Human Genetic Technology Research Articles

Cardiovascular Pharmacogenetics: From Discovery of Genetic Association to Clinical Adoption of Derived Test.

Recent breakthroughs in human genetics and in information technologies have markedly expanded our understanding at the molecular level of the response to drugs, i.e., pharmacogenetics (PGx), across therapy areas. This review is restricted to PGx for cardiovascular (CV) drugs. First, we examined the PGx information in the labels approved by regulatory agencies in Europe, Japan, and North America and related recommendations from expert panels. Out of 221 marketed CV drugs, 36 had PGx information in their labels approved by one or more agencies. The level of annotations and recommendations varied markedly between agencies and expert panels. Clopidogrel is the only CV drug with consistent PGx recommendation (i.e., "actionable"). This situation prompted us to dissect the steps from discovery of a PGx association to clinical translation. We found 101 genome-wide association studies that investigated the response to CV drugs or drug classes. These studies reported significant associations for 48 PGx traits mapping to 306 genes. Six of these 306 genes are mentioned in the corresponding PGx labels or recommendations for CV drugs. Genomic analyses also highlighted the wide between-population differences in risk allele frequencies and the individual load of actionable PGx variants. Given the high attrition rate and the long road to clinical translation, additional work is warranted to identify and validate PGx variants for more CV drugs across diverse populations and to demonstrate the utility of PGx testing. To that end, pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond. SIGNIFICANCE STATEMENT: Despite spectacular breakthroughs in human molecular genetics and information technologies, consistent evidence supporting PGx testing in the cardiovascular area is limited to a few drugs. Additional work is warranted to discover and validate new PGx markers and demonstrate their utility. Pre-emptive PGx combining genomic profiling with electronic medical records opens unprecedented opportunities to improve healthcare, for CV diseases and beyond.

Impact of Genetic Variation on Human Disease: From Genomics to Phenotype

The impact of genetic variation on human disease is a multifaceted phenomenon involving genomics, epigenetics, and phenotype relationships. Advances in human genetic analysis technology have revolutionized our understanding of genetic disorders, enabling large-scale screens to explore associations between sequence variants and disease susceptibility. Environmental stimuli also contribute to epigenetic modifications that shape gene expression and phenotypic traits. Recent research on monozygotic twins highlights the role of non-genetic factors in phenotypic differences, underscoring the complex interplay between genetics and environment. The literature review highlights seminal studies that elucidate genetic and evolutionary mechanisms underlying human disease, providing insights for personalized medicine. Methods such as pharmacogenetics and immunomics provide avenues for precision therapies and immunological research. The Heterogeneity Weighted U test and the Gaussian random effects model facilitate the exploration of phenotype-genotype relationships and help to assess genetic heterogeneity in disease models. Simulation experiments deepen our understanding of the impact of genetic variation on disease manifestation. The interdisciplinary approaches are crucial to unravel the complex genetic landscape of human diseases and to develop tailored therapeutic interventions.

The application of human genetic technology in the medical field urgently needs standardization

Human gene editing technology is a hot spot and focus in the development of biotechnology, but it has also caused controversies over technical risks, genetic biosecurity, ethical dignity of human society and the legality of application, causing people to worry about the application of this technology. Gene editing for reproductive purposes is generally prohibited internationally, and countries have established legal regulatory systems to regulate the application of gene editing technology according to their own conditions. China shall establish a security risk access system for gene editing technology, ensure national biosecurity, establish and improve the system of ethical norms for scientific research, improve the construction of legislative standardization, and provide legal guarantees for the research and application of gene editing technology.

Zebrafish, an In Vivo Platform to Screen Drugs and Proteins for Biomedical Use.

