Gametic frequencies in a panmictic population under forward and backward mutation and selection.
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Models, Biological↗
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Results for “Forward genetics”
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Closing the gap between science and clinical practice: the thiopurine S-methyltransferase polymorphism moves forward.
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Genotype↗
Gene therapy: two steps forward, one step back.
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Bone Marrow Transplantation↗
Learning to "think like a geneticist" with the de Serres ad-3 forward-mutation test in Neurospora crassa.
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Adenine↗
Integrating microarrays into disease-gene identification strategies.
Positional cloning represents one of the most successful paradigm shifts in identifying the underlying patho-mechanisms in human disease. While traditional discovery tools focused on identifying defects at the tissue or cellular level, positional cloning identifies the damaged region of the genome as the preliminary step. While a large number of inherited single gene disorders have been mapped using this approach, a bottleneck still exists in combing through the genomic interval, often millions of nucleotides in length, to identify the nucleotide changes which result in a defective protein and subsequent disease. Along with the recent unravelling of the human genetic code, the development of massively parallel tools, such as microarrays, represent an equally important step forward in unraveling pathogenic genome dysfunctions. There are many emerging variants on microarray technology, such as expression arrays, exon arrays, array-based comparative genomic hybridization and sequencing arrays. Several of these platforms, if used properly, can accelerate the positional cloning process. The proper use of the platform is driven by knowledge of the underlying molecular defect being searched for and the operating characteristics of the array. The resultant insight forms the basis for improved molecular diagnostics and novel therapeutic targets.
Computational Biology↗
New probabilistic graphical models for genetic regulatory networks studies.
This paper introduces two new probabilistic graphical models for reconstruction of genetic regulatory networks using DNA microarray data. One is an independence graph (IG) model with either a forward or a backward search algorithm and the other one is a Gaussian network (GN) model with a novel greedy search method. The performances of both models were evaluated on four MAPK pathways in yeast and three simulated data sets. Generally, an IG model provides a sparse graph but a GN model produces a dense graph where more information about gene-gene interactions may be preserved. The results of our proposed models were compared with several other commonly used models, and our models have shown to give superior performance. Additionally, we found the same common limitations in the prediction of genetic regulatory networks when using only DNA microarray data.
Algorithms↗
Gene expression and regulation in the extended longevity phenotypes of Drosophila.
We used both selection and single-gene mutagenesis studies to identify the mechanisms underlying the genetic control of longevity in Drosophila. The expression of the extended longevity phenotype (ELP) in our forward-selected strains depends on an early and specific upregulation of the antioxidant defense system (ADS) genes and enzymes, which results in decreased oxidative damage levels and a delayed onset of senescence. This mechanism does not alter metabolic rate and is itself reversed by a reverse selection regime. Single-gene mutational analysis of the regulatory genes controlling ADS gene expression show they are under the positive and negative control of several such genes, each of which can bring about the expression/repression of the ELP. Sister strains with identical ELPs have different patterns of ADS gene expression, showing that phenotypic equivalence does not require molecular equivalence. The organism may have multiple genetic strategies to cope with similar levels of oxidative stress.
Animals↗
New intermediates in the B12 pathway.
Vitamin B12 has a complex structure which represents one of the most challenging biosynthetic problems in Nature. Exciting progress has been made by combining the techniques, approaches and strengths of chemistry, spectroscopy and biology. Most of the advances until recently came from experiments based either on labelling simpler precursors with radioactive isotopes followed by controlled degradation of the labelled products, or on the use of stable isotopes, 13C in particular, because it can be detected and its environment can be studied by NMR spectroscopy. These experiments imposed heavy demands on synthesis which provided the specifically labelled starting materials. More recently, the powerful methods of genetics and molecular biology have been added to the armoury, leading to another massive surge forward by allowing the preparation, through gene overexpression, of large quantities of the enzymes of the biosynthetic pathway. Equally important has been the generation of mutant forms of B12-producing organisms in which the biosynthetic pathway is blocked at specific points. Here I focus on the latest advances. The structures of the newly discovered intermediates are described and some of the chemistry involved is explored. In conclusion, the presently known pathway to vitamin B12 is reviewed.
