Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Forward genetics”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 343 records · Page 19Linked to original sources
PubMed2004

Dissecting large and complex genomes: flow sorting and BAC cloning of individual chromosomes from bread wheat.

The analysis of the complex genome of common wheat (Triticum aestivum, 2n = 6x = 42, genome formula AABBDD) is hampered by its large size ( approximately 17 000 Mbp) and allohexaploid nature. In order to simplify its analysis, we developed a generic strategy for dissecting such large and complex genomes into individual chromosomes. Chromosome 3B was successfully sorted by flow cytometry and cloned into a bacterial artificial chromosome (BAC), using only 1.8 million chromosomes and an adapted protocol developed for this purpose. The BAC library (designated as TA-3B) consists of 67 968 clones with an average insert size of 103 kb. It represents 6.2 equivalents of chromosome 3B with 100% coverage and 90% specificity as confirmed by genetic markers. This method was validated using other chromosomes and its broad application and usefulness in facilitating wheat genome analysis were demonstrated by target characterization of the chromosome 3B structure through cytogenetic mapping. This report on the successful cloning of flow-sorted chromosomes into BACs marks the integration of flow cytogenetics and genomics and represents a great leap forward in genetics and genomic analysis.

Chromosome Mapping↗
PubMed1977

Plasma paroxonase activity in old age.

Genetic factors are known to be of importance in determining the rate of biotransformation of foreign compounds in the liver. Adverse reactions to drugs are increased and pharmacokinetic parameters altered with age. In the present study, the effect of age on plasma paroxonase activity is studied. Paroxonase is a hepatically synthesized enzyme whose activity is almost entirely determined by genetic factors. It therefore serves as a model to determine whether changes in the frequency or expression of genes could explain the altered responses to drugs observed with age. The frequency distribution for paroxonase activity for 186 elderly people is closely similar to that obtained from 190 blood transfusion volunteers and 189 family members. Paroxonase activity, as with all other previously investigated pharmacogenetic polymorphisms, is unchanged with age. The hypothesis is put forward that genetic determinants of drug metabolism remain unchanged with age.

Aged↗
PubMed2026

A bi-directional Mendelian randomization study of sarcopenia-related traits and renal function.

The association between sarcopenia and renal function has been reported in observational studies; however, the directionality and potential causal nature of these associations remain uncertain. We assessed whether genetically predicted sarcopenia-related traits are associated with renal function and vice versa using bidirectional Mendelian randomization (MR). We conducted a bidirectional two-sample MR analysis using publicly available European-ancestry GWAS summary statistics for appendicular lean mass (ALM), hand-grip strength (left and right), and walking pace, and for renal function (cystatin C-based estimated glomerular filtration rate [eGFRcystatin C] and urinary albumin excretion [UAE]). Causal estimates were primarily obtained using inverse-variance weighted (IVW) models, complemented by sensitivity analyses (MR-Egger intercept, weighted median/mode, MR-PRESSO, Radial MR, and leave-one-out). In forward MR, genetically predicted walking pace was positively associated with eGFRcystatin C. Genetically predicted ALM and grip strength (right and left) were inversely associated with UAE. In reverse MR, genetically predicted UAE was inversely associated with ALM and right-hand grip strength. Estimates were broadly consistent across sensitivity analyses, and outlier-robust analyses (MR-PRESSO/Radial MR) yielded similar results. These findings provide genetic evidence consistent with bidirectional relationships between sarcopenia-related traits and renal function (particularly UAE), under standard MR assumptions. Given potential limitations (e.g., heterogeneity, pleiotropy, and possible sample overlap), the results should be interpreted cautiously and complemented by other lines of evidence.

Humans↗
PubMed2026

Hyperthyroidism Is Genetically Associated With Reduced Risk of Parkinson's Disease: A Mendelian Randomization Analysis.

