Genomic Revolution Research Articles

Genetic and other omics-based information in the most-cited recent clinical trials

Abstract Introduction Since the genomic revolution, the utilization of genetic and omics technologies has undergone considerable expansion within clinical studies, employed in design, analysis, and interpretation. Methods A recent study of Siena et al. developed a database containing the 600 most cited clinical trials published from 2019 to 2022. Building on this database, the aim of our study is to assess how frequently genetic and other omics-based information has been used in the design, analysis, results or conclusion of these recent influential trials. Results 132 out 600 (22%) trials used genetic or other omics. These trials were more likely to be oncology trials (76%vs34%), having industry funding (59%vs47%), and having industry authors (75%vs54%) than others. Overall, genetics and genomics were present in 75% of the trials (100/132), and oncology was the predominant medical field (76%, n = 101). The prevailing use was detection of specific mutations (n = 99), often (n = 60) used as eligibility criterion. These mutations were mostly somatic (n = 85), while 14 were germline. Other applications included transcriptomics (20.4%), proteomics (10.6%), metabolomics (8.3%) and metagenomics (8.3%). 36 studies (27%) employed multiple applications. Genetics or other omics were used in 10% of the studies (14/132) for randomization stratification and in 63% (83/132) to conduct subgroup analysis. Among the latter, in 48% (40/83) the presence of a somatic mutation was significantly associated with the investigated health outcomes, while germline mutation or other omics only in the 12% (10/83). In the trials conclusions, authors addressed the relevance of the genetic or omics information in 62.1% (82/132) of the trials. Conclusions A sizeable proportion of the most-cited clinical trials use genetics or omics-based information, but the large majority pertains to cancer mutations in oncology trials. Use of genetics and omics needs to become more common in other clinical trial fields. Key messages • Genetic profiling and omics applications should be incorporated into trial design. • Genomic research is mostly oncology related and it needs to be expanded to other medical fields.

Bacterial live therapeutics for human diseases.

The genomic revolution has fueled rapid progress in synthetic and systems biology, opening up new possibilities for using live biotherapeutic products (LBP) to treat, attenuate or prevent human diseases. Among LBP, bacteria-based therapies are particularly promising due to their ability to colonize diverse human tissues, modulate the immune system and secrete or deliver complex biological products. These bacterial LBP include engineered pathogenic species designed to target specific diseases, and microbiota species that promote microbial balance and immune system homeostasis, either through local administration or the gut-body axes. This review focuses on recent advancements in preclinical and clinical trials of bacteria-based LBP, highlighting both on-site and long-reaching strategies.

Decoding the Genomic Revolution: The Impact of Machine Learning on Personalized Medicine

Decoding the Genomic Revolution: The Impact of Machine Learning on Personalized Medicine

Bringing the Genomic Revolution to Comparative Oncology: Human and Dog Cancers.

Dogs are humanity's oldest friend, the first species we domesticated 20,000-40,000years ago. In this unequaled collaboration, dogs have inadvertently but serendipitously been molded into a potent human cancer model. Unlike many common model species, dogs are raised in the same environment as humans and present with spontaneous tumors with human-like comorbidities, immunocompetency, and heterogeneity. In breast, bladder, blood, and several pediatric cancers, in-depth profiling of dog and human tumors has established the benefits of the dog model. In addition to this clinical and molecular similarity, veterinary studies indicate that domestic dogs have relatively high tumor incidence rates. As a result, there are a plethora of data for analysis, the statistical power of which is bolstered by substantial breed-specific variability. As such, dog tumors provide a unique opportunity to interrogate the molecular factors underpinning cancer and facilitate the modeling of new therapeutic targets. This review discusses the emerging field of comparative oncology, how it complements human and rodent cancer studies, and where challenges remain, given the rapid proliferation of genomic resources. Increasingly, it appears that human's best friend is becoming an irreplaceable component of oncology research.

Prevalence rates for ectodermal dysplasia syndromes.

