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Cancer Discovery Jul 2022Epithelial stem cells accumulate mutations throughout life. Some of these mutants increase competitive fitness and may form clones that colonize the stem cell niche and... (Review)
Review
UNLABELLED
Epithelial stem cells accumulate mutations throughout life. Some of these mutants increase competitive fitness and may form clones that colonize the stem cell niche and persist to acquire further genome alterations. After a transient expansion, mutant stem cells must revert to homeostatic behavior so normal tissue architecture is maintained. Some positively selected mutants may promote cancer development, whereas others inhibit carcinogenesis. Factors that shape the mutational landscape include wild-type and mutant stem cell dynamics, competition for the niche, and environmental exposures. Understanding these processes may give new insight into the basis of cancer risk and opportunities for cancer prevention.
SIGNIFICANCE
Recent advances in sequencing have found somatic mutations in all epithelial tissues studied to date. Here we review how the mutational landscape of normal epithelia is shaped by clonal competition within the stem cell niche combined with environmental exposures. Some of the selected mutant genes are oncogenic, whereas others may be inhibitory of transformation. Discoveries in this area leave many open questions, such as the definition of cancer driver genes, the mechanisms by which tissues constrain a high proportion of oncogenic mutant cells, and whether clonal fitness can be modulated to decrease cancer risk.
Topics: Carcinogenesis; Clone Cells; Epithelium; Humans; Mutation; Neoplasms
PubMed: 35397477
DOI: 10.1158/2159-8290.CD-22-0145 -
Hereditas Mar 2024Mutants have had a fundamental impact upon scientific and applied genetics. They have paved the way for the molecular and genomic era, and most of today's crop plants... (Review)
Review
BACKGROUND
Mutants have had a fundamental impact upon scientific and applied genetics. They have paved the way for the molecular and genomic era, and most of today's crop plants are derived from breeding programs involving mutagenic treatments.
RESULTS
Barley (Hordeum vulgare L.) is one of the most widely grown cereals in the world and has a long history as a crop plant. Barley breeding started more than 100 years ago and large breeding programs have collected and generated a wide range of natural and induced mutants, which often were deposited in genebanks around the world. In recent years, an increased interest in genetic diversity has brought many historic mutants into focus because the collections are regarded as valuable resources for understanding the genetic control of barley biology and barley breeding. The increased interest has been fueled also by recent advances in genomic research, which provided new tools and possibilities to analyze and reveal the genetic diversity of mutant collections.
CONCLUSION
Since detailed knowledge about phenotypic characters of the mutants is the key to success of genetic and genomic studies, we here provide a comprehensive description of mostly morphological barley mutants. The review is closely linked to the International Database for Barley Genes and Barley Genetic Stocks ( bgs.nordgen.org ) where further details and additional images of each mutant described in this review can be found.
Topics: Hordeum; Plant Breeding; Mutagenesis; Genomics
PubMed: 38454479
DOI: 10.1186/s41065-023-00304-w -
Frontiers in Plant Science 2020Gametophytic mutants share very small proportion of the total mutants generated by any mutagenic approach; even rarer are the fertilization-defective gametophytic... (Review)
Review
Gametophytic mutants share very small proportion of the total mutants generated by any mutagenic approach; even rarer are the fertilization-defective gametophytic mutants. They require an efficient and targeted strategy instead of 'brute force' screening approach. The classical gametophyte mutant screening method, mainly based on the segregation distortion, can distinguish gametophytic mutants from the others. However, the mutants pooled after the screening constitute both fertilization-defective and developmental-defective gametophytic mutants. Until recently, there has not been any straightforward way to screen the former from the latter. Additionally, most of the mutations affecting both gametes are lost during the screening process. The novel gametophyte screening approach tends to circumvent those shortcomings. This review discusses on the classical approach of gametophytic mutant screening and focuses on the novel approach on distinguishing fertilization-/developmental-defective gametophytic mutants (both male and female). It offers an empirical basis of screening such mutants by taking in the consideration of earlier studies on fertilization failure, initiation of seed coat formation, and fertilization recovery system in plants.
