Modern Genetics Research Articles

Assessing the foliar diseases (Septoria tritici) tolerance of modern genetics wheat varieties, compared to the classic ones – Fungicide treatments effect

Assessing the foliar diseases (Septoria tritici) tolerance of modern genetics wheat varieties, compared to the classic ones – Fungicide treatments effect

Validation of the Learning Progression-based Assessment of Modern Genetics in a college context

ABSTRACTBuilding upon a methodologically diverse research foundation, we adapted and validated the Learning Progression-based Assessment of Modern Genetics (LPA-MG) for college students’ knowledge of the domain. Toward collecting valid learning progression-based measures in a college majors context, we redeveloped and content validated a majority of a previous version of the LPA-MG which was developed for high school students. Using a Rasch model calibrated on 316 students from 2 sections of majors introductory biology, we demonstrate the validity of this version and describe how college students’ ideas of modern genetics are likely to change as the students progress from low to high understanding. We then utilize these findings to build theory around the connections college students at different levels of understanding make within and across the many ideas within the domain.

The discovery of vemurafenib for the treatment of BRAF-mutated metastatic melanoma

ABSTRACTIntroduction: In the era of precision medicine and sophisticated modern genetics, the discovery of the BRAFV600 inhibitor, vemurafenib, quickly became the model for targeted therapy in melanomas. As early as 2002, the majority of metastatic melanomas were described to harbor the BRAFV600 mutation, setting the stage for an explosion of interest for targeting this protein as a novel therapeutic strategy. The highly selective BRAFV600 inhibitor, vemurafenib, was identified initially through a large-scale drug screen.Areas covered: Here we examine vemurafenib’s journey from discovery to clinical use in metastatic melanoma. Topics covered include preclinical data, single agent Phase 1,2 and 3 clinical trials, resistance issues and mechanisms, adverse effects including the development of squamous cell cancers, and combination trials.Expert opinion: Due to its tolerance, low toxicity profile, rapid tumor response, and improved outcomes in melanoma patients with BRAFV600 mutations, vemurafenib was advanced rapidly through clinical trials to receive FDA approval in 2011. While its efficacy is well documented, durability has become an issue for most patients who experience therapeutic resistance in approximately 6–8 months. In addition, a concerning toxicity observed in patients taking the drug include development of localized cutaneous squamous cell carcinomas (SCCs). It is hypothesized that drug resistance and SCC development result from a similar paradoxical activation of protein signaling pathways, specifically MAPK. Identification of these mechanisms has led to additional treatment strategies involving new combination therapies.

The Future of Genetics and Genomics: Closing the Phenotype Gap in Precision Medicine.

In this forward-facing review, we briefly summarize what we see as the state of modern cardiovascular genetics and genomics before outlining some of the key areas in which we believe there is a need for investment if we are to realize the full clinical potential of the field. There is clearly substantial overlap with the field of precision medicine, yet it may be in understanding where genetics and genomics currently fall short that we will identify how precision medicine might move forward.1,2 The recognition over the last decade that genetics or genomics alone is unlikely to offer the predictive utility necessary for precision medicine is matched by our dependence on genetics and genomics for much of the mechanistic insight necessary to achieve precision diagnostics or precision therapeutics.2 The overarching strategies we discuss emphasize that the future of cardiovascular genetics and genomics is inextricably linked with those of every other field of medicine. We must move beyond the silos of traditional organ-based disease if we are to realize fully the need for generalizable biological rules that constitute the truly mechanistic medicine or molecular medicine first envisaged >40 years ago.3 The cardiovascular arena has been a focus of much work on the practical application of genetics. Given the potential for coincident presentation and demise in sudden death and the availability of the implantable defibrillator (a mechanism-agnostic preventive therapy), cardiovascular medicine has been focused on the predictive utility of genetics for some time.4 The long tradition of physiological measurements and classic epidemiology in cardiovascular research has facilitated large genotype-phenotype correlation studies.5,6 Cardiovascular research has also had to tackle truly complex paroxysmal phenotypes such as arrhythmias that have challenged our ability to resolve traits into their constituent components.7 Large kindreds, with what in retrospect …