Ectodermal dysplasias (EDs) are a heterogeneous group of genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. There are currently 49 recognized EDs with molecularly confirmed etiology. The EDs are very rare disorders, individually and in aggregate. Very little is published regarding the prevalence of these rare disorders. As a result of the genomics revolution, rare diseases have emerged as a global health priority. The various disabilities arising from rare disorders, as well as diagnostic and treatment uncertainty, have been demonstrated to have detrimental effects on the health, psychosocial, and economic aspects of families affected by rare disorders. Contemporary research methodologies and databases can address what have been historic challenges encountered when conducting research on rare diseases. In this study, we aim to ascertain period prevalence rates for several of the more common ectodermal dysplasia syndromes, by querying a large multicenter database of electronic health records, Oracle Real-World Data. For each of the included ectodermal dysplasia syndromes a clinical definition was developed by a committee of international experts with interests in EDs. The clinical definitions were based upon a combination of clinical features and designated by ICD-9 and ICD-10 codes. The January 2023 version of the Oracle Real-World Data database was queried for medical records that coincided with the clinical definitions. For our study, there were 64,523,460 individual medical records queried. Period prevalence rates were calculated for the following ED disorders: hypohidrotic ectodermal dysplasia, found to be 2.99 per 100,000; ectodermal dysplasia and immunodeficiency 1, 0.23 per 100,000; Clouston syndrome, 0.15 per 100,000; ectrodactyly ectodermal dysplasia and cleft lip/palate syndrome, 0.61 per 100,000; ankyloblepharon-ectodermal defects-cleft lip/palate syndrome, 0.36 per 100,000; focal dermal hypoplasia, 0.10 per 100,000; and incontinentia pigmenti, 0.88 per 100,000. This study established estimated period prevalence rates for several of the ectodermal dysplasia syndromes, and it demonstrated the feasibility of utilizing large multicenter databases of electronic health records, such as Oracle Real World Data.

The potential and translational application of infant genetic research.

In the current genomic revolution, the infancy life stage is the most neglected. Although clinical genetics recognizes the value of early identification in infancy of rare genetic causes of disorders and delay, common genetic variation is almost completely ignored in research on infant behavioral and neurodevelopmental traits. In this Perspective, we argue for a much-needed surge in research on common genetic variation influencing infant neurodevelopment and behavior, findings that would be relevant for all children. We now see convincing evidence from different research designs to suggest that developmental milestones, skills and behaviors of infants are heritable and thus are suitable candidates for gene-discovery research. We highlight the resources available to the field, including genotyped infant cohorts, and we outline, with recommendations, special considerations needed for infant data. Therefore, infant genetic research has the potential to impact basic science and to affect educational policy, public health and clinical practice.

From Sanger to genome sequencing - an overview of DNA sequencing technologies

There is no technique that would make a greater contribution to the development of genetics, molecular biology and medicine than DNA sequencing. For many years, the method based on enzymatic DNA synthesis developed by Frederic Sanger was the gold standard in this area. At the end of the 20th century, there was a dynamic development of next-generation sequencing (NGS) technologies, which ended the era of single gene analysis and initiated the era of genome sequencing. Despite fierce competition, one NGS technology has practically completely dominated the global market. In the article, we present our own review of DNA sequencing methods, starting from the Sanger method to high-throughput second- and third-generation sequencing technologies, with particular emphasis on those that have achieved commercial success. We present their short history, principles of operation, technical possibilities, applications and limitations. In the summary, we reveal how much human genome sequencing costs at the current stage of the genomic revolution and outline the prospects for further development of genomics.

Delimiting the rare, endangered and actively speciating.

Species delimitation is a contentious topic. The genomics revolution initially brought hope that identifying and classifying species would be easier through better methods and more data, but genomics has also brought complexity and controversy to delimitation. One solution can be to collect a larger sample of individuals at a finer geographic scale. But what if taxa are rare and collecting more samples is difficult or detrimental to the organisms at hand? In this issue of Molecular Ecology Resources, Opatova etal. (2023) tackle the ambiguity of species delimitation in rare and endangered trapdoor spiders (genus Cyclocosmia). The authors propose a framework for delimiting species when samples are hard to come by, such as in these rare and cryptic spiders. The authors combine extensive genomic sampling with statistical approaches that consider both the genetic distinctiveness of each population of spiders and how much gene flow occurs between these populations. Their proposed taxonomy balances two opposing signals, structure and gene flow, to count eight lineages of Cyclocosmia, and to point the way for future taxonomic studies of the rare or difficult to obtain.