PubMed: 32714355
DOI: 10.3389/fpls.2020.00967 -
Nature Communications Oct 2023The literature about mutant invasion and fixation typically assumes populations to exist in isolation from their ecosystem. Yet, populations are part of ecological...
The literature about mutant invasion and fixation typically assumes populations to exist in isolation from their ecosystem. Yet, populations are part of ecological communities, and enemy-victim (e.g. predator-prey or pathogen-host) interactions are particularly common. We use spatially explicit, computational pathogen-host models (with wild-type and mutant hosts) to re-visit the established theory about mutant fixation, where the pathogen equally attacks both wild-type and mutant individuals. Mutant fitness is assumed to be unrelated to infection. We find that pathogen presence substantially weakens selection, increasing the fixation probability of disadvantageous mutants and decreasing it for advantageous mutants. The magnitude of the effect rises with the infection rate. This occurs because infection induces spatial structures, where mutant and wild-type individuals are mostly spatially separated. Thus, instead of mutant and wild-type individuals competing with each other, it is mutant and wild-type "patches" that compete, resulting in smaller fitness differences and weakened selection. This implies that the deleterious mutant burden in natural populations might be higher than expected from traditional theory.
Topics: Humans; Models, Biological; Ecosystem; Probability; Population Dynamics
PubMed: 37863909
DOI: 10.1038/s41467-023-41787-5 -
Cellular Signalling Jan 2020Vav1 is physiologically active as a GDP/GTP nucleotide exchange factor (GEF) in the hematopoietic system. Its wild-type form was recently implicated in mammalian... (Review)
Review
Vav1 is physiologically active as a GDP/GTP nucleotide exchange factor (GEF) in the hematopoietic system. Its wild-type form was recently implicated in mammalian malignancies of hematologic and non-hematologic tissue origins. Moreover, it was recently identified as a mutated gene in human cancers of various origins. In this review we focus on the functional activities of several of the Vav1 mutants analyzed for their tumorigenic properties. We also discuss the relationship of the tested biochemical properties of Vav1 mutants, E59K, D517E and L801P, to their computer-based predicted properties. These comparisons further enhance the need for integration of computation-based structural analyses with experimental data in order to fully appreciate the activity of mutant proteins. Our comprehensive evaluation supports the classification of Vav1 as a bona fide oncogene in human cancers.
Topics: Animals; Carcinogenesis; Humans; Mutant Proteins; Mutation; Neoplasms; Oncogenes; Proto-Oncogene Proteins c-vav
PubMed: 31654719
DOI: 10.1016/j.cellsig.2019.109438 -
PloS One 2022Lens culinaris is a proteinaceous food crop that is consumed worldwide for protein requirements. Mutation breeding has been used to improve protein content, yield, and...
Lens culinaris is a proteinaceous food crop that is consumed worldwide for protein requirements. Mutation breeding has been used to improve protein content, yield, and related traits, as well as to select highly desirable mutants that are economically significant. An investigation of genotypic variation in lentil germplasm was carried out using induced mutagenesis, with caffeine, ethyl methane sulfonate (EMS), lead nitrate, and cadmium nitrate as mutagens that resulted in 18 mutant lines in the M3 generation. For the present study, we analyzed the genetic diversity of lentil mutant lines using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and random amplified polymorphic DNA markers (RAPD). The heterozygosity of RAPD markers per primer ranged from 50.00-90.90% with an average of 71.04%. The genetic divergent analysis was performed using hierarchical clustering (UPGMA), exhibited that these mutant lines were classified mainly into five subpopulation or clusters. A close resemblance with highest genetic coefficient similarity (1.00) were observed between control and mutant H; between mutant M and E; between mutant Q and J2, while more divergent mutants were N2 with mutant B; and mutant R with mutant J1with least genetic coefficient similarity (0.22). Protein and mineral content (Fe, Zn and Cu) were increased significantly in some high yielding mutant lines concerning to the control plant, and showed polymorphic variations in polypeptide chains in terms of banding pattern. Stomatal morphology in high yielding mutants were perceived utilizing scanning electron microscopy (SEM), exhibiting variations in stomatal size, stomatal opening and number of stomata. The present study's promising mutant lines' biological, physiological, and molecular profiles provide a foundation for forthcoming preservation and consumption strategies to broaden the genetic diversity of the breeding population of lentil.