Carbon Radioisotopes↗
Prediction of Australian wheat genotype by environment interactions and mega-environments.
Latent environmental effects of genotype by environment interactions could be predicted from observed environmental covariates. Predictions into the wider target population of environments revealed greater insights. Wheat is grown across a diverse range of environments in Australia with contrasting environmental constraints. Targeted breeding to optimise genotypes in target environments is hindered by large and ubiquitous genotype by environment interactions (GEI). Common GEI in multi-environment trial experiments, which sample the target population of environments, can be efficiently modelled using latent environmental effects from factor analytic mixed models. However, generalised prediction into the full target population of environments is difficult without a clear link to observed environmental covariates (ECs) that are defined from high-resolution weather and soil data. Here, we used a large wheat multi-environment trial dataset and demonstrated that latent environmental effects can be associated with and predicted from observed ECs. We found GEI-based environment classes could be defined by combinations of key ECs. Prediction of main and latent effects in a wider set of environments covering the full TPE across the Australian grain belt over 13 years revealed the complex trends of environmental effects and GEI over regional scales demonstrating high year-to-year variability. Regional environment types often shifted year-to-year. Cross-validation of forward genomic prediction into untested year environments demonstrated that increased accuracy is possible if estimated genetic effects are also accurate and ECs of new environments are known. These findings may guide Australian wheat breeders to better target specifically adapted material to mega-environments defined by static GEI while also considering broad adaptability and non-static GEI resulting from year-to-year variability.
Triticum↗
Validation of a pXO2-A PCR assay to explore diversity among Italian isolates of Bacillus anthracis strains closely related to the live, attenuated Carbosap vaccine.
Several circulating Bacillus anthracis strains isolated in Italy and belonging to the A1.a cluster, genotype 3 (A1.a-3) are genotypically indistinguishable from Carbosap, a live attenuated vaccine strain, containing both pXO1 and pXO2 plasmids. The genotype was assessed by using eight-locus multilocus variable-number tandem repeat analysis. We describe here the use of a ninth locus able to explore variability among strains that have the same genotype. It is important to be able to genotype the wild isolate of B. anthracis strains from outbreaks of anthrax in areas where Carbosap vaccination of cattle and sheep is common practice. A total of 27 representative field strains isolated in Italy and four vaccinal strains, namely, Carbosap, Sterne, Pasteur I, and Pasteur II, were characterized by a ninth marker, called pXO2-A. Twenty-three field strains were genotype 3 and therefore identical to Carbosap. The marker was in the pXO2 plasmid and is based on the polymorphism of the already-known VX2-3 locus. Detection was obtained by PCR with fluorescence-labeled forward primers in order to produce appropriate fragments for capillary electrophoresis with an ABI 310 genetic analyzer. Genetic relationships showed heterogeneity in all of the examined samples. Interestingly, with respect to genotype 3, samples grouped into eight different subtypes, A to H, and the subtype G, had only two samples indistinguishable from Carbosap. The results of the present study confirm the validity of a hierarchical progressive protocol for discrimination among closely related isolates.
Animals↗
[Selective vitamin B 12 malabsorption in a 19-year-old patient].
Selective malabsorption of vitamin B12, or Imerslund-Gräsbeck disease, is a rare congenital condition. The normal ileal uptake of intrinsic-factor-bound vitamin B12 is deficient. Inheritance is autosomal recessive. Megaloblastic anemia generally appears in infancy and is usually accompanied by mild proteinuria. The case is presented of a 19-year-old woman with megaloblastic anemia due to selective vitamin B12 malabsorption. As far as we know this is the only patient in whom the disease appeared so late. Of special interest are also the marginally low Schilling tests of the patient's parents. Further conditions which may lead to vitamin B12 deficiency are also discussed. A hypothesis is put forward concerning the late appearance of the disease in this particular case. Pathophysiologic, nephrologic and genetic aspects of selective vitamin B12 malabsorption are briefly reviewed.
