Human Genome Project Research Articles

Green Day: An Interview with NHGRI Director Eric Green

Green Day: An Interview with NHGRI Director Eric Green

The Long and Winding Road: On-Demand DNA Synthesis in High Demand

The Long and Winding Road: On-Demand DNA Synthesis in High Demand

Billion-Dollar Drugs with Misallocated Rewards

Billion-Dollar Drugs with Misallocated Rewards

Maximizing the utility of public data.

The human genome project galvanized the scientific community around an ambitious goal. Upon completion, the project delivered several discoveries, and a new era of research commenced. More importantly, novel technologies and analysis methods materialized during the project period. The cost reduction allowed many more labs to generate high-throughput datasets. The project also served as a model for other extensive collaborations that generated large datasets. These datasets were made public and continue to accumulate in repositories. As a result, the scientific community should consider how these data can be utilized effectively for the purposes of research and the public good. A dataset can be re-analyzed, curated, or integrated with other forms of data to enhance its utility. We highlight three important areas to achieve this goal in this brief perspective. We also emphasize the critical requirements for these strategies to be successful. We draw on our own experience and others in using publicly available datasets to support, develop, and extend our research interest. Finally, we underline the beneficiaries and discuss some risks involved in data reuse.

Whole‐exome sequencing analyses in a Saudi Ischemic Stroke Cohort reveal association signals, and shows polygenic risk scores are related to Modified Rankin Scale Risk

Ischemic stroke represents a significant societal burden across the globe. Rare high penetrant monogenic variants and less pathogenic common single nucleotide polymorphisms (SNPs) have been described as being associated with risk of diseases. Genetic studies in Saudi Arabian patients offer a greater opportunity to detect rare high penetrant mutations enriched in these consanguineous populations. We performed whole exome sequencing on 387 ischemic stroke subjects from Saudi Arabian hospital networks with up to 20,230 controls from the Saudi Human Genome Project and performed gene burden analyses of variants in 177 a priori loci derived from knowledge-driven curation of monogenic and genome-wide association studies of stroke. Using gene-burden analyses, we observed significant associations in numerous loci under autosomal dominant and/or recessive modelling. Stroke subjects with modified Rankin Scale (mRSs) above 3 were found to carry greater cumulative polygenic risk score (PRS) from rare variants in stroke genes (standardized PRS mean > 0) compared to the population average (standardized PRS mean = 0). However, patients with mRS of 3 or lower had lower cumulative genetic risk from rare variants in stroke genes (OR (95%CI) = 1.79 (1.29–2.49), p = 0.0005), with the means of standardized PRS at or lower than 0. In conclusion, gene burden testing in Saudi stroke populations reveals a number of statistically significant signals under different disease inheritance models. However, interestingly, stroke subjects with mRS of 3 or lower had lower cumulative genetic risk from rare variants in stroke genes and therefore, determining the potential mRS cutoffs to use for clinical significance may allow risk stratification of this population.

A Short Review on 4P Domain in Oncology (Personalized, Predictive, Preventive and Participative)

Since the 1970s, our society has been undergoing rapid digitalization. This has been paralleled by rapid advancements in biology, in particular with the sequencing of the human genome and the development of proteomics and metabolomics. This digital world presents an unmatched opportunity to revolutionize health. Today, genetic medicines deal with patients who have inherited diseases. Tomorrow, we will be able to deal with a much larger scope, including the multigenic susceptibility to disease. This is the promise of precision medicine. Cancer is a major focus of precision medicine. Initiative and developments in precise and effective treatment could benefit many other chronic diseases. Precision oncology focuses on matching the most accurate and effective treatment to this individual cancer patient based on the genetic profile of cancer and the individual,(Precision Medicine the Foundation of Future Cancer Therapeutics - Google Search, n.d.). Because every single cancer patient exhibits a different genetic profile. It can help make more accurate diagnosis and improve treatment that can help people to make decisions regarding their own health and they can deal with areas of uncertainty that might have lowered their risk of cancer.