The nearly simultaneous convergence of human genetics and advanced molecular technologies has led to an improved understanding of human diseases. At the same time, the demand for drug screening and gene function identification has also increased, albeit time- and labor-intensive. However, bridging the gap between in vitro evidence from cell lines and in vivo evidence, the lower vertebrate zebrafish possesses many advantages over higher vertebrates, such as low maintenance, high fecundity, light-induced spawning, transparent embryos, short generation interval, rapid embryonic development, fully sequenced genome, and some phenotypes similar to human diseases. Such merits have popularized the zebrafish as a model system for biomedical and pharmaceutical studies, including drug screening. Here, we reviewed the various ways in which zebrafish serve as an in vivo platform to perform drug and protein screening in the fields of rare human diseases, social behavior and cancer studies. Since zebrafish mutations faithfully phenocopy many human disorders, many compounds identified from zebrafish screening systems have advanced to early clinical trials, such as those for Adenoid cystic carcinoma, Dravet syndrome and Diamond–Blackfan anemia. We also reviewed and described how zebrafish are used to carry out environmental pollutant detection and assessment of nanoparticle biosafety and QT prolongation.

Human genetic issues from scientific and Islamic perspectives

This paper aims at revealing the Human Genome Project (HGP) and human genetic issues arising from science and Islamic perspectives such as Darwin's evolutionary theory, human cloning and eugenics. Finally, issues arising from the applications of human genetic technology need to be addressed to the best possible way through ethics in science as well as through integration of Islamic teachings so that all achievements of this field do not spoil the nature and human populations. This in turn will make human life become better and more conducive from time to time. Keywords : human genetics; Darwinism; human cloning; human genome project; eugenics.

Moral Schemas in Articulation and Intuition: How Religious People Evaluate Human Reproductive Genetic Technologies

As new and more effective human reproductive genetic technologies (RGTs) rapidly develop, religious voices remain an important part of public discussion about the moral standing of such technologies. Here, we compare how individuals from different religious traditions evaluate disease RGTs (detecting genetic diseases in vitro) when compared to enhancement RGTs, allowing parents to select features of a child. Findings are gleaned from analysis of 270 interviews with individuals from 23 Christian, Muslim, and Jewish religious organizations, with supporting data from a national survey of more than 10,000 Americans. We find that respondents engage in clearly defined discursive moral reasoning to evaluate the propriety of disease RGTs while moral intuitions manifest themselves in responses to enhancement RGTs. We argue that schemas provide resources for moral discourses while also shaping moral intuitions expressed through emotions. Our results have implications for how religious people respond to new technologies when their institutional and denominational structures do not have readily discernable moral frameworks to guide responses.

In Genes We Trust: Germline Engineering, Eugenics, and the Future of the Human Genome.

Liberal proponents of genetic engineering maintain that developing human germline modification technologies is morally desirable because it will result in a net improvement in human health and well-being. Skeptics of germline modification, in contrast, fear evolutionary harms that could flow from intervening in the human germline, and worry that such programs, even if well intentioned, could lead to a recapitulation of the scientifically and morally discredited projects of the old eugenics. Some bioconservatives have appealed as well to the value of retaining our "given" human biological nature as a reason for restraining the development and use of human genetic modification technologies even where they would tend to increase well-being. In this article, I argue that germline intervention will be necessary merely to sustain the levels of genetic health that we presently enjoy for future generations-a goal that should appeal to bioliberals and bioconservatives alike. This is due to the population-genetic consequences of relaxed selection pressures in human populations caused by the increasing efficacy and availability of conventional medicine. This heterodox conclusion, which I present as a problem of intergenerational justice, has been overlooked in medicine and bioethics due to certain misconceptions about human evolution, which I attempt to rectify, as well as the sordid history of Darwinian approaches to medicine and social policy, which I distinguish from the present argument.

Welcome to Neurology: Genetics.

The powers of human genetics and genetic technologies have transformed the complexities of neurology and neuroscience at the basic, translational, and now also the clinical level. We have left an era of black and white views of causative genetic variation and are entering a period of more than 50 shades of grey, fascinated with DNA variants that increase or decrease risk, epigenetic modification, and an unexpectedly large number of variants of unknown or potentially pathogenic significance. Loss-of-function alleles and even complete human gene knockouts for certain genes appear to be compatible with a normal phenotype.