Adult↗
Studies of mechanical aspects of amoeboid locomotion.
When a cell crawls over a surface, it exerts forces which both change its shape and deformability and propel it forward. The mechanisms involved are poorly understood. They can best be studied by combining biochemical and molecular genetic methods with direct, quantitative measurements of mechanical properties. Measurements of cellular deformability provide indications of contractile tension developed within the cell and of cytoskeletal reorganizations which influence local cellular viscoelasticity. An example is the capping of cross-linked cell surface proteins, which occurs on cells as diverse as mammalian lymphocytes and the unicellular amoeba, Dictyostelium discoideum. Deformability measurements show that cells stiffen as they cap. Measurements on wild-type Dictyostelium cells and on cells engineered to lack conventional myosin (myosin II) demonstrate that capping requires myosin II and that the concurrent cellular stiffening results from a myosin-II-dependent contractile force. Measurements of the systematic transport of beads rearward over the surfaces of cells characterize a mechanism of movement which could be used to drive the cell forward. Capping is one such mechanism. A distinct myosin-II-independent form of rearward transport is revealed in measurements of fluorescent beads on the Dictyostelium cells which lack this protein. In addition to studies of cell locomotion, measurements of cellular mechanical properties can provide quantitative assays of the functions of cytoskeletal components. Such studies are motivated by the nature of cytoskeletal proteins whose function, in contrast to enzymes, are mechanical rather that catalytic.
Animals↗
Genetic counseling for psychiatric disorders.
Like other medical conditions, some psychiatric disorders are inherited, whereas others are not. Human genetics research is moving at a rapid pace. Genes for over 450 genetic disorders have been cloned and many disease-causing mutations have also been identified. The explosion of this new knowledge has created many new exciting opportunities in the diagnosis of these heritable disorders. The rapid pace of gene discovery will aid the identification of susceptibility genes for psychiatric disorders. Indeed, we can look forward to answers to many clinical and research questions. These are some of the gifts that the expanding field of human genetics research will continue to bring to medical science. However, as genetic tests for the detection of psychiatric disorders become available, many ethical, legal, and social implications will need to be considered. In this article, we review the principles of genetic counseling for psychiatric disorders, as well as the social and ethical dilemmas that genetic testing may bring. Although medical and scientific advances may bring many gifts, we should approach this new knowledge with caution, as one of the gifts may be a Pandora's box.
Ethics, Medical↗
Gene therapy of diabetes mellitus--aims, methods and future prospects.
Progress in pancreatic islet research and molecular biology techniques has opened the perspective for gene therapy of diabetes mellitus. This review will focus on the prerequisites for the generation of genetically engineered insulin-producing cells and current methods of gene transfer. A short account of the genetically modified insulin-secreting cell lines generated so far is also given. Although still experimental each of these new insulin-secreting cell lines is a step forward on the way to gene therapy of human diabetes.
Animals↗
Analysis of forward mutations induced by N-methyl-N'-nitro-N-nitrosoguanidine in the bacteriophage P22 mnt repressor gene.
We describe the isolation and genetic characterization of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG)-induced mutations in the phage P22 mnt repressor gene cloned in plasmid pBR322. Mutations in the mnt repressor gene or its operator on this plasmid, pPY98, confer a tetracycline resistance phenotype, whereas the wild-type plasmid confers tetracycline sensitivity. Cells carrying pPY98 were briefly exposed to MNNG to give 20 to 40% survival and a 50- to 100-fold increase in tetracycline-resistant cells. DNA sequence analysis showed that 29 of 30 MNNG-induced mutations were GC-to-AT transitions and one was an AT-to-GC transition. About 80% of the mutations are in three hotspots. This mutation spectrum is consistent with the proposed mechanism of mutagenic action of MNNG, which involves mispairing of an alkylated base, O6-methylguanine. The mnt gene may be a useful target for determining mutagenic specificity at the nucleotide level because forward mutations are easily isolated, the target size is small, and the DNA sequence changes of mutations can be determined rapidly.
