Genetics
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Caenorhabditis elegans mutants resistant to inhibitors of acetylcholinesterase. Abstract
We characterized 18 genes from Caenorhabditis elegans that, when mutated, confer recessive resistance to inhibitors of acetylcholinesterase. These include previously described genes as well as newly identified genes; they encode essential as well as nonessential functions. In the absence of acetylcholinesterase inhibitors, the different mutants display a wide range of behavioral deficits, from mild uncoordination to almost complete paralysis. Measurements of acetylcholine levels in these mutants suggest that some of the genes are involved in presynaptic functions.
Genetics - Tập 140 Số 2 - Trang 527-535 - 1995
Pharmacogenetic Analysis Reveals a Post-Developmental Role for Rac GTPases in<i>Caenorhabditis elegans</i>GABAergic Neurotransmission Abstract The nerve-cell cytoskeleton is essential for the regulation of intrinsic neuronal activity. For example, neuronal migration defects are associated with microtubule regulators, such as LIS1 and dynein, as well as with actin regulators, including Rac GTPases and integrins, and have been thought to underlie epileptic seizures in patients with cortical malformations. However, it is plausible that post-developmental functions of specific cytoskeletal regulators contribute to the more transient nature of aberrant neuronal activity and could be masked by developmental anomalies. Accordingly, our previous results have illuminated functional roles, distinct from developmental contributions, for Caenorhabditis elegans orthologs of LIS1 and dynein in GABAergic synaptic vesicle transport. Here, we report that C. elegans with function-altering mutations in canonical Rac GTPase-signaling-pathway members demonstrated a robust behavioral response to a GABAA receptor antagonist, pentylenetetrazole. Rac mutants also exhibited hypersensitivity to an acetylcholinesterase inhibitor, aldicarb, uncovering deficiencies in inhibitory neurotransmission. RNA interference targeting Rac hypomorphs revealed synergistic interactions between the dynein motor complex and some, but not all, members of Rac-signaling pathways. These genetic interactions are consistent with putative Rac-dependent regulation of actin and microtubule networks and suggest that some cytoskeletal regulators cooperate to uniquely govern neuronal synchrony through dynein-mediated GABAergic vesicle transport in C. elegans.
Genetics - Tập 183 Số 4 - Trang 1357-1372 - 2009
Multiple Subunits of the <i>Caenorhabditis elegans</i> Anaphase-Promoting Complex Are Required for Chromosome Segregation During Meiosis I Abstract
Two genes, originally identified in genetic screens for Caenorhabditis elegans mutants that arrest in metaphase of meiosis I, prove to encode subunits of the anaphase-promoting complex or cyclosome (APC/C). RNA interference studies reveal that these and other APC/C subunits are essential for the segregation of chromosomal homologs during meiosis I. Further, chromosome segregation during meiosis I requires APC/C functions in addition to the release of sister chromatid cohesion.
Genetics - Tập 160 Số 2 - Trang 805-813 - 2002
A Mosaic Genetic Screen for Drosophila Neoplastic Tumor Suppressor Genes Based on Defective Pupation Abstract The Drosophila neoplastic tumor suppressor genes (TSGs) coordinately control cell polarity and proliferation in epithelial and neuronal tissues. While a small group of neoplastic TSG mutations have been isolated and their corresponding genes cloned, the regulatory pathways that normally prevent inappropriate growth remain unclear. Identification of additional neoplastic TSGs may provide insight into this question. We report here the design of an efficient screen for isolating neoplastic TSG mutations utilizing genetically mosaic larvae. This screen is based on a defective pupation phenotype seen when a single pair of imaginal discs is homozygous for a neoplastic TSG mutation, which suggests that continuously proliferating cells can interfere with metamorphosis. Execution of this screen on two chromosome arms led to the identification of mutations in at least seven new neoplastic TSGs. The isolation of additional loci that affect hyperplastic as well as neoplastic growth indicates the utility of this screening strategy for studying epithelial growth control.
Genetics - Tập 177 Số 3 - Trang 1667-1677 - 2007
The Response to Heat Shock and Oxidative Stress in<i>Saccharomyces cerevisiae</i> Abstract A common need for microbial cells is the ability to respond to potentially toxic environmental insults. Here we review the progress in understanding the response of the yeast Saccharomyces cerevisiae to two important environmental stresses: heat shock and oxidative stress. Both of these stresses are fundamental challenges that microbes of all types will experience. The study of these environmental stress responses in S. cerevisiae has illuminated many of the features now viewed as central to our understanding of eukaryotic cell biology. Transcriptional activation plays an important role in driving the multifaceted reaction to elevated temperature and levels of reactive oxygen species. Advances provided by the development of whole genome analyses have led to an appreciation of the global reorganization of gene expression and its integration between different stress regimens. While the precise nature of the signal eliciting the heat shock response remains elusive, recent progress in the understanding of induction of the oxidative stress response is summarized here. Although these stress conditions represent ancient challenges to S. cerevisiae and other microbes, much remains to be learned about the mechanisms dedicated to dealing with these environmental parameters.
Genetics - Tập 190 Số 4 - Trang 1157-1195 - 2012
Transcriptional Regulators of the <i>Schizosaccharomyces pombe fbp1</i> Gene Include Two Redundant Tup1p-like Corepressors and the CCAAT Binding Factor Activation Complex Abstract
The Schizosaccharomyces pombe fbp1 gene, which encodes fructose-1,6-bis-phosphatase, is transcriptionally repressed by glucose through the activation of the cAMP-dependent protein kinase A (PKA) and transcriptionally activated by glucose starvation through the activation of a mitogen-activated protein kinase (MAPK). To identify transcriptional regulators acting downstream from or in parallel to PKA, we screened an adh-driven cDNA plasmid library for genes that increase fbp1 transcription in a strain with elevated PKA activity. Two such clones express amino-terminally truncated forms of the S. pombe tup12 protein that resembles the Saccharomyces cerevisiae Tup1p global corepressor. These clones appear to act as dominant negative alleles. Deletion of both tup12 and the closely related tup11 gene causes a 100-fold increase in fbp1-lacZ expression, indicating that tup11 and tup12 are redundant negative regulators of fbp1 transcription. In strains lacking tup11 and tup12, the atf1-pcr1 transcriptional activator continues to play a central role in fbp1-lacZ expression; however, spc1 MAPK phosphorylation of atf1 is no longer essential for its activation. We discuss possible models for the role of tup11- and tup12-mediated repression with respect to signaling from the MAPK and PKA pathways. A third clone identified in our screen expresses the php5 protein subunit of the CCAAT-binding factor (CBF). Deletion of php5 reduces fbp1 expression under both repressed and derepressed conditions. The CBF appears to act in parallel to atf1-pcr1, although it is unclear whether or not CBF activity is regulated by PKA.
Genetics - Tập 157 Số 3 - Trang 1205-1215 - 2001
THE INTERACTION OF SELECTION AND LINKAGE. I. GENERAL CONSIDERATIONS; HETEROTIC MODELS
Genetics - Tập 49 Số 1 - Trang 49-67 - 1964
Bacterial Persistence Abstract
The persistence phenotype is an epigenetic trait exhibited by a subpopulation of bacteria