Celebrating Mendel’s 150th anniversary

> If Darwinian evolution be natural selection combined with heredity then the single statement which embraces the whole field of heredity must prove as epoch-making to the biologist as the law of gravitation to the astronomer . 1 > > K. Pearson, mathematician and statistician (1857–1936). Gregor Mendel (1822–84) discovered such a statement encompassing the whole field of heredity by sexual reproduction, and as endorsed by Karl Pearson, must be compared to Isaac Newton, one of the world’s greatest scientists. This year is the 150th anniversary that Mendel’s laws of inheritance were published in 1866 entitled Versuche uber Pflanzen-Hybriden. 2 Mendel appears as the sole founding father of modern genetics, unlike most sciences where several people are often credited. Mendel came from Heinzendorf, a village close to Brunn (now called Brno) in the Czech Republic. He spent almost all his working life in the Augustinian Monastery of St. Thomas in Brunn and rose from a monk to elected Abbot from 1868 to 1884.3 Comparing a Catholic monk to Isaac Newton raises controversy. Many people attacked Mendel’s results and most virulent was the British geneticist Professor Sir Ronald A Fisher FRS (1890–1962) who wrote4: ‘the paper is only intelligible if the experiments reported in it were fictitious; the data of the later experiments were biased strongly in agreement with expectation’; concluding ‘the data of most, if not all of the experiments have been falsified so as to agree closely with Mendel’s expectations’. Mud sticks and many people react to Mendel's …

A Modular, Tn 7 -Based System for Making Bioluminescent or Fluorescent Salmonella and Escherichia coli Strains

Our goal was to develop a robust tagging method that can be used to track bacterial strains in vivo To address this challenge, we adapted two existing systems: a modular plasmid-based reporter system (pCS26) that has been used for high-throughput gene expression studies in Salmonella and Escherichia coli and Tn7 transposition. We generated kanamycin- and chloramphenicol-resistant versions of pCS26 with bacterial luciferase, green fluorescent protein (GFP), and mCherry reporters under the control of σ(70)-dependent promoters to provide three different levels of constitutive expression. We improved upon the existing Tn7 system by modifying the delivery vector to accept pCS26 constructs and moving the transposase genes from a nonreplicating helper plasmid into a temperature-sensitive plasmid that can be conditionally maintained. This resulted in a 10- to 30-fold boost in transposase gene expression and transposition efficiencies of 10(-8) to 10(-10) in Salmonella enterica serovar Typhimurium and E. coli APEC O1, whereas the existing Tn7 system yielded no successful transposition events. The new reporter strains displayed reproducible signaling in microwell plate assays, confocal microscopy, and in vivo animal infections. We have combined two flexible and complementary tools that can be used for a multitude of molecular biology applications within the Enterobacteriaceae This system can accommodate new promoter-reporter combinations as they become available and can help to bridge the gap between modern, high-throughput technologies and classical molecular genetics. This article describes a flexible and efficient system for tagging bacterial strains. Using our modular plasmid system, a researcher can easily change the reporter type or the promoter driving expression and test the parameters of these new constructs in vitro Selected constructs can then be stably integrated into the chromosomes of desired strains in two simple steps. We demonstrate the use of this system in Salmonella and E. coli, and we predict that it will be widely applicable to other bacterial strains within the Enterobacteriaceae This technology will allow for improved in vivo analysis of bacterial pathogens.

Close-Kin Mark-Recapture

Mark-recapture (MR) methods are commonly used to study wildlife populations. Taking advantage of modern genetics one can generalize from “recapture of self” to “recapture of closely-related kin”. Abundance and other demographic parameters of adults can then be estimated using, if necessary, only samples from dead animals (live-release is optional). This greatly widens the scope of MR, e.g. to commercial fisheries where largescale tagging is impractical, and enhances the power of conventional MR studies where live release and tissue sampling is possible. We give explicit formulae for kinship (i.e., recapture) probabilities in general and specific cases. These yield a pseudo-likelihood based on pairwise comparisons of individuals in the samples. It is shown that the pseudo-likelihood approximates the full likelihood under sparse sampling of large populations. Experimental design is addressed via the principle of maximizing the Fisher information for parameters of interest. Finally, we discuss challenges related to kinship determination from genetic data, focusing on current limitations and future possibilities.