Exploring an immortal Turritopsis sp. as a less conventional natural system for study of aging

AimGiven its excellent capability of escaping from unavoidable harm and death, Turritopsissp. (T. sp.) has captured the attention and fascination of scientists as a less conventional tool for aging research. The current study introduces a method for establishment of a research model and comprehensive transcriptomic analysis to reveal the structural and functional diversity of T. sp. MethodsT. sp. medusae collected from the Pacific Ocean near Japan were reared using a common laboratory setting. Tissues of the gastrovascular cavity part (GP) and nerve ring part (NP) were collected, and total RNA was extracted. Bulk RNA-seq was performed to compare the different transcriptome landscapes between GP and NP. ResultsThe GP fragment could be utilized for studies related to stress response and systemic senescence, while the NP fragment could be used to explore system rejuvenation, self-repair and regeneration. ConclusionsAs a less conventional system for aging research, by employing the most recently developed tools and techniques in the genomic revolution, comprehensive elucidation of the composition, development, and functions of T. sp. enabled us to explore the underlying mechanisms of the response to environmental stress and rejuvenation.

Optimized whole-genome sequencing workflow for tumor diagnostics in routine pathology practice.

Two decades after the genomics revolution, oncology is rapidly transforming into a genome-driven discipline, yet routine cancer diagnostics is still mainly microscopy based, except for tumor type-specific predictive molecular tests. Pathology laboratories struggle to quickly validate and adopt biomarkers identified by genomics studies of new targeted therapies. Consequently, clinical implementation of newly approved biomarkers suffers substantial delays, leading to unequal patient access to these therapies. Whole-genome sequencing (WGS) can successfully address these challenges by providing a stable molecular diagnostic platform that allows detection of a multitude of genomic alterations in a single cost-efficient assay and facilitating rapid implementation, as well as by the development of new genomic biomarkers. Recently, the Whole-genome sequencing Implementation in standard Diagnostics for Every cancer patient (WIDE) study demonstrated that WGS is a feasible and clinically valid technique in routine clinical practice with a turnaround time of 11 workdays. As a result, WGS was successfully implemented at the Netherlands Cancer Institute as part of routine diagnostics in January 2021. The success of implementing WGS has relied on adhering to a comprehensive protocol including recording patient information, sample collection, shipment and storage logistics, sequencing data interpretation and reporting, integration into clinical decision-making and data usage. This protocol describes the use of fresh-frozen samples that are necessary for WGS but can be challenging to implement in pathology laboratories accustomed to using formalin-fixed paraffin-embedded samples. In addition, the protocol outlines key considerations to guide uptake of WGS in routine clinical care in hospitals worldwide.

Green revolution to genome revolution: driving better resilient crops against environmental instability.

Crop improvement programmes began with traditional breeding practices since the inception of agriculture. Farmers and plant breeders continue to use these strategies for crop improvement due to their broad application in modifying crop genetic compositions. Nonetheless, conventional breeding has significant downsides in regard to effort and time. Crop productivity seems to be hitting a plateau as a consequence of environmental issues and the scarcity of agricultural land. Therefore, continuous pursuit of advancement in crop improvement is essential. Recent technical innovations have resulted in a revolutionary shift in the pattern of breeding methods, leaning further towards molecular approaches. Among the promising approaches, marker-assisted selection, QTL mapping, omics-assisted breeding, genome-wide association studies and genome editing have lately gained prominence. Several governments have progressively relaxed their restrictions relating to genome editing. The present review highlights the evolutionary and revolutionary approaches that have been utilized for crop improvement in a bid to produce climate-resilient crops observing the consequence of climate change. Additionally, it will contribute to the comprehension of plant breeding succession so far. Investing in advanced sequencing technologies and bioinformatics will deepen our understanding of genetic variations and their functional implications, contributing to breakthroughs in crop improvement and biodiversity conservation.

Linking race and genes: racial conceptualization among genetic ancestry test-takers

ABSTRACT The genomic revolution is highly relevant to scholarship on racial conceptualization. As genomic research has increasingly focused on small amounts of variation between ancestral groups, it may promote beliefs in racial essentialism. Genetic ancestry tests (GATs) are one of the primary ways the consequences of the genomic revolution are communicated to laypersons, necessitating a better understanding of how test-takers conceptualize race. We analyse 108 in-depth interviews with U.S. and Canadian test-takers to examine how they conceptualize the relationship between race and genes and how they believe GATs influenced their race concepts. We present a typology of racial conceptualization that moves beyond a dichotomy and toward a continuum between social constructivism and genetic essentialism. We also find that test-takers believe GATs reinforce their pre-existing race concepts, regardless of what those were. Our results support an emerging view that people selectively interpret genetic information to confirm rather than transform their race concepts.

