat1-142, constitutes 2.1% of the genome, while the least abundant, AnSat40-52, represents 0.0034%. The length of the monomer repeat varies from 16 to 142 base pairs, with an average length of 61 bp. These results contribute to understanding the genomic dynamics and evolution of satDNAs in Ancistrus sp. Conclusion: The study underscores the variability of satDNAs between fish species and provides valuable information on chromosome organization and the evolution of repetitive elements in non-model organisms.

Public health genomics research in Italy: an overview of ongoing projects.

Public health genomics (PHG) aims to integrate advances in genomic sciences into healthcare for the benefit of the general population. As in many countries, there are various research initiatives in this field in Italy, but a clear picture of the national research portfolio has never been sketched. Thus, we aimed to provide an overview of current PHG research projects at the national or international level by consultation with Italian institutional and academic experts. We included 68 PHG projects: the majority were international projects in which Italian researchers participated (n = 43), mainly funded by the European Commission, while the remainder were national initiatives (N = 25), mainly funded by central government. Funding varied considerably, from € 50,000 to € 80,803,177. Three main research themes were identified: governance (N = 20); precision medicine (PM; N = 46); and precision public health (N = 2). We found that research activities are preferentially aimed at the clinical application of PM, while other efforts deal with the governance of the complex translation of genomic innovation into clinical and public health practice. To align such activities with national and international priorities, the development of an updated research agenda for PHG is needed.

A Children's Rights Framework for Genomic Medicine: Newborn Screening as a Use Case.

The year 2023 marked the 60th anniversary of screening newborns in the United States for diseases that benefit from early identification and intervention. All around the world, the goal of NBS is to facilitate timely diagnosis and management to improve individual health outcomes in all newborns regardless of their place of birth, economic circumstances, ability to pay for treatment, and access to healthcare. Advances in technology to screen and treat disease have led to a rapid increase in the number of screened conditions, and innovations in genomics are expected to exponentially expand this number further. A system where all newborns are screened, coupled with rapid technological innovation, provides a unique opportunity to improve pediatric health outcomes and advance children's rights, including the unique rights of sick and disabled children. This is especially timely as we approach the 100th anniversary of the 1924 Geneva Declaration of the Rights of the Child, which includes children's right to healthcare, and the 1989 United Nations Convention on the Rights of the Child that expanded upon this aspect and affirmed each child's right to the highest attainable standard of health. In this manuscript, we provide background on the evolving recognition of the rights of children and the foundational rights to healthcare and non-discrimination, provide two examples that highlight issues to access and equity in newborn screening that may limit a child's right to healthcare and best possible outcomes, detail ways the current approach to newborn screening advances the rights of the child, and finally, propose that the incorporation of genomics into newborn screening presents a useful case study to recognize and uphold the rights of every child.

Plant kinetochore complex: composition, function, and regulation.

The kinetochore complex, an important protein assembly situated on the centromere, plays a pivotal role in chromosome segregation during cell division. Like in animals and fungi, the plant kinetochore complex is important for maintaining chromosome stability, regulating microtubule attachment, executing error correction mechanisms, and participating in signaling pathways to ensure accurate chromosome segregation. This review summarizes the composition, function, and regulation of the plant kinetochore complex, emphasizing the interactions of kinetochore proteins with centromeric DNAs (cenDNAs) and RNAs (cenRNAs). Additionally, the applications of the centromeric histone H3 variant (the core kinetochore protein CENH3, first identified as CENP-A in mammals) in the generation of ploidy-variable plants and synthesis of plant artificial chromosomes (PACs) are discussed. The review serves as a comprehensive roadmap for researchers delving into plant kinetochore exploration, highlighting the potential of kinetochore proteins in driving technological innovations in synthetic genomics and plant biotechnology.

The motivation and process for developing a consortium-wide time and motion study to estimate resource implications of innovations in the use of genome sequencing to inform patient care.