The case for universal prenatal genetic counseling.

Recent scientific advances in human genetics and prenatal diagnostic technologies challenge the counseling infrastructure of most obstetric services. In just the past several years, the American College of Obstetricians and Gynecologists has published guidelines on fragile X, spinal muscular atrophy, and cystic fibrosis screening, and new technologies including microarray analysis, cell-free fetal DNA, and carrier gene panels have become available. Obstetrics is at a crossroads, which requires consideration of new ways of providing genetic counseling. Currently a two-tiered process is used. Specific tests such as first- or second-trimester screening for aneuploidy are offered to virtually all women by a clinician who provides counseling and who may offer additional tests to patients in particular ethnic groups and those with unique obstetric or family histories. Frequently only this latter group and those who "screen positive" on the universally offered tests are sent to a genetic counselor. This approach worked well when screening focused on a relatively small number of diagnoses, but that is no longer the case. We argue that obstetricians, who were able to maintain mastery over the content of counseling when aneuploidies and karyotype analysis were the essential diagnoses and diagnostic tools available, are rarely able to offer the same level of expertise regarding the chromosomal, genomic, and genetic diseases now diagnosable and the newest available diagnostic methodologies. Therefore, all women, not just those surpassing some poorly defined level of risk, deserve genetic counseling. Approaches for achieving this goal are discussed.

Applied and Translational Genomics for Human Genetics and Clinical Science

Applied and Translational Genomics for Human Genetics and Clinical Science

Chromosome 7q Hemizygosity Recapitulates MDS-Related Cellular Phenotypes In Genetically Engineered Human Pluripotent Stem Cells

Loss of the entire or part of one copy of chromosome 7 [del(7/7q)] is a recurrent cytogenetic abnormality in MDS. Its strong association with previous exposure to alkylating agents, consistently poor response to therapy and discrete gene expression profile strongly suggest that del(7/7q)-MDS is a distinct disease in the MDS spectrum whose pathogenesis is intimately linked to loss of chr7q genetic material. Understanding the role of chr7q loss in cell biology can provide key insights into the pathogenesis of MDS and leukemogenesis.Narrowing down the responsible region on chr7q presents a challenge that has proved intractable with existing approaches. Chr7q deletions physically mapped in large cohorts of patients are typically very large and dispersed along most of the length of chr7q. Modeling in the mouse is problematic for reasons of synteny. Deletion of the syntenic region of one commonly deleted region (7q22 CDR) failed to demonstrate a phenotype.Several lines of evidence point to haploinsufficiency of chr7q genetic material – rather than a 2-hit model – as the underlying mechanism in del(7q)-MDS. No inactivating mutations of candidate 7q genes have been detected by resequencing the remaining allele and haploinsufficiency of coding and miRNA genes has been strongly linked to the pathogenesis of del(5q)-MDS. Haploinsufficiency can only be assessed through functional studies (and not genomic technologies), but these are currently hindered by the lack of a clearly described del(7q)-associated phenotype.With recent advances in human pluripotent stem cell (hPSC) research and genetic engineering technologies, reverse human genetics in an isogenic setting by disruption of genomic elements into their cognate genomic and cellular context - hitherto unthinkable for the human genome – are now a realistic prospect. To determine the impact of hemizygous chr7q loss on the cellular phenotype, we have generated isogenic del(7q)- and normal hPSCs by engineering deletions spanning variable overlapping regions encompassing the entire length of chr7q using adeno-associated virus (AAV)-mediated gene targeting combined with Cre-lox technology. Specifically, we targeted two inverted loxP sites together with a positive (puro) and a negative (HSVtk) selection marker in a near-telomeric region of chromosome 7q (7q36.3) into the H1 hESC line, as well as a karyotypically normal iPSC line (line 2-12) derived from BMMCs of a patient with del(7q)-MDS. Following transient expression of Cre recombinase and ganciclovir selection, clones were screened by qPCR probing different regions along the length of chr7. Four H1-derived and four 2-12-derived clones were selected following screening of 24 and 34 clones, respectively, and after excluding clones with additional chromosomal abnormalities by karyotyping and the exact extent of their chr7q deletions was mapped by aCGH.We focused our phenotypic characterization on two cellular phenotypes that we recently reported in del(7q)-iPSCs derived from MDS BMMCs: cell proliferation and in vitro hematopoietic differentiation potential. 7 of the 8 clones harboring deletions spanning variable lengths along the entire chr7q had a lower (by ½ log) proliferation rate than their corresponding isogenic parental lines. All these clones also exhibited a markedly reduced differentiation potential along all hematopoietic lineages and almost absent clonogenic capacity in methylcellulose. These cellular phenotypes are highly similar to those we find in our del(7q)-MDS-iPSCs. Notably, one of the eight clones (2-12.Cre-44), harboring a smaller deletion spanning 7q11.21-7q.31.1 retained comparable proliferation and differentiation capacity to that of normal isogenic and non-isogenic hPSCs.In conclusion, our results demonstrate that hemizygous loss of chr7q material recapitulates the cellular phenotypes of impaired proliferation and hematopoietic differentiation that we find in del(7q)-MDS-iPSCs, supporting a haploinsufficiency pathogenesis of del(7q)-MDS. Correlation of the phenotypes with the boundaries of chr7q deletions in our collection of hESC and iPSC clones points to a region spanning 7q31.1-7q36.1 as the critical region in del(7q)-MDS. Further studies in additional clones harboring smaller chr7q deletions will further narrow down the responsible region and guide prioritization of candidate genes. Disclosures:No relevant conflicts of interest to declare.