Base Sequence↗
Metabolic imprinting on genetically predisposed neural circuits perpetuates obesity.
There is an obesity epidemic in the industrialized world that is not simply explained by excess energy intake and decreased energy expenditure. Persistent obesity develops when genetically predisposed individuals are in a chronic state of positive energy balance. Once established, the obese body weight is avidly defended against both over- and underfeeding. Animal studies have shown that lean individuals who are genetically predisposed toward obesity have abnormalities of neural function that prime them to become obese when caloric density of the diet is raised. These neural abnormalities are gradually "corrected" as obesity becomes fully developed, suggesting that obesity is the normal state for such individuals. Thus, defense of the obese body weight may be perpetuated by the formation of new neural circuits involved in energy-homeostasis pathways that are not then easily abolished. Such neural plasticity can occur in both adult life and during nervous-system development. Early pre- and postnatal metabolic conditions (maternal diabetes, obesity, undernutrition) can lead genetically predisposed offspring to become even more obese as adults. This enhanced obesity is associated with altered brain neural circuitry, and these changes can then be passed on to subsequent generations in a feed-forward cycle of ever-increasing body weight. Thus, the metabolic perturbations associated with obesity during both brain development and adult life can produce "metabolic imprinting" on genetically predisposed neural circuits involved in energy homeostasis. Drugs that reduce body weight decrease the defended body weight and alter neural pathways involved in energy homeostasis but have no permanent effect on body weight or neural function in most individuals. Thus, early intervention in mothers, infants, children, and adults may be the only way to prevent the formation of permanent neural connections that promote and perpetuate obesity in genetically predisposed individuals.
Animals↗
Thirteen years of manipulating the mouse genome: a personal history.
In 1974, Dr. Ralph Brinster published a paper describing the consequences of injecting embryonal carcinoma cells, the predecessors of embryonic stem cells, into mouse blastocysts. Despite their early promise, embryonal carcinoma cells would not efficiently populate the germ line of mice. A decade later Elizabeth Robertson and I described the efficient generation of germline chimaeras from cultured embryonic stem cells and shortly afterwards the genetic manipulation of the mouse germline using ES cells. Our demonstration of the potency of Embryonic Stem cells gave birth to a new era in manipulative mouse genetics, one in which endogenous genes can now be mutated at will using gene targeting of retroviral mutagenesis. This review focuses on the development and testing of concepts and techniques during the thirteen years after we knew germline modification of endogenous genes in the mouse would be possible. This period is one in which more and more sophisticated tools for manipulating the mouse germline were developed and implemented. In this review I have taken the rare opportunity to reveal some of my thought processes, frustrations, successes and failures as we moved through this exciting period of rapid technological change. As I look forward to the next thirteen years, I feel that this will be an equally exciting period for manipulative genetics as we struggle to formulate concepts and design experiments that enable us to understand gene function in an era when the sequence of all genes will be known.
Animals↗
A developmental hypothesis for adult blood pressure.
Observed increases in phenotypic variance for blood pressure during adulthood are a predictable consequence of an a priori model for developmental change and continuity previously applied to cognitive development. The implications of this model for genetic and environmental covariances depend on the mechanism which maintains developmental continuity. Using data from young adult twins and their parents, it is shown how traditionally estimated genetic and environmental parameters may be reinterpreted in the light of the developmental model. Illustrative data suggest a hypothesis that genetic effects on blood pressure are largely temporally pleiotropic, acting consistently but not cumulatively throughout adulthood, while environmental influences act haphazardly but their effects are transmitted forward with high fidelity.
Adolescent↗