Advances in the Study of Heart Development and Disease Using Zebrafish.

Animal models of cardiovascular disease are key players in the translational medicine pipeline used to define the conserved genetic and molecular basis of disease. Congenital heart diseases (CHDs) are the most common type of human birth defect and feature structural abnormalities that arise during cardiac development and maturation. The zebrafish, Danio rerio, is a valuable vertebrate model organism, offering advantages over traditional mammalian models. These advantages include the rapid, stereotyped and external development of transparent embryos produced in large numbers from inexpensively housed adults, vast capacity for genetic manipulation, and amenability to high-throughput screening. With the help of modern genetics and a sequenced genome, zebrafish have led to insights in cardiovascular diseases ranging from CHDs to arrhythmia and cardiomyopathy. Here, we discuss the utility of zebrafish as a model system and summarize zebrafish cardiac morphogenesis with emphasis on parallels to human heart diseases. Additionally, we discuss the specific tools and experimental platforms utilized in the zebrafish model including forward screens, functional characterization of candidate genes, and high throughput applications.

Language Evolution: Constraints and Opportunities From Modern Genetics.

Our understanding of language, its origins and subsequent evolution (including language change), is shaped not only by data and theories from the language sciences, but also fundamentally by the biological sciences. Recent developments in genetics and evolutionary theory offer both very strong constraints on what scenarios of language evolution are possible and probable, but also offer exciting opportunities for understanding otherwise puzzling phenomena. Due to the intrinsic breathtaking rate of advancement in these fields, and the complexity, subtlety, and sometimes apparent non-intuitiveness of the phenomena discovered, some of these recent developments have either being completely missed by language scientists or misperceived and misrepresented. In this short paper, we offer an update on some of these findings and theoretical developments through a selection of illustrative examples and discussions that cast new light on current debates in the language sciences. The main message of our paper is that life is much more complex and nuanced than anybody could have predicted even a few decades ago, and that we need to be flexible in our theorizing instead of embracing a priori dogmas and trying to patch paradigms that are no longer satisfactory.

The mechanisms of transgenerational inheritance and their potential contribution to human phenotypes

As of today, classical genetics has already completed the majority of groundwork to describe the laws of inheritance, identify the causes of many human diseases, and dissect the mechanisms of transfer of genetic information from parents to offspring. However, recent studies indicate that inheritance of phenotypic traits may also occur through nongenetic factors, in particular, through epigenetic factors, that manifest their effects in a transgenerational fashion. This review discusses findings in the area of transgenerational inheritance that open a new era in modern genetics. We discuss the mechanisms of transgenerational inheritance, including DNA methylation, histone modifications, and noncoding RNA transfer, and give an overview of the approaches to detect transgenerational effects in humans.