Negotiating the interface of genetic testing, biobanking and Māori ontology and epistemology

This article privileges lay perspectives drawn from three Māori (indigenous people of New Zealand) participant contact groups asked to respond to stimulus materials about genetic therapies, predictive tests and biobanking as new health biotechnologies become readily accessible. Findings from an MA study found the groups did not respond directly to information that referred to genes, tests and medicine. Rather, their talk was suffused with reference to spiritual and cultural contexts bound up in a web of interrelated aspects of life processes governed within hapū and iwi ontologies and epistemologies realities. These realities and knowledge systems incorporate protocols, histories, whakapapa (genealogies), roles and responsibilities, spirituality and physical interdependence. Based on the interconnectedness expressed by participants, this article will highlight the subtle ontological oscillation moments of sense-making that occurred when participants changed their views depending on the situation presented before them. This observation gives rise to the notion that while no single Māori view emerged on the potential risks and benefits genetic tests and biobanking might have for these participants, more poignant questions are critical to identify suitable pathways for Māori to engage and contribute to decision-making processes which arise from the ontological assumptions in human genetic science technologies and biobanking.

Genetics and genomics of human ageing

Ageing in humans is typified by the decline of physiological functions in various organs and tissues leading to an increased probability of death. Some individuals delay, escape or survive much of this age-related decline and live past age 100. Studies comparing centenarians to average-aged individuals have found polymorphisms in genes that are associated with long life, including APOE and FOXOA3, which have been replicated many times. However, the associations found in humans account for small percentages of the variance in lifespan and many other gene associations have not been replicated in additional populations. Therefore, ageing is probably a highly polygenic trait. In humans, it is important to also consider differences in age-related decline that occur within and among tissues. Longitudinal data of age-related traits can be used in association studies to test for polymorphisms that predict how an individual will change over time. Transcriptional and genetic association studies of different tissues have revealed common and unique pathways involved in human ageing. Genomic convergence is a method that combines multiple types of functional genomic information such as transcriptional profiling, expression quantitative trait mapping and gene association. The genomic convergence approach has been used to implicate the gene MMP20 in human kidney ageing. New human genetics technologies are continually in development and may lead to additional breakthroughs in human ageing in the near future.