Parkinson's disease (PD) is a progressive neurodegenerative disorder whose aetiology involves an intricate interplay of genetic, immune, metabolic and environmental factors. Endocrine dysfunction-particularly disturbances of thyroid hormone signalling-has been proposed as a contributor to neurodegeneration, but conventional observational studies have produced inconsistent results, and prior Mendelian randomization (MR) work has largely focused on continuous thyroid biomarkers rather than clinically defined hyperthyroid disease states. To clarify this relationship, we performed a two-sample bidirectional and multivariable MR (MVMR) analysis using large-scale genome-wide association study (GWAS) summary statistics from the FinnGen and IEU Open GWAS databases (European ancestry). Single-nucleotide polymorphisms (SNPs) reaching genome-wide significance (p&#x2009;<&#x2009;5&#x2009;&#xd7;&#x2009;10-8) for Graves' disease and thyrotoxicosis with diffuse goitre served as instrumental variables. The inverse-variance weighted (IVW) method was the primary analysis, complemented by MR-Egger, weighted median, weighted mode and simple mode estimators, and MVMR adjusted for smoking, alcohol consumption, and body mass index (BMI). In forward analyses, genetically proxied Graves' disease (OR&#x2009;=&#x2009;0.942, 95% CI 0.901-0.985, p&#x2009;=&#x2009;0.008) and thyrotoxicosis with diffuse goitre (OR&#x2009;=&#x2009;0.929, 95% CI 0.879-0.982, p&#x2009;=&#x2009;0.009) were associated with a lower risk of PD, whereas reverse analyses showed no significant effect of genetic liability to PD on either thyroid trait. The inverse associations remained stable across MVMR models, and sensitivity analyses (Cochran's Q, MR-Egger intercept, MR-PRESSO, leave-one-out) showed no evidence of heterogeneity or horizontal pleiotropy. Collectively, these findings provide genetic evidence consistent with a protective relationship between hyperthyroid disease states and PD, independent of major lifestyle confounders. By focusing on clinically defined hyperthyroid entities rather than continuous thyroid indices, our study complements prior MR work and highlights the thyroid-brain axis-encompassing thyroid hormone signalling and autoimmune-mediated immune modulation-as a biologically plausible and potentially modifiable contributor to PD risk that warrants further mechanistic and translational investigation.

Humans↗
PubMed2025

SimHumanity: Using SLiM 5.0 to run whole-genome simulations of human evolution.

The reconstruction of human evolutionary history has undergone repeated advances, each made possible by methodological innovations. In recent decades, genetic and genomic data played a central role in the reconstruction of major evolutionary events such as the out-of-Africa migration, and genetic simulations of human evolutionary history have come to play a major role in testing more specific hypotheses including proposed patterns of migration and admixture with archaic hominins. Increasing computational power has allowed human evolutionary history to be modeled at ever-larger scales, but simulations that encompass the complete human genome, including sex chromosomes and mitochondrial DNA, have been difficult due to the lack of support for whole-genome models in commonly used evolutionary simulation frameworks. With the recent introduction of SLiM 5 such simulations are now straightforward to construct, allowing the easy simulation of humans at whole-genome scale under different demographic models and evolutionary dynamics. We here present three versions of a reusable, customizable, open-source SLiM 5 model for simulating the molecular evolution of the full human genome. We also show some simple analyses of results from the model, to illustrate its utility. We hope this model, which we have nicknamed "SimHumanity" in jest, will facilitate further progress in the field of human evolutionary simulations.

SLiM↗
PubMed2003

Markers of genetic susceptibility in human environmental hygiene and toxicology: the role of selected CYP, NAT and GST genes.

Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1*0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology.

Arylamine N-Acetyltransferase↗
PubMed2005

Identifying small molecule inhibitors of the ubiquitin-proteasome pathway in Xenopus egg extracts.

Small molecule inhibitors of the proteasome have been crucial for dissecting the mechanism of proteasome-dependent protein degradation and identifying substrates of the ubiquitin-proteasome system (UPS). To identify small molecules that block ubiquitin-dependent protein degradation through other mechanisms, we have developed pathway-based screening approaches in Xenopus egg extracts. The regulated degradation of UPS substrates can be reconstituted in these extracts, providing an excellent system in which to perform forward chemical genetic screens. The ability to manipulate extracts biochemically and to compare the activity of small molecules across different assays facilitates the identification of potential target proteins. Here we describe methods for identifying inhibitors of the proteolytic pathways that regulate cell cycle progression and Wnt signaling in Xenopus extracts.

Animals↗
PubMed2005

Identification of the F1F0 mitochondrial ATPase as a target for modulating skin pigmentation by screening a tagged triazine library in zebrafish.