A witness seminar on the history of the Human Gene Mapping Workshops

In June 2015 the transcript of a ‘Witness Seminar’ on the history of the Human Gene Mapping Workshops c.1973–c.1991 was published by the History of Modern Biomedicine Research Group (www.histmodbiomed.org/witsem/vol54). The publication came from a meeting held in March 2014 to which key, mostly UK-based scientists contributed, two of whom had participated in the first Human Gene Mapping Workshop in 1973, and many of whom had been involved in subsequent HGMW (Table 1). Table 1 Locations and dates of the Human Gene Mapping Workshops. Witness Seminars are meetings to which a group of people who have been involved in particular discoveries, debates or events are invited to share their reminiscences and memories of ‘what really happened, the stories behind the published literature’ to quote Professor Tilli Tansey who heads the Group, and who developed this approach (Jones & Tansey, 2015). Through the use of oral history in a group format, the Witness Seminar publications make a unique contribution to the international corpus of primary historical resources on twentieth century human/medical/clinical genetics, with a focus on the life stories of UK-based geneticists. The group format enables participants in the seminars to challenge, corroborate, and/or expand on the reminiscences of their peers. Although these Witness Seminar events and publications differ in style and content from the more traditional one-to-one approach to oral history, they also relate to the body of interviews conducted with scientists and clinicians by other individuals and institutions, such as: the Genetics and Medicine Historical Network of Cardiff University led by Professor Peter Harper (Genetics and Medicine Historical Network's, 2016); ‘Conversations in Genetics’ by the Genetics Society of America with USA-based scientists (Conversations in Genetics, 2016), and the National Human Genome Research Institute's staff interviews in Bethesda (NHGRI, 2016). Similar to other high-quality oral history resources, the Witness Seminar publications are intended to interact with many other primary source materials which researchers and interested publics may engage with; for example, the ‘Codebreakers: Makers of Modern Genetics’ archival collections of geneticists and related organisations digitised by the Wellcome Library, London, in collaboration with other institutions (Codebreakers, 2016). The Witness Seminar publications also stand alone as significant historical narratives of biomedicine in their own right. Each Witness Seminar meeting is facilitated by a chairman, the entire proceedings are recorded and transcribed, and then edited, with the addition of references, bibliographies and biographies, and published both in hard copy and as a freely available pdf. Several meetings have already been held and published on genetics-related or genetics-focused topics, including on haemophilia (Tansey & Christie, 1999); rhesus factor (Zallen et al., 2004); genetic testing (Christie & Tansey, 2003); clinical genetics (Harper et al., 2010); clinical cancer genetics (polyposis and familial colorectal cancer) (Jones & Tansey, 2013); and clinical molecular genetics (Jones & Tansey, 2014). All publications can be downloaded from the Group's website at: www.histmodbiomed.org/article/wellcome-witnesses-volumes.

Scalable linkage-disequilibrium-based selective sweep detection: a performance guide.

BackgroundLinkage disequilibrium is defined as the non-random associations of alleles at different loci, and it occurs when genotypes at the two loci depend on each other. The model of genetic hitchhiking predicts that strong positive selection affects the patterns of linkage disequilibrium around the site of a beneficial allele, resulting in specific motifs of correlation between neutral polymorphisms that surround the fixed beneficial allele. Increased levels of linkage disequilibrium are observed on the same side of a beneficial allele, and diminish between sites on different sides of a beneficial mutation. This specific pattern of linkage disequilibrium occurs more frequently when positive selection has acted on the population rather than under various neutral models. Thus, detecting such patterns could accurately reveal targets of positive selection along a recombining chromosome or a genome. Calculating linkage disequilibria in whole genomes is computationally expensive because allele correlations need to be evaluated for millions of pairs of sites. To analyze large datasets efficiently, algorithmic implementations used in modern population genetics need to exploit multiple cores of current workstations in a scalable way. However, population genomic datasets come in various types and shapes while typically showing SNP density heterogeneity, which makes the implementation of generally scalable parallel algorithms a challenging task.FindingsHere we present a series of four parallelization strategies targeting shared-memory systems for the computationally intensive problem of detecting genomic regions that have contributed to the past adaptation of the species, also referred to as regions that have undergone a selective sweep, based on linkage disequilibrium patterns. We provide a thorough performance evaluation of the proposed parallel algorithms for computing linkage disequilibrium, and outline the benefits of each approach. Furthermore, we compare the accuracy of our open-source sweep-detection software OmegaPlus, which implements all four parallelization strategies presented here, with a variety of neutrality tests.ConclusionsThe computational demands of selective sweep detection algorithms depend greatly on the SNP density heterogeneity and the data representation. Choosing the right parallel algorithm for the analysis can lead to significant processing time reduction and major energy savings. However, determining which parallel algorithm will execute more efficiently on a specific processor architecture and number of available cores for a particular dataset is not straightforward.Electronic supplementary materialThe online version of this article (doi:10.1186/s13742-016-0114-9) contains supplementary material, which is available to authorized users.

Squash Plants between Classic and Modern Genetics

Squash fruits are used for local consumption and for export. Squash fruits contain some nutritional compounds for human feeding such as moderate quantity of mineral salts, it is eaten cocked as an immature fruit which is rich with fibers and vitamins or consumed for the mature seed which is a good source of fats and protein. Summer squash has twenty pairs of chromosomes and has a wide range of variability in shape and color. It is an interesting plant for genetically studies. Many of the genetic variations that have arisen were perpetuated for their horticultural values and rich reservoir of genetic diversity.