Costs of implementing genomic testing innovations extend beyond the cost of sequencing, affecting personnel and infrastructure for which little data are available. We developed a time and motion (T&M) study within the Clinical Sequencing Evidence-Generating Research (CSER) consortium to address this gap, and herein describe challenges of conducting T&M studies within a research consortium and the approaches we developed to overcome them. CSER investigators created a subgroup to carry out the T&M study (authors). We describe logistical and administrative challenges associated with resource use data collection across heterogeneous projects conducted in real-world clinical settings, and our solutions for completing this study and harmonizing data across projects. We delineate processes for feasible data collection on workflow, personnel, and resources required to deliver genetic testing innovations in each CSER project. A critical early step involved developing detailed project-specific process flow diagrams of innovation implementation in projects' clinical settings. Analyzing diagrams across sites, we identified common process-step themes, used to organize project-specific data collection and cross-project analysis. Given the heterogeneity of innovations, study design, and workflows, which affect resources required to deliver genetic testing innovations, flexibility was necessary to harmonize data collection. Despite its challenges, this heterogeneity provides rich insights about variation in clinical processes and resource implications for implementing genetic testing innovations.

Quantification and modeling of turnover dynamics of de novo transcripts in Drosophila melanogaster.

Most of the transcribed eukaryotic genomes are composed of non-coding transcripts. Among these transcripts, some are newly transcribed when compared to outgroups and are referred to as de novo transcripts. De novo transcripts have been shown to play a major role in genomic innovations. However, little is known about the rates at which de novo transcripts are gained and lost in individuals of the same species. Here, we address this gap and estimate the de novo transcript turnover rate with an evolutionary model. We use DNA long reads and RNA short reads from seven geographically remote samples of inbred individuals of Drosophila melanogaster to detect de novo transcripts that are gained on a short evolutionary time scale. Overall, each sampled individual contains around 2500 unspliced de novo transcripts, with most of them being sample specific. We estimate that around 0.15 transcripts are gained per year, and that each gained transcript is lost at a rate around 5× 10-5 per year. This high turnover of transcripts suggests frequent exploration of new genomic sequences within species. These rate estimates are essential to comprehend the process and timescale of de novo gene birth.

Examining the Relationship between Attitudes Towards Genomic Technology and Genetic Entrepreneurial Intention among Egyptian Healthcare Professionals

In the contemporary landscape, nurturing genomic entrepreneurial attitudes and intentions poses a substantial challenge for healthcare organizations. The present paper examines the factors affecting attitudes towards genomic technology and entrepreneurial intentions among Egyptian healthcare professionals. The study applied a quantitative approach and collected cross-sectional data from 276 health professionals using convenience sampling. Using structural equation modeling (SEM) through SmartPLS 4, the findings suggest a positive significant effect of innovation and genomic knowledge on attitudes towards genetic technology. On the other hand, risk perception negatively predicts attitudes towards genetic technology. Finally, the path analysis also confirmed a positive significant effect of attitudes towards genetic technology on entrepreneurial intention. The study's findings would help develop policies regarding genomic innovation among healthcare professionals. Unraveling the dynamics at the genomics-entrepreneurship intersection empowers healthcare professionals to seize genomic technology opportunities, advancing the healthcare sector.

A chromosome-level reference genome for the common octopus, Octopus vulgaris (Cuvier, 1797).

Cephalopods are emerging animal models and include iconic species for studying the link between genomic innovations and physiological and behavioral complexities. Coleoid cephalopods possess the largest nervous system among invertebrates, both for cell counts and brain-to-body ratio. Octopus vulgaris has been at the center of a long-standing tradition of research into diverse aspects of cephalopod biology, including behavioral and neural plasticity, learning and memory recall, regeneration, and sophisticated cognition. However, no chromosome-scale genome assembly was available for O. vulgaris to aid in functional studies. To fill this gap, we sequenced and assembled a chromosome-scale genome of the common octopus, O. vulgaris. The final assembly spans 2.8 billion basepairs, 99.34% of which are in 30 chromosome-scale scaffolds. Hi-C heatmaps support a karyotype of 1n = 30 chromosomes. Comparisons with other octopus species' genomes show a conserved octopus karyotype and a pattern of local genome rearrangements between species. This new chromosome-scale genome of O. vulgaris will further facilitate research in all aspects of cephalopod biology, including various forms of plasticity and the neural machinery underlying sophisticated cognition, as well as an understanding of cephalopod evolution.

Genomic Insights into Mollusc terrestrialization: Parallel and Convergent Gene Family Expansions as Key Facilitators in out-of-the-sea transitions.