Topics: Lens Plant; Random Amplified Polymorphic DNA Technique; Genetic Markers; Caffeine; Sodium Dodecyl Sulfate; Plant Breeding; Mutagens; Methane; Genetic Variation
PubMed: 36279277
DOI: 10.1371/journal.pone.0274937 -
International Journal of Molecular... Oct 2022Mutation is a source of genetic diversity widely used in breeding programs for the acquisition of agronomically interesting characters in commercial varieties of the... (Review)
Review
Mutation is a source of genetic diversity widely used in breeding programs for the acquisition of agronomically interesting characters in commercial varieties of the species, as well as in the rest of crop species. Mutation can occur in nature at a very low frequency or can be induced artificially. Spontaneous or bud sport mutations in somatic cells can be vegetatively propagated to get an individual with the mutant phenotype. Unlike animals, plants have unlimited growth and totipotent cells that let somatic mutations to be transmitted to the progeny. On the other hand, in vitro tissue culture makes it possible to induce mutation in plant material and perform large screenings for mutant's selection and cleaning of chimeras. Finally, targeted mutagenesis has been boosted by the application of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)/Cas9 and Transcription activator-like effector nuclease (TALEN) editing technologies. Over the last few decades, environmental stressors such as global warming have been threatening the supply of global demand for food based on population growth in the near future. For this purpose, the release of new varieties adapted to such changes is a requisite, and selected or generated mutants by properly regulated mechanisms could be helpful to this task. In this work, we reviewed the most relevant mutations for breeding traits in species such as flowering time, self-compatibility, fruit quality, and disease tolerance, including new molecular perspectives in the present postgenomic era including CRISPR/Cas9 and TALEN editing technologies.
Topics: Animals; Gene Editing; CRISPR-Cas Systems; Transcription Activator-Like Effector Nucleases; Prunus; Plant Breeding; Mutation; Endonucleases; Genome, Plant
PubMed: 36362061
DOI: 10.3390/ijms232113273 -
International Journal of Molecular... Dec 2019The p53 family of proteins has grown substantially over the last 40 years. It started with p53, then p63, p73, isoforms and mutants of these proteins. The function of... (Review)
Review
The p53 family of proteins has grown substantially over the last 40 years. It started with p53, then p63, p73, isoforms and mutants of these proteins. The function of p53 as a tumour suppressor has been thoroughly investigated, but the functions of all isoforms and mutants and the interplay between them are still poorly understood. Mutant p53 proteins lose p53 function, display dominant-negative (DN) activity and display gain-of-function (GOF) to varying degrees. GOF was originally attributed to mutant p53's inhibitory function over the p53 family members p63 and p73. It has become apparent that this is not the only way in which mutant p53 operates as a large number of transcription factors that are not related to p53 are activated on mutant p53 binding. This raises the question to what extent mutant p53 binding to p63 and p73 plays a role in mutant p53 GOF. In this review, we discuss the literature around the interaction between mutant p53 and family members, including other binding partners, the functional consequences and potential therapeutics.
Topics: Humans; Mutant Proteins; Mutation; Neoplasms; Protein Binding; Protein Isoforms; Transcription Factors; Tumor Protein p73; Tumor Suppressor Protein p53; Tumor Suppressor Proteins
PubMed: 31817935
DOI: 10.3390/ijms20246188 -
Journal of Evolutionary Biology Feb 2023Mutant dynamics in fragmented populations have been studied extensively in evolutionary biology. Yet, open questions remain, both experimentally and theoretically. Some...