A triazine-based combinatorial library of small molecules was screened in zebrafish to identify compounds that produced interesting phenotypes. One compound (of 1536 screened) induced a dramatic increase in the pigmentation of early stage zebrafish embryos. This compound, PPA, was also found to increase pigmentation in cultured mammalian melanocytes. The cellular target was identified as the mitochondrial F1F0-ATP synthase (ATPase) by affinity chromatography. Oligomycin, a small molecule known to inhibit the mitochondrial ATPase, competed with PPA for its cellular target in melanocytes. In addition, PPA was shown to alter the membrane potential of mitochondria, consistent with inhibition of the mitochondrial ATPase. Thus, PPA has been successfully used as a chemical probe in a forward chemical genetic approach to establish a link between the phenotype and the protein. The results attest to the power of screening small molecule libraries in zebrafish as a means of identifying mammalian targets and suggest the mitochondrial ATPase as a target for modulating pigmentation in both melanocytes and melanoma cells.

Amino Acid Sequence↗
PubMed2005

Small molecule regulation of Sir2 protein deacetylases.

The Sir2 family of histone/protein deacetylases (sirtuins) is comprised of homologues found across all kingdoms of life. These enzymes catalyse a unique reaction in which NAD+ and acetylated substrate are converted into deacetylated product, nicotinamide, and a novel metabolite O-acetyl ADP-ribose. Although the catalytic mechanism is well conserved across Sir2 family members, sirtuins display differential specificity toward acetylated substrates, which translates into an expanding range of physiological functions. These roles include control of gene expression, cell cycle regulation, apoptosis, metabolism and ageing. The dependence of sirtuin activity on NAD+ has spearheaded investigations into how these enzymes respond to metabolic signals, such as caloric restriction. In addition, NAD+ metabolites and NAD+ salvage pathway enzymes regulate sirtuin activity, supporting a link between deacetylation of target proteins and metabolic pathways. Apart from physiological regulators, forward chemical genetics and high-throughput activity screening has been used to identify sirtuin inhibitors and activators. This review focuses on small molecule regulators that control the activity and functions of this unusual family of protein deacetylases.

Enzyme Activation↗
PubMed2006

A step forward in studying the compact genetic algorithm.

The compact Genetic Algorithm (cGA) is an Estimation of Distribution Algorithm that generates offspring population according to the estimated probabilistic model of the parent population instead of using traditional recombination and mutation operators. The cGA only needs a small amount of memory; therefore, it may be quite useful in memory-constrained applications. This paper introduces a theoretical framework for studying the cGA from the convergence point of view in which, we model the cGA by a Markov process and approximate its behavior using an Ordinary Differential Equation (ODE). Then, we prove that the corresponding ODE converges to local optima and stays there. Consequently, we conclude that the cGA will converge to the local optima of the function to be optimized.

Algorithms↗
PubMed2005

Forward in reverse: how reverse genetics complements chemical genetics.

Pharmaceutical discovery has a renewed interest in physiological screening, while chemical genomics initiatives will soon provide a large amount of cellular assay data. However, there is no single robust approach to connect active compounds with their targets, limiting their experimental and therapeutic use. Systematic matching of chemical genetic phenotypes with reverse genetic phenotypes would provide a valuable starting point for many investigations.

Animals↗
PubMedDate not supplied

[Autism].

Autism is a static, neuro-developmental disorder, that is life-long and comprises a wide range of behavioral disorders. It has a prevalence of 1-2 per 1,000 with a broad range of severity. Multiple causes have been put forward and genetics plays the major role. According to DSM-IV the main clinical manifestations include impaired social skills, language and non-verbal communication and changes in range of interests and activities. Cognitive deficits are frequent but not universal. Perseveration, affective flatness and lack of insight into other people's thinking and feelings is conspicuous. The neurobiological basis of autism is unknown, but histopathological and biochemical findings suggest a diffuse disorder of neuronal development, most severe in the fronto-temporal cortex, some limbic structures and in the cerebellum. At a biochemical level, abnormalities in serotonin and other neurotransmitters have been reported.

Autistic Disorder↗
PubMed1978

The thymidine kinase gene of herpes simplex virus type 1: cell-free protein synthesis and substrate specificity studies.