Animals abandoned their marine niche and successfully adapted to life on land multiple times throughout evolution, providing a rare opportunity to study the mechanisms driving large scale macroevolutionary convergence. However, the genomic factors underlying this process remain largely unknown. Here, we investigate the macroevolutionary dynamics of gene repertoire evolution during repeated transitions out of the sea in molluscs, a lineage that has transitioned to freshwater and terrestrial environments multiple independent times. Through phylogenomics and phylogenetic comparative methods, we examine approximately 100 genomic datasets encompassing all major molluscan lineages. We introduce a conceptual framework for identifying and analyzing parallel and convergent evolution at the orthogroup level (groups of genes derived from a single ancestral gene in the species in question), and explore the extent of these mechanisms. Despite deep temporal divergences, we found that parallel expansions of ancient gene families played a major role in facilitating adaptation to non-marine habitats, highlighting the relevance of the pre-existing genomic toolkit in facilitating adaptation to new environments. The expanded functions primarily involve metabolic, osmoregulatory, and defense-related systems. We further found functionally convergent lineage-exclusive gene gains, while family contractions appear to be driven by neutral processes. Also, genomic innovations likely contributed to fuel independent habitat transitions. Overall, our study reveals that various mechanisms of gene repertoire evolution -parallelism, convergence and innovation- can simultaneously contribute to major evolutionary transitions. Our results provide a genome-wide gene repertoire atlas of molluscan terrestrialization that pave the way towards further understanding the functional and evolutionary bases of this process.

Enhancing biosecurity against virus disease threats to Australian grain crops: current situation and future prospects

Australia is a major grain exporter, and this trade makes an important contribution to its economy. Fortunately, it remains free of many damaging virus diseases and virus vectors found elsewhere. However, its crop biosecurity is under increasing pressure from global ecological, climatic, and demographic challenges. Stringent biosecurity and plant health programs safeguard Australian grain production from damaging virus and virus vector incursions entering via different pathways. These programs formerly relied upon traditional testing procedures (indicator hosts, serology, PCRs) to intercept incoming virus-contaminated plant material. Recently, the integration of rapid genomic diagnostics innovation involving High Throughput Sequencing (HTS) smart tools into sample testing schedules is under exploration to improve virus testing accuracy, efficiency, and cost effectiveness under diverse circumstances. This process includes evaluating deployment of Illumina and Oxford Nanopore Technology shotgun sequencing. It also includes evaluating targeted viral genome HTS and virus vector metabarcoding approaches. In addition, using machine learning and deep learning capacities for big data analyses and remote sensing technologies will improve virus surveillance. Tracking damaging virus variants will be improved by surveillance networks which combine virus genomic-surveillance systems with an interoperable virus database. Sequencing Australian virus specimen collections will help ensure the accuracy of virus identifications based solely on genetic information. Enhancing routine diagnosis and data collection using these innovations will improve post entry virus interception and background virus and vector surveillance. This will help reduce the frequency of new incursions, improve virus management during eradication, containment and other plant health activities, and achieve more profitable Australian grain production.

Cas9-targeted Nanopore sequencing rapidly elucidates the transposition preferences and DNA methylation profiles of mobile elements in plants.

Transposable element insertions (TEIs) are an important source of genomic innovation by contributing to plant adaptation, speciation, and the production of new varieties. The often large, complex plant genomes make identifying TEIs from short reads difficult and expensive. Moreover, rare somatic insertions that reflect mobilome dynamics are difficult to track using short reads. To address these challenges, we combined Cas9-targeted Nanopore sequencing (CANS) with the novel pipeline NanoCasTE to trace both genetically inherited and somatic TEIs in plants. We performed CANS of the EVADÉ (EVD) retrotransposon in wild-type Arabidopsis thaliana and rapidly obtained up to 40× sequence coverage. Analysis of hemizygous T-DNA insertion sites and genetically inherited insertions of the EVD transposon in the ddm1 (decrease in DNA methylation 1) genome uncovered the crucial role of DNA methylation in shaping EVD insertion preference. We also investigated somatic transposition events of the ONSEN transposon family, finding that genes that are downregulated during heat stress are preferentially targeted by ONSENs. Finally, we detected hypomethylation of novel somatic insertions for two ONSENs. CANS and NanoCasTE are effective tools for detecting TEIs and exploring mobilome organization in plants in response to stress and in different genetic backgrounds, as well as screening T-DNA insertion mutants and transgenic plants.