Mutant dynamics in fragmented populations have been studied extensively in evolutionary biology. Yet, open questions remain, both experimentally and theoretically. Some of the fundamental properties predicted by models still need to be addressed experimentally. We contribute to this by using a combination of experiments and theory to investigate the role of migration in mutant distribution. In the case of neutral mutants, while the mean frequency of mutants is not influenced by migration, the probability distribution is. To address this empirically, we performed in vitro experiments, where mixtures of GFP-labelled ("mutant") and non-labelled ("wid-type") murine cells were grown in wells (demes), and migration was mimicked via cell transfer from well to well. In the presence of migration, we observed a change in the skewedness of the distribution of the mutant frequencies in the wells, consistent with previous and our own model predictions. In the presence of de novo mutant production, we used modelling to investigate the level at which disadvantageous mutants are predicted to exist, which has implications for the adaptive potential of the population in case of an environmental change. In panmictic populations, disadvantageous mutants can persist around a steady state, determined by the rate of mutant production and the selective disadvantage (selection-mutation balance). In a fragmented system that consists of demes connected by migration, a steady-state persistence of disadvantageous mutants is also observed, which, however, is fundamentally different from the mutation-selection balance and characterized by higher mutant levels. The increase in mutant frequencies above the selection-mutation balance can be maintained in small ( ) demes as long as the migration rate is sufficiently small. The migration rate above which the mutants approach the selection-mutation balance decays exponentially with . The observed increase in the mutant numbers is not explained by the change in the effective population size. Implications for evolutionary processes in diseases are discussed, where the pre-existence of disadvantageous drug-resistant mutant cells or pathogens drives the response of the disease to treatments.
Topics: Animals; Mice; Selection, Genetic; Models, Genetic; Mutation; Population Dynamics; Biological Evolution
PubMed: 36514852
DOI: 10.1111/jeb.14131 -
Molecular Psychiatry Jun 2021Genome-wide association studies uncovered the association of ZNF804A (Zinc-finger protein 804A) with schizophrenia (SZ). In vitro data have indicated that ZNF804A might...
Genome-wide association studies uncovered the association of ZNF804A (Zinc-finger protein 804A) with schizophrenia (SZ). In vitro data have indicated that ZNF804A might exert its biological roles by regulating spine and neurite morphogenesis. However, no in vivo data are available for the role of ZNF804A in psychiatric disorders in general, SZ in particular. We generated ZFP804A mutant mice, and they showed deficits in contextual fear and spatial memory. We also observed the sensorimotor gating impairment, as revealed by the prepulse inhibition test, but only in female ZFP804A mutant mice from the age of 6 months. Notably, the PPI difference between the female mutant and control mice was no longer existed with the administration of Clozapine or after the ovariectomy. Hippocampal long-term potentiation was normal in both genders of the mutant mice. Long-term depression was absent in male mutants, but facilitated in the female mutants. Protein levels of hippocampal serotonin-6 receptor and GABAB1 receptor were increased, while those of cortical dopamine 2 receptor were decreased in the female mutants with no obvious changes in the male mutants. Moreover, the spine density was reduced in the cerebral cortex and hippocampus of the mutant mice. Knockdown of ZFP804A impaired the neurite morphogenesis of cortical and hippocampal neurons, while its overexpression enhanced neurite morphogenesis only in the cortical neurons in vitro. Our data collectively support the idea that ZFP804A/ZNF804A plays important roles in the cognitive functions and sensorimotor gating, and its dysfunction may contribute to SZ, particularly in the female patients.
Topics: Animals; Fear; Female; Genome-Wide Association Study; Hippocampus; Humans; Kruppel-Like Transcription Factors; Male; Mice; Neurons; Schizophrenia
PubMed: 33303946
DOI: 10.1038/s41380-020-00972-4