Patterns of actionable biomarker testing in lung cancer patients: Disparity or an opportunity for improvement.

e21211 Background: In 2018, lung cancer represented about 13% of new cancer diagnosis but was still the leading cause of cancer deaths at 25%. In the last five years, rates of new cases of lung cancer have decreased by 11% and survival has increased 21% nationally; largely due to advancements in screening, diagnosis and expanding treatment modalities, including targeted therapies geared toward specific molecular alterations. Despite these advancements, there are still shortcomings in terms of next generation sequencing (NGS) utilization for detection of molecular aberrations. A recent query of 37,925 patients with stage IV non-small cell lung cancer (NSCLC), diagnosed between 2010 and 2018 discovered that only 22% of all patients had any molecular testing. Only 3% of these patients received any form of targeted therapy. This further illustrates the ongoing gap between molecular diagnostics and its clinical utilization. Methods: Our project serves to assess this shortcoming in our patient population. In this retrospective chart review and quality improvement project, the goal was to identify the limitations that led to delays or omittance of timely NGS in patients with newly diagnosed NSCLC. Under an IRB approval, a system was created where once a biopsy was confirmed to be NSCLC, tissue was sent for NGS. Prior to this intervention, molecular testing had to be ordered by an Oncologist after the patient was seen in clinic, generally during their first outpatient appointment or when discussed in multidisciplinary meetings. Additionally, testing was shifted from individual molecular studies, which would frequently exhaust tissue sample, to only comprehensive panels. Results: The charts of 194 patients with newly diagnosed NSCLC between 2014 and 2022 were analyzed. Of these patients, 125 patients (64.4%) had completion of at least one molecular test. 36 patients (18.6%) had only been tested for programmed death-ligand 1 (PDL1) and 33 patients (17.0%) had no immunohistochemical or molecular testing following biopsy results. The time from biopsy to completion of molecular testing was compared to 34 patients following implementation of our protocol. The median time from biopsy to availability of results was 29 days before our intervention and decreased to 23 days afterwards. Additionally, molecular testing increased to 100% in our newly diagnosed NSCLC patient population. Conclusions: As the genomic revolution continues and the importance of targeted therapy for NSCLC in both the adjuvant and metastatic setting progresses, timely next generation sequencing will be paramount for optimal treatment selection. Our project shows that through the implementation of systems codeveloped between medical oncology and anatomic pathology, turnaround times of molecular testing can be greatly improved and widely implemented.

High-resolution structural variants catalogue in a large-scale whole genome sequenced bovine family cohort data

BackgroundStructural variants (SVs) are chromosomal segments that differ between genomes, such as deletions, duplications, insertions, inversions and translocations. The genomics revolution enabled the discovery of sub-microscopic SVs via array and whole-genome sequencing (WGS) data, paving the way to unravel the functional impact of SVs. Recent human expression QTL mapping studies demonstrated that SVs play a disproportionally large role in altering gene expression, underlining the importance of including SVs in genetic analyses. Therefore, this study aimed to generate and explore a high-quality bovine SV catalogue exploiting a unique cattle family cohort data (total 266 samples, forming 127 trios).ResultsWe curated 13,731 SVs segregating in the population, consisting of 12,201 deletions, 1,509 duplications, and 21 multi-allelic CNVs (> 50-bp). Of these, we validated a subset of copy number variants (CNVs) utilising a direct genotyping approach in an independent cohort, indicating that at least 62% of the CNVs are true variants, segregating in the population. Among gene-disrupting SVs, we prioritised two likely high impact duplications, encompassing ORM1 and POPDC3 genes, respectively. Liver expression QTL mapping results revealed that these duplications are likely causing altered gene expression, confirming the functional importance of SVs. Although most of the accurately genotyped CNVs are tagged by single nucleotide polymorphisms (SNPs) ascertained in WGS data, most CNVs were not captured by individual SNPs obtained from a 50K genotyping array.ConclusionWe generated a high-quality SV catalogue exploiting unique whole genome sequenced bovine family cohort data. Two high impact duplications upregulating the ORM1 and POPDC3 are putative candidates for postpartum feed intake and hoof health traits, thus warranting further investigation. Generally, CNVs were in low LD with SNPs on the 50K array. Hence, it remains crucial to incorporate CNVs via means other than tagging SNPs, such as investigation of tagging haplotypes, direct imputation of CNVs, or direct genotyping as done in the current study. The SV catalogue and the custom genotyping array generated in the current study will serve as valuable resources accelerating utilisation of full spectrum of genetic variants in bovine genomes.

Single-cell Genomics: A Quantum Leap toward Understanding Complexity?

Single-cell Genomics: A Quantum Leap toward Understanding Complexity?