The Development of Genetics in the Light of Thomas Kuhn's Theory of Scientific Revolutions.

The concept of a paradigm is in the key position in Thomas Kuhn's theory of scientific revolutions. A paradigm is the framework within which the results, concepts, hypotheses and theories of scientific research work are understood. According to Kuhn, a paradigm guides the working and efforts of scientists during the time period which he calls the period of normal science. Before long, however, normal science leads to unexplained matters, a situation that then leads the development of the scientific discipline in question to a paradigm shift--a scientific revolution. When a new theory is born, it has either gradually emerged as an extension of the past theory, or the old theory has become a borderline case in the new theory. In the former case, one can speak of a paradigm extension. According to the present author, the development of modern genetics has, until very recent years, been guided by a single paradigm, the Mendelian paradigm which Gregor Mendel launched 150 years ago, and under the guidance of this paradigm the development of genetics has proceeded in a normal fashion in the spirit of logical positivism. Modern discoveries in genetics have, however, created a situation which seems to be leading toward a paradigm shift. The most significant of these discoveries are the findings of adaptive mutations, the phenomenon of transgenerational epigenetic inheritance, and, above all, the present deeply critical state of the concept of the gene.

Identifying novel protein phenotype annotations by hybridizing protein-protein interactions and protein sequence similarities.

Studies of protein phenotypes represent a central challenge of modern genetics in the post-genome era because effective and accurate investigation of protein phenotypes is one of the most critical procedures to identify functional biological processes in microscale, which involves the analysis of multifactorial traits and has greatly contributed to the development of modern biology in the post genome era. Therefore, we have developed a novel computational method that identifies novel proteins associated with certain phenotypes in yeast based on the protein-protein interaction network. Unlike some existing network-based computational methods that identify the phenotype of a query protein based on its direct neighbors in the local network, the proposed method identifies novel candidate proteins for a certain phenotype by considering all annotated proteins with this phenotype on the global network using a shortest path (SP) algorithm. The identified proteins are further filtered using both a permutation test and their interactions and sequence similarities to annotated proteins. We compared our method with another widely used method called random walk with restart (RWR). The biological functions of proteins for each phenotype identified by our SP method and the RWR method were analyzed and compared. The results confirmed a large proportion of our novel protein phenotype annotation, and the RWR method showed a higher false positive rate than the SP method. Our method is equally effective for the prediction of proteins involving in all the eleven clustered yeast phenotypes with a quite low false positive rate. Considering the universality and generalizability of our supporting materials and computing strategies, our method can further be applied to study other organisms and the new functions we predicted can provide pertinent instructions for the further experimental verifications.

Prospects of molecular genetic approaches in controlling technological properties of wheat grain in the context of the "grain – flour – bread" chain

The potential of molecular approaches in the management of the technological properties of wheat grain affecting the quality of the end product of industry is considered. Currently, along with the growth of grain production, the traditional range of staples is crowded out, the quality of most popular varieties deteriorates, and dozens of different substances of biological and chemical origin are used as improvers. Meanwhile, the genetic potential of wheat allows the development of varieties with technological parameters of grain suitable for production of high-quality bread. In Russia, multiple examples of the creation of varieties for the production of first and second-class grain are known, and modern molecular genetics offers techniques that can supplement classical breeding approaches and accelerate the development of new varieties adapted to the conditions and requirements of the baking industry, using the natural genetic potential of wheat. We summarize the diversity of requirements for grain and flour for different end-use products. Statistics on the volume and structure of grain quality in Russia in 2011–2014 is analyzed. An essential deformation of the quality structure of the produced wheat grain in favor of less valuable classes is observed. A brief retrospective analysis of research in wheat genetics, demonstrating the contribution of genetic factors to grain and flour technological properties, is performed. Various approaches to rapid breeding of varieties with desired properties are considered in relation with the development of plant molecular genetics. The paper provides examples illustrating the feasibility of using methods of DNA diagnostics in various stages of the process, during which the genetic potential of food crops expresses itself and affects the quality of the end product. The results of molecular studies on the localization and isolation of genes determining technological properties (protein and wet gluten contents, milling properties, rheological properties, flour color, and starch properties) are reviewed. The data on diagnostic DNA markers, which are suitable for efficient selection of genotypes instead of the time-consuming analysis of technological properties during breeding process, are summarized. Thus, the information about the genetic potential of wheat and modern technologies that provide grounds for moving from excessive use of chemicals to a more benign and organic effect on the quality of the products throughout the grain – flour – bread chain, is summarized.