The HSV thymidine kinase genetic system has a number of advantages for the study of virus and cell genetics. Both forward and reverse mutants are readily selected. The enzyme can be assayed directly in the presence of the cell TK by the choice of the appropriate substrate, for example, 125IdC. The gene product, HSV TK, can be identified by SDS-polyacrylamide gel electrophoresis and mutants can be found with alterations in the electrophoretogram. The in vitro synthesis of HSV TK in response to HSV mRNA has been achieved and can be used to analyse specific mutant virus.

Cell-Free System↗
PubMedDate not supplied

Marker-assisted study of genetic background and gene-targeted locus modifiers in lymphopoietic phenotypes.

Forward and reverse genetic approaches facilitate the molecular dissection of individual gene functions and the integration of individual gene functions into multi-gene processes in the context of the whole organism. Variations in mutant phenotypes due to genetic background differences have been well documented through the analysis of mouse mutants. Nevertheless, recommendations concerning the assessment of genetic background as it impacts on phenotype, and utilization of genetic background differences to identify and integrate gene functions have been largely overlooked. Genetic background as it relates to immunological mutants will be discussed utilizing an Ets1-targeted allele to exemplify phenotypic variation due to background. Marker-assisted strategies for the identification of genetic modifiers, especially those linked to the targeted locus, will also be considered.

Animals↗
PubMedDate not supplied

Identifying and testing for hereditary susceptibility to common cancers.

Hereditary cancer syndromes account for an estimated 5% of breast, ovarian, and colon cancers. The rapid discovery of cancer-related genes in the last 15 years has propelled the field of cancer genetic risk assessment forward. With patients becoming increasingly aware of available genetic testing options, it is important that various health professionals become knowledgeable in identifying and advising patients at increased risk for a hereditary cancer syndrome. This article will outline the components of providing a hereditary cancer risk assessment with a focus on hereditary breast and ovarian cancer syndrome and hereditary colon cancer.

Genetic Counseling↗
PubMed2006

Dual selection of a genetic switch by a single selection marker.

Forward engineering of synthetic genetic circuits in living cells is expected to deliver various applications in biotechnology and medicine and to provide valuable insights into the design principles of natural gene networks. However, lack of biochemical data and complexity of biological environment complicate rational design of such circuits based on quantitative simulation. Previously, we have shown that directed evolution can complement our weakness in designing genetic circuits by screening or selecting functional circuits from a large pool of nonfunctional ones. Here we describe a dual selection strategy that allows selection of both ON and OFF states of genetic circuits using tetA as a single selection marker. We also describe a successful demonstration of a genetic switch selection from a 2000-fold excess background of nonfunctional switches in three rounds of iterative selection. The dual selection system is more robust than the previously reported selection system employing three genes, with no observed false positive mutants during the simulated selections.

Computer Simulation↗
PubMed2002

Complexities of cancer research: mouse genetic models.

Cancer susceptibility is a complex interaction of an individual's genetic composition and environmental exposures. Huge strides have been made in understanding cancer over the past 100 yr, from recognition of cancer as a genetic disease, to identification of specific carcinogens, isolation of oncogenes, and recognition of tumor suppressors. A tremendous amount of knowledge has accumulated about the etiology of cancer. Cancer genetics has played a significant role in these discoveries. Analysis of high-risk familial cancers has led to the discovery of new tumor suppressor genes and important cancer pathways. These families, however, represent only a small fraction of cancer in the general population. Most cancer is instead probably the result of an intricate interaction of polymorphic susceptibility genes with the sea of environmental exposures that humans experience. Although the central cadre of cancer genes is known, little is understood about the peripheral genes that likely comprise the polymorphic susceptibility loci. The challenge for cancer genetics is therefore to move forward from the mendelian genetics of the rare familial cancer syndromes into the field of quantitative trait loci, susceptibility factors, and modifier genes. By identifying the genes that modulate an individual's susceptibility to cancer after an environmental exposure, researchers will be able to gain important insights into human biology, cancer prevention, and cancer treatment. This article summarizes the current state of quantitative trait genetic analysis and the tools, both proven and theoretical, that may be used to unravel one of the great challenges in cancer genetics.

Animals↗