2023 Watch List: Top 10 Precision Medicine Technologies and Issues

CADTH’s 2023 Watch List presents the top 10 precision medicine technologies and issues that have the potential to make a significant and meaningful impact in transforming health systems in Canada over the next 5 years. These technologies and issues are likely to shape the future of health care. The Human Genome Project was completed 20 years ago and offers new opportunities to use an individual's genetic information to manage their health care. Today, as health systems see an emergence of new precision medicine technologies that can use a person’s unique characteristics to inform and tailor their care, the 2023 Watch List unpacks the hype from hope, and indicates where there is likely real opportunity to improve patient care and health systems delivery. As part of the 2023 Watch List, we identify and describe the 5 top precision medicine technologies; among them, examples such as liquid biopsies for informing cancer treatments and pharmacogenomics testing for mental health conditions that may shape the future of health care. To prepare health systems for their wider adoption and implementation, the 2023 Watch List explores some considerations for health care decision-makers about the impact and implications the technologies may have on care pathways, health human resources, health care infrastructure, and health equity. The 2023 Watch List also identifies the top 5 issues that crosscut the broader scope of precision medicine technologies and could limit health systems from realizing the full potential of the technologies. Among them, issues such as increasing complexity related to interpreting test results and challenges in regulating precision medicine technologies are key issues that likely warrant more attention and will influence the wider adoption, diffusion, and implementation of precision medicine technologies. Collectively, monitoring ongoing developments and evidence related to the top technologies and issues highlighted in the 2023 Watch List can help support health care stakeholders to future-proof health systems and guide health system planning in Canada.

The promise of ELSI: coproducing the future of life on earth

ABSTRACT Scientific knowledge and authority are central to dire warnings of biodiversity loss and climate change, as well as corollary visions of pathways for environmental repair and the provision of future human wellbeing. Such articulations of futures possible through the advance of science and technology, and especially genetics, have been extensively studied by STS scholars concerned with the ways society, government, and capital are ordered in relation to these expectations. In the Human Genome Project, projections of future benefit reached almost mythical – for some alarming – proportions, and initiated the now familiar model of institutional funding of Ethical, Legal and Social Implications (ELSI) research. Following this model, the Earth Biogenome Project seeks to sequence the genomes of all life on earth, with expansive promises about the good that will follow. While the inclusion of an ELSI committee is treated as the application of a known model of social ordering, and as routine and natural for such a project, its remit and role in negotiating right modes of relationality between humans and the environment are neither straightforward nor well institutionalized. In so doing, the project contributes to the stabilization of a particular set of concepts and practices as constitutive of environmental ethics while at the same time constructing biodiversity in distinct ways that align with its vision of the scientific pursuit of good human futures. As such, the constructions of environmental ethics and biodiversity that the project advances are coproduced, contributing to the shared articulations of right human-environment relationships, and institutionalized practices for ordering the world accordingly.

Supporting Antiracism Through the Thoughtful Conduct, Evaluation, and Use of Research

Supporting Antiracism Through the Thoughtful Conduct, Evaluation, and Use of Research

Brain‐X: A new interdisciplinary journal for advancing neuroscience research

Despite significant advancements in brain research, the intricacies of the brain remain a mystery. The Human Brain Project (HBP) is an international research initiative modeled1-3 after the Human Genome Project (HGP), launched in both the United States and Europe,4, 5 that aims to unravel the complex structure and function of the human brain. HBP takes an interdisciplinary approach, incorporating fields such as biology, medicine, informatics, chemistry, materials, and physics. Such an approach is necessary for furthering our understanding of the brain and advancing neuroscience as a field. However, there is currently no professional journal that focuses specifically on interdisciplinary approaches to brain and neuroscience research. To fill this gap, we are proud to announce the launch of Brain-X. The “X” in the name represents the intersection of brain and neuroscience with a strong emphasis on interdisciplinary research. This international publication will showcase the latest discoveries and technological breakthroughs, providing novel insights into all aspects of brain, neuroscience, and neurology. Brain-X is dedicated to promoting interdisciplinarity and welcomes contributions from diverse fields. In particular, the journal strongly encourages studies that utilize mathematics, physics, chemistry, engineering, materials science, or information science to tackle issues in brain and neuroscience research across various disciplines. As a peer-reviewed and open-access journal, Brain-X partners with Wiley to enhance the visibility of interdisciplinary research in this field. The journal publishes a range of article types, including original research articles, data articles, methods articles, reviews, perspectives, research letters, commentaries, and correspondences. Brain-X will comprehensively cover a broad range of topics, including but not limited to aging and brain, brain-computer interface, brain injury and rehabilitation, brain-inspired computing and artificial intelligence (AI), brain-inspired 3D printing, brain rhythm and disease, brain-gut axis, cellular and molecular neuroscience, cerebral organoids, chemical neuroscience, clinical neurology, computational neuroscience, crosstalk between brain and other organs, nanoparticles for brain drug delivery, and nerve regeneration materials. The editorial board of Brain-X comprises influential scientists from around the world who enthusiastically encourage contributions from researchers. The journal guarantees a rapid review process with fair and prompt decisions. Upon acceptance, high-quality support from the editorial team ensures that the manuscript reaches its full potential in brain and neuroscience research. Brain-X aims to serve as a platform for students, scientists, and clinicians to share their discoveries and perspectives on brain, neuroscience, and neurology. The journal is committed to providing valuable and helpful information to the community in a timely and innovative manner. Kunlin Jin: Writing – original draft; Writing – review & editing. The author declares no conflicts of interest.

Fecal Microbiota Transplantation as a Cancer Therapeutic.

For decades, cancer research and treatment focused on the cellular level, viewing cancer as a genetic disease of cell transformation. In the era of chemotherapy and radiotherapy, studies from the second half of the 19th century suggesting an association between the microbiota and cancer were almost neglected. The main focus of the field was limited to identification of specific viruses and bacteria that may serve as direct carcinogens leading to the recognition of 7 viruses (i.e., human papillomavirus, hepatitis B virus, and Kaposi sarcoma-associated herpesvirus) and 1 bacterium (Helicobacter pylori) as human carcinogens by the International Agency for Research on Cancer (https://monographs.iarc.who.int/agents-classified-by-the-iarc/). Shortly after the publication of the first draft of the human genome project in February 2001, the Nobel laureate microbiologist Joshua Lederberg raised the question: "Is human identity all in the genes?" It took more than a decade later and the development of multiomic techniques to confirm that his answer "each one of us is a small ecological community" was correct (Lederberg J. Keynote Address: Beyond the Genome. Brooklyn Law Rev 67). This ecological notion became relevant to cancer prevention, prediction, and treatment following the immunotherapy revolution and the understanding of the metabolic and immunologic roles of the microbiota in health and disease. Recently, the microbiota was recognized as an emerging hallmark of cancer following a large body of research showing its role in tumorigenesis, treatment efficacy and toxicity, and initial data regarding the role of microbial modulation in cancer therapy (Cancer Discov 2022;12(1):31-46). In the current review, we will focus on the role of fecal microbiota transplantation, the first microbial modulation technique that is used mainly in low-complexity conditions such as recurrent Clostridium difficile infections (Aliment Pharmacol Ther 2017;46(5):479-493), as a possible cancer therapeutic. However, to better understand the suggested roles of fecal microbiota transplantation in medical oncology, we first need to understand cancer as an ecological niche and the role of the microbiota in tumorigenesis and cancer treatment, specifically immunotherapy.

Gene and schizophrenia in the pregenome and postgenome-wide association studies era: a bibliometric analysis and network visualization.

This study aimed to perform a bibliometric analysis on genetic studies in schizophrenia in the pregenome-wide association studies (GWAS) and post-GWAS era. We searched the literature on genes and schizophrenia using the Scopus database. The documents increased with time, especially after the human genome project and International HapMap Project, with the highest citation in 2008. The top occurrence author keywords were discovered to be different in the pre-GWAS and post-GWAS eras, reflecting the progress of genetic studies connected to schizophrenia. Emerging keywords highlighted a trend towards an application of precision medicine, showing an interplay of environmental exposures as well as genetic factors in schizophrenia pathogenesis, progression, and response to therapy. In conclusion, the gene and schizophrenia literature has grown rapidly after the human genome project, and the temporal variation in the author keywords pattern reflects the trend of genetic studies related to schizophrenia in the pre-GWAS and post-GWAS era.

Temporal-Regulation of Serum Lipids and Stearoyl CoA Desaturase and Lipoprotein Lipase mRNA in BALB/cHnn Mice

Databases for genes expressed in humans or cell cultures are being developed as a part of the Human Genome Project. Because genomes respond to nutritional and other environmental variables, quantitative analyses of mRNA abundance under defined nutritional and physiological states are required to understand normal metabolism and to clarify differences between normal and disease phenotypes. Reported here are comparisons of food intake, growth, serum lipids and expression of mRNA for hepatic stearoyl CoA desaturase (Scd1) and heart lipoprotein lipase (Lpl) in female BALB/cHnn mice following food deprivation and refeeding at the end of 2 wk of feeding semipurified diets with 3, 10 or 20% corn oils. Body weights and utilization of dietary energy were similar for mice fed all three diets. There were no differences in serum lipid concentrations associated with the level of dietary fat during subsequent food deprivation and refeeding, but significant differences in serum triglycerides and total serum cholesterol were observed between food-deprived and fed mice. Heart lipoprotein lipase and hepatic Scd1 mRNA expression levels were affected significantly by concentration of corn oil and by time after eating. These and other studies examining gene regulation by dietary variables and nutrient availability are discussed in relation to development of diet-regulated gene databases for laboratory animals fed semipurified diets.

Translating the Genome into Drugs.

The Human Genome Project ultimately aimed to translate DNA sequence into drugs. With the draft in hand, the Molecular Libraries Program set out to prosecute all genome-encoded proteins for drug discovery with automated high-throughput screening (HTS). This ambitious vision remains unfulfilled, even while innovations in sequencing technology have fully democratized access to genome-scale sequencing. Why? While the central dogma of biology allows us to chart the entirety of cellular metabolism through sequencing, there is no direct coding for chemistry. The rules of base pairing that relate DNA gene to RNA transcript and amino acid sequence do not exist for relating small-molecule structure with macromolecular binding partners and subsequently cellular function. Obtaining such relationships genome-wide is unapproachable via state-of-the-art HTS, akin to attempting genome-wide association studies using turn-of-the-millennium Sanger DNA sequencing.Our laboratory has been engaged in a multipronged technology development campaign to revolutionize molecular screening through miniaturization in pursuit of genome-scale drug discovery capabilities. The compound library was ripe for miniaturization: it clearly needed to become a consumable. We employed DNA-encoded library (DEL) synthesis principles in the development of solid-phase DELs prepared on microscopic beads, each harboring 100 fmol of a single library member and a DNA tag whose sequence describes the structure of the library member. Loading these DEL beads into 100 pL microfluidic droplets followed by online photocleavage, incubation, fluorescence-activated droplet sorting, and DNA sequencing of the sorted DEL beads reveals the chemical structures of bioactive compounds. This scalable library synthesis and screening platform has proven useful in several proof-of-concept projects involving current clinical targets.Moving forward, we face the problem of druggability and proteome-scale assay development. Developing biochemical or cellular assays for all genome-encoded targets is not scalable and likely impossible as most proteins have ill-defined or unknown activity and may not function outside of their native contexts. These are the dark undruggable expanses, and charting them will require advanced synthesis and analytical technologies that can generalize probe discovery, irrespective of mature protein function, to fulfill the Genome Project's vision of proteome-wide control of cellular pharmacology.

An assessment of bioinformatics tools for the detection of human endogenous retroviral insertions in short-read genome sequencing data.

There is a growing interest in the study of human endogenous retroviruses (HERVs) given the substantial body of evidence that implicates them in many human diseases. Although their genomic characterization presents numerous technical challenges, next-generation sequencing (NGS) has shown potential to detect HERV insertions and their polymorphisms in humans. Currently, a number of computational tools to detect them in short-read NGS data exist. In order to design optimal analysis pipelines, an independent evaluation of the available tools is required. We evaluated the performance of a set of such tools using a variety of experimental designs and datasets. These included 50 human short-read whole-genome sequencing samples, matching long and short-read sequencing data, and simulated short-read NGS data. Our results highlight a great performance variability of the tools across the datasets and suggest that different tools might be suitable for different study designs. However, specialized tools designed to detect exclusively human endogenous retroviruses consistently outperformed generalist tools that detect a wider range of transposable elements. We suggest that, if sufficient computing resources are available, using multiple HERV detection tools to obtain a consensus set of insertion loci may be ideal. Furthermore, given that the false positive discovery rate of the tools varied between 8% and 55% across tools and datasets, we recommend the wet lab validation of predicted insertions if DNA samples are available.

A path towards personalized medicine for autoinflammatory and related diseases.

The human genome project led to the advancement of genetic technologies and genomic medicine for a variety of human diseases, including monogenic autoimmune and autoinflammatory diseases. As a result, the genome of an individual can now be rapidly sequenced at a low cost, and this technology is beginning to change the practice of rheumatology. In this Perspective, we describe how new sequencing technologies combined with careful clinical phenotyping have led to the discovery of rare rheumatic diseases and their corresponding disease-causing mutations. Additionally, we explore ways in which single-gene mutations, including somatic mutations, are creating opportunities to develop personalized medicines. To illustrate this idea, we focus on diseases affecting the TREX1-cGAS-STING pathway, which is associated with monogenic autoinflammatory diseases and vasculopathies. For many of the affected patients and families, there is an urgent, unmet need for the development of personalized therapies. New innovations related to small molecular inhibitors and gene therapies have the potential to benefit these families, and might help drive further innovations that could prove useful for patients with more common forms of autoimmunity and autoinflammation.

Integrative Proteomics and Phosphoproteomics Analysis of the Rat Adenohypophysis after GnRH Treatment

The regulation of mammalian reproductive activity is tightly dependent on the HPG axis crosstalk, in which several reproductive hormones play important roles. Among them, the physiological functions of gonadotropins are gradually being uncovered. However, the mechanisms by which GnRH regulates FSH synthesis and secretion still need to be more extensively and deeply explored. With the gradual completion of the human genome project, proteomes have become extremely important in the fields of human disease and biological process research. To explore the changes of protein and protein phosphorylation modifications in the adenohypophysis after GnRH stimulation, proteomics and phosphoproteomics analyses of rat adenohypophysis after GnRH treatment were performed by using TMT markers, HPLC classification, LC/MS, and bioinformatics analysis in this study. A total of 6762 proteins and 15,379 phosphorylation sites contained quantitative information. Twenty-eight upregulated proteins and fifty-three downregulated proteins were obtained in the rat adenohypophysis after GnRH treatment. The 323 upregulated phosphorylation sites and 677 downregulated phosphorylation sites found in the phosphoproteomics implied that a large number of phosphorylation modifications were regulated by GnRH and were involved in FSH synthesis and secretion. These data constitute a protein-protein phosphorylation map in the regulatory mechanism of "GnRH-FSH," which provides a basis for future studies on the complex molecular mechanisms of FSH synthesis and secretion. The results will be helpful for understanding the role of GnRH in the development and reproduction regulated by the pituitary proteome in mammals.

Imaging genomics: data fusion in uncovering disease heritability.

Sequencing of the human genome in the early 2000s enabled probing of the genetic basis of disease on a scale previously unimaginable. Now, two decades later, after interrogating millions of markers in thousands of individuals, a significant portion of disease heritability still remains hidden. Recent efforts to unravel this 'missing heritability' have focused on garnering new insight from merging different data types, including medical imaging. Imaging offers promising intermediate phenotypes to bridge the gap between genetic variation and disease pathology. In this review we outline this fusion and provide examples of imaging genomics in a range of diseases, from oncology to cardiovascular and neurodegenerative disease. Finally, we discuss how ongoing revolutions in data science and sharing are primed to advance the field.