An ASGCT Perspective on the National Academies Genome Editing Summit.

The armamentarium of modern genetics and gene therapy has recently expanded with the rapid development of the tools of “genome editing,” including zinc-finger nucleases, TALENs, and CRISPR/Cas9 techniques that allow exquisitely targeted sequence modifications. An alluring application of such technology is somatic cell genome editing for the prevention and therapy of genetic disease. Most scientific, ethics, and policy agencies support somatic cell applications of genome editing; the gene therapy community has understandably taken deep interest because we represent the major biomedical conduit through which the technology will eventually be translated to clinical application.

Johann Gregor Mendel: paragon of experimental science.

This is a foreword on the life and work of one of the greatest minds of the 20th century, the father of modern genetics, Johann Gregor Mendel.

Wide awake under anesthesia: Scoline apnoea update

Butyrylcholinesterase (BChE) catalyses the hydrolysis of choline esters and thus deactivates muscle relaxants such as succinylcholine and mivacurium. The prolonged neuromuscular blockade following the use of succinylcholine, called scoline apnea, occurs in patients with significant BChE deficiency. It is proved that BChE activity can be reduced in certain physiological conditions, in a number of diseases and after the administration of certain drugs. Gene encoding butyrylcholinesterase (BChE, CHE1) is located on the locus 3q26.1-q26.2. This gene shows a high level of polyallelism and so far about 75 natural mutations of this gene have been documented. The development of modern genetics has provided more insight into the cause of this disorder and is now considered to be caused by a number of genetic variations in the BChE gene. The most commonly observed gene variant is 209A > G, Asp70Gly. If neuromuscular relaxants are used during anesthesia, the use of monitoring in the form of nerve stimulator is recommended. Scoline apnea should be investigated by conventional biochemical tests and molecular genetic tests. This testing should include the closest relatives of the patient if it is suspected to be inherited rather than acquired.

Mining candidate genes associated with powdery mildew resistance in cucumber via super-BSA by specific length amplified fragment (SLAF) sequencing.

BackgroundPowdery mildew (PM) is the most common fungal disease of cucumber and other cucurbit crops, while breeding the PM-resistant materials is the effective way to defense this disease, and the recent development of modern genetics and genomics make us aware of that studying the resistance genes is the essential way to breed the PM high-resistance plant. With the ever increasing throughput of next-generation sequencing (NGS), the development of specific length amplified fragment sequencing (SLAF-seq) as a high-resolution strategy for large-scale de novo SNP discovery is gradually applied for functional gene mining. Here we combined the bulked segregant analysis (BSA) with SLAF-seq to identify candidate genes associated with PM resistance in cucumber.MethodsA segregating population comprising 251 F2 individuals was developed using H136 (female parent) as susceptible parent and BK2 (male parent) as resistance donor. After PMR test, total genomic DNA was prepared from each plant. Systemic genomic analysis of the GC content, repeat sequence, etc. was carried out by prediction software SLAF_Predict to establish condition to ensure the uniformity and density of the molecular markers. After samples were gel purified, SLAFs were generated at Biomarker Technologies Corporation in Beijing. Based on SLAF tags and the PMR test result, the hot region were annotated.ResultsA total of 73,100 high-quality SLAF tags with an average depth of 99.11× were sequenced. Among these, 5,355 polymorphic tags were identified with a polymorphism rate of 7.34 %, including 7.09 % SNPs and other polymorphism types. Finally, 140 associated SLAFs were identified, and two main Hot Regions were detected on chromosome 1 and 6, which contained five genes invovled in defense response, toxin metabolism, cell stress response, and injury response in cucumber.ConclusionsAssociated markers identified by super-BSA in this study, could not only speed up the study of the PMR genes, but also provide a feasible solution for breeding the marker-assisted PMR cucumber. Moreover, this study could also be extended to any other species with reference genome.