Patent Regulation in the Field of Genome: Trends, Problems, Prospects

The paper examines the situation that has developed in recent years in the field of patenting the results of genomic and genetic research and manipulation, the main trends and possible ways of developing relations and regulation in this area. This includes the role of Russia and the BRICS countries in the future world order, where genetic and genomic technologies and the fruits of their application will (and partly are already) one of the most important values. The author analyzes the existing and possible forms of securing rights to these values for copyright holders, and accounts the difference between genetics and genomics (and the gradual erosion of this difference with the appearance of «designer genes»). The author concludes that now there is no sufficiently developed, reasonable and workable alternative to the existing system of protection of the rights to the achievements of genetics and genomics while maintaining the expediency of searching for such an alternative. The existing system provides unreasonably many advantages to individual corporations and states that have managed to secure the largest possible amount of rights to the achievements of genetics and genomics. The paper analyzes some international acts designed to ensure a fair distribution of benefits between the owners of advanced technologies and the «suppliers» of the original genetic material. These have so far been undeservedly ignored in our country, but are gaining new significance in the course of the ongoing «genomic revolution» based on the mass application of the CRISPR-Cas genomic editing method. Possible directions for coordinated actions of the BRICS countries on patent cooperation in relation to the results of genomic and genetic research and manipulation are proposed. As one of the conclusions, it is indicated that the use of BRICS as a platform for building a better future for all mankind, and not only for patent holders, fully corresponds to the role and prospects of BRICS in the modern international system, stated in the Concept of the Participation of the Russian Federation in the BRICS association.

How Latin America's genomics revolution began - and why the field is under threat.

How Latin America's genomics revolution began - and why the field is under threat.

New Therapeutic Approaches to Inherited Metabolic Pediatric Epilepsies.

Treatment options for inherited metabolic epilepsies are rapidly expanding with advances in molecular biology and the genomic revolution. Traditional dietary and nutrient modification and inhibitors or enhancers of protein and enzyme function, the mainstays of therapy, are undergoing continuous revisions to increase biological activity and reduce toxicity. Enzyme replacement and gene replacement and editing hold promise for genetically targeted treatment and cures. Molecular, imaging, and neurophysiologic biomarkers are emerging as key indicators of disease pathophysiology, severity, and response to therapy.

An adagio for viruses, played out on ancient DNA.

Studies of ancient DNA have transformed our understanding of human evolution. Palaeogenomics can also reveal historic and prehistoric agents of disease, including endemic, epidemic and pandemic pathogens. Viruses - and in particular those with single or double-stranded DNA genomes - are an important part of the palaeogenomic revolution, preserving within some remains or environmental samples for tens of thousands of years. The results of these studies capture the public imagination, as well as giving scientists a unique perspective on some of the more slowly-evolving viruses which cause disease. In this review, we will revisit the first studies of historical virus genetic material in the 1990s, through to the genomic revolution of recent years. We will look at how palaeogenomics works for viral pathogens, such as the need for careful precautions against modern contamination, and robust computational pipelines to identify and analyse authenticated viral sequences. We will discuss the insights into virus evolution which have been gained through palaeogenomics, concentrating on three DNA viruses in particular: parvovirus B19, herpes simplex virus 1, and smallpox. As we consider recent worldwide transmission of monkeypox and synthetic biology tools that allow the potential reconstruction of extinct viruses, we show that studying historical and ancient virus evolution has never been more topical.

Using omics to breathe new life into our understanding of the ductus arteriosus oxygen response

The ductus arteriosus (DA) connects the aorta to the pulmonary artery (PA), directing placentally oxygenated blood away from the developing lungs. High pulmonary vascular resistance and low systemic vascular resistance facilitate shunting of blood in utero from the pulmonary to the systemic circulation through the widely patent DA, thereby optimizing fetal oxygen (O2) delivery. With the transition from fetal (hypoxia) to neonatal (normoxia) oxygen conditions, the DA constricts while the PA dilates. This process often fails in prematurity, promoting congenital heart disease. Impaired O2-responsivness in the DA promotes persistent ductus arteriosus (PDA), the most common form of congenital heart disease. Knowledge of DA oxygen sensing has greatly advanced in the past few decades, however we still lack a complete understanding of the sensing mechanism. The genomic revolution of the past two decades has facilitated unprecedented discovery in every biological system. This review will demonstrate how multiomic integration of data generated from the DA can breathe new life into our understanding of the DA's oxygen response.