Alvin William Trivelpiece

An outstanding leader, physicist, and administrator, Alvin William Trivelpiece died on 7 August 2022 in Rancho Santa Margarita, California.Alvin William TrivelpieceAIP ESVA/PHYSICS TODAY COLLECTIONPPT|High resolutionBorn on 15 March 1931 in Stockton, California, Al put himself through California Polytechnic State College and graduated in 1953 with a degree in electrical engineering. He earned a PhD in electrical engineering in 1958 from Caltech under the guidance of Roy Gould. His dissertation was titled “Space charge waves in cylindrical plasma columns.”After spending a year in the Netherlands as a Fulbright scholar, Al became a professor of electrical engineering at the University of California, Berkeley. In 1966 he became a professor of physics at the University of Maryland, College Park, where he supervised 19 doctoral candidates and published more than 40 papers on plasma physics. Al also wrote, with Nicholas Krall, Principles of Plasma Physics, which remains a classic textbook 50 years after publication.Taking a leave of absence from the University of Maryland in 1973, Al served for two years with the Atomic Energy Commission as an assistant director for research in the division of controlled thermonuclear research. Among his achievements was the establishment of the national Controlled Thermonuclear Research Computer Center (CTRCC), which provided fusion researchers across the country with remote access to leading-edge computing resources. The idea was met with considerable skepticism, but it became a model used by other science agencies.In 1976 Al became vice president for engineering and research at Maxwell Laboratories, and in 1978 he was appointed corporate vice president of Science Applications Inc. Three years later Al was nominated by President Ronald Reagan and confirmed by the Senate as director of the Department of Energy’s Office of Energy Research (now the Office of Science), where he had responsibility for 5 research programs and 10 of DOE’s laboratories. He also served as the energy secretary’s science adviser.As director, Al developed a plan for construction of five major scientific research facilities: the Advanced Light Source, the Advanced Photon Source, the Relativistic Heavy Ion Collider, the Continuous Electron Beam Accelerator Facility, and the Spallation Neutron Source (SNS). Those facilities continue to sustain US leadership in many fields of science today. Al’s planning was informed by federal advisory committees that he established and the National Academy of Sciences, an approach that continues to serve DOE’s Office of Science well.Al and Charles DeLisi in 1986 initiated the Human Genome Project, which has had an enormous impact on the life sciences and medical research. Al was masterful in obtaining support for the project from DOE management, the Office of Management and Budget, and the US Congress. The National Institutes of Health joined the project two years later.Al expanded the scope of the CTRCC to form the National Energy Research Scientific Computing Center, which continues to serve the research programs in the Office of Science as well as other DOE programs.In 1987 Al became the executive officer of the American Association for the Advancement of Science and publisher of Science. Then in January 1989, he became director of Oak Ridge National Laboratory, where he was responsible for several initiatives. He created the Office of Laboratory Computing to enhance Oak Ridge’s ability to meet complex scientific challenges. Al led the development of a successful proposal for the Center for Computational Sciences, which brought together computational-science teams, computer scientists, and the hardware vendor Intel. It was designated as one of two DOE high-performance computing research centers in 1993.A second major achievement was the SNS. The lab had been designing a reactor-based neutron source. When the cost became unacceptable, Al took the lead in shifting to the accelerator-based SNS and gathered a multilab consortium to execute design and construction and broaden the project’s base of support. The SNS returned the US to a world-leading position in neutron-scattering research.Al was an advocate for international cooperation in science. His work behind the scenes with Evgeny Velikhov led to an agreement between the US and the Soviet Union on developing a magnetic-fusion demonstration model, which laid the groundwork for the ITER project.Al’s outstanding achievements extend across research, education, science administration, and national security. He was an innovator in the positions he held. Many of his accomplishments resulted from his understanding of science and politics and his ability to guide projects through government processes.Those of us who worked closely with Al have been fortunate to have had the opportunity. Al was a continuous source of ideas and wisdom. He had a great sense of humor and was quick to generate puns. He enjoyed playing poker, chess, and golf and was an avid runner. He piloted his own airplane to the age of 85. His wisdom, leadership, and friendship will be missed.© 2023 American Institute of Physics.

Health inequity in genomic personalized medicine in underrepresented populations: a look at the current evidence

Improvements in sequencing technology coupled with dramatic declines in the cost of genome sequencing have led to a proportional growth in the size and number of genetic datasets since the release of the human genetic sequence by The Human Genome Project (HGP) international consortium. The HGP was undeniably a significant scientific success, a turning point in human genetics and the beginning of human genomics. This burst of genetic information has led to a greater understanding of disease pathology and the potential of employing this data to deliver more precise patient care. Hence, the recognition of high-penetrance disease-causing mutations which encode drivers of disease has made the management of most diseases more specific. Nonetheless, while genetic scores are becoming more extensively used, their application in the real world is expected to be limited due to the lack of diversity in the data used to construct them. Underrepresented populations, such as racial and ethnic minorities, low-income individuals, and those living in rural areas, often experience greater health disparities and worse health outcomes compared to the general population. These disparities are often the result of systemic barriers, such as poverty, discrimination, and limited access to healthcare. Addressing health inequity in underrepresented populations requires addressing the underlying social determinants of health and implementing policies and programs which promoted health equity and reduce disparities. This can include expanding access to affordable healthcare, addressing poverty and unemployment, and promoting policies that combat discrimination and racism.