GenEthics and religion

GenEthics and religion

Abstract PL03-02: Public health genomics: A scientific foundation for using genetic information in cancer prevention

Abstract With the accelerating pace of discoveries of human genetic variation, and molecular, biochemical, and cellular technologies for cancer care and prevention, there is an urgent need to develop population-level research, policy and practice processes to translate basic science discoveries into actions that reduce the population burden of cancer in the United States. The emerging scientific translation needs in the genomics era are substantial. Clinical and population sciences are now urgently needed to assess the distribution of genetic variants and their products biomarkers, and interactions with other genes and environmental factors. New methods are needed to assess the contribution of genes and gene-environment interactions (behavior, nutrition, chemicals, and other exposures) to individual and population risks for various cancers. Behavioral and social sciences are needed to assess how genetic information can be used to effect behavior change to reduce the burden of cancer. As importantly, delivery research on clinical utility, effectiveness, and economics of genomics-based health care applications are needed to assess their added value in cancer care and prevention. Genomics and related fields will also affect surveillance, dissemination and diffusion research as well as evaluation of cancer progression and survivorship. Without the expansion of clinical and population sciences in genomics, the promise of genome research and discoveries may not reach its full potential in the genomics era. Citation Information: Cancer Prev Res 2010;3(1 Suppl):PL03-02.

The emergence of ‘The HUGO Journal’

In August 2007, a new bio-medical journal Genomic Medicine was launched to capture the key developments in genome sciences and technologies relevant to medicine and human health. Since then, several major journals emerged also to compete in the same conceptual space. Because, many of the leading biomedical journals are affiliated with major organisations (for example, the EMBO Journal, Journal of ASHG, Journal of ESHG, National Academy of Sciences, etc.), the future of Genomic Medicine depended on successful partnership with an institution or organisation. In 2008, the Human Genome Organisation (HUGO), one of the leading international science organisations, entered discussions with Springer (the publisher for Genomic Medicine), and the Editorial leadership of Genomic Medicine, to assume responsibility for the journal. This proposal was formally accepted by the governing HUGO Council held at the HGM2008 conference in Hyderabad, India (2008), and by the broad editorial board of Genomic Medicine. This merger was viewed as mutually beneficial to ensure a unique place for a journal in the competitive area of genomic medicine, and to provide HUGO with a publication vehicle for its concepts and ideas. The journal was renamed The HUGO Journal and rebranded as the official publication for this international organisation. The initial leadership of the journal was to be shared by Dhavendra Kumar (University of Cardiff), and Edison T. Liu (President, HUGO). The HUGO Journal is focused on discoveries arising from the basic, clinical, and population explorations of the human genome, and genomes of organisms relevant to human health. As such we wish to publish primary research papers of the highest quality investigating topics in genomic medicine. In depth review articles on important topics pertinent to genomic medicine, human genetics, computational genomics, and genomic technologies will be featured. Because the HUGO Journal represents the voice of the Human Genome Organisation, we will be publishing key consensus reports and policy guidelines from HUGO Council and its subcommittees. Because of its history, The HUGO Journal will have the advantage of being fully indexed in PubMed from the outset thus providing visibility for all articles published in the journal. Besides the current research articles, commentaries, and reviews, several new sections will be offered to enhance the exchange of information relevant to genomic scientists: Data-bases: This section specifically encourages the publication of the description and utility of specific genomic databases. These reports will be fully indexed in PubMed. Innovation Reports: These are short reports of <1,000 words that describe a specific finding of interest to the genomics community. The focus is on early publication of a highly innovative finding that may not have large scale validation. This includes case reports of unique genotype-phenotype associations. The HUGO Journal welcomes article submissions in many of the following categories: Genomic sciences and human disease: e.g., pharmacogenomics, cancer genomics, genetics of Mendelian disorders, genetics of complex diseases Genome structure and genetic variation Comparative genomics between humans and other organisms Microbial genomics of organisms pertinent to human disease Population genetics Human evolution and migration Genome-to-systems strategies in systems biology Genomic technologies Genomics and genetic epidemiology Computational genomics Ethical, legal, and societal research relevant to genomics and human genetics Science policy analyses pertinent to genomics and genetics. Genomic and genetic research from emerging and developing countries. Our goal is for The HUGO Journal to become one of the leading bio-medical journals reporting state of the art developments in genome sciences and technologies as applied to medicine and human health.

Protecting the Privacy of Genetic Information

Advances in the study of human genetics and predictive genetic technologies, most notably the mapping of the human genome, have led to an increased understanding of how genetic code might relate to future health outcomes. These insights have raised concerns relating to the privacy of genetic information. The question becomes, what privacy protections does the law afford to individual persons and their genetic code, and how might the law protect individuals from discrimination when their privacy is violated?

Social Movements and Ethnographic Methodologies: An Analysis Using Case Study Examples

AbstractThis paper defines and discusses the viability and applicability of specific ethnographic methods for the study and theorising of social movements and related social mobilisation. Ethnographic methods are shown to be one tool in a box of available methods, but are perhaps especially suited for the in‐depth study of social movements and social networks. Pros and cons of such methods are identified, using examples drawn from an ethnographic narrative comprising over a decade of research; ethnography of UK environmental direct activists, and more recent ethnography of UK publics engaging with human genetic technologies. Ethnography enables developments in latent social interactions to be identified in the field, providing data sources that inform social analysis and the development of theoretical stakes. This ethnographic narrative has contributed to the theorising of complexity in movement collective identity and complex social mobilisation patterns; namely the theorising of social movement. Findings can be disseminated to a range of stakeholders, including the research participants. Thus, ethnography can be both a method for studying social movements and a means of ‘upstream’ public engagement, understanding what is happening at the grassroots, with the aim of enabling capacity building between all actors in the research process. This methodological rationale is defined as ‘action research’.

Patenting Human Evolution

Patent protection for genetic enhancements would tend to spur genetic innovation, but would tend to limit access to those genetic enhancements through discriminatory mechanisms such as price and favoritism. The patent system would likely ensure high rates of genetic enhancement innovation, research, and development, efficiently mediate access to genetic enhancements, but would also likely allow access to genetic enhancements to fewer members of society. Most importantly, the patent system has the potential to promote the kinds of genetic enhancements that might lead to human evolutionary change. Public policy and the law must grapple with the implications of genetic enhancement before current technological possibilities become societal realities. The patent system is an odd candidate to become a substantial arbiter of parental decisions regarding genetic enhancement of their offspring. It is certain that the implications the patent system has for future human genetic enhancement should be subjected to thorough analysis and debate prior to the imminent arrival of human genetic enhancement technologies. Otherwise, patent law may drive human evolution in directions either unplanned - or worse - undesired.

Human Genetic and Reproductive Technologies: A Muslim’s Understanding of the Secular Perspective

DOI: http://dx.doi.org/10.5915/39-4-6321 Physically and intellectually, man is not the same as he was a million years ago. These improvements in humans have come from within over a period of time by the process of adaptation, new learning, and out of a need. So, what is the need now for biotechnical intervention? The fine line between what can be done technically and what should be done morally is the reason for the role of biomedical ethics in the area of human genetic technologies. What is the relationship between the individual and society? Whose interests and needs are we, the scientists and physicians, to serve? Where does the government fit in between the needs of the individual patient and duties of his or her physician? Are social justice, human dignity, and human rights to be considered in genetic modification? While it may be appropriate and desirable to seek treatment for a disease such as infertility, we have moved beyond treating infertility to the quest of making a super healthy super human. As a result, are we embarking on a path of ethnic cleansing of humans of lesser abilities? In this paper, such concerns and questions are discussed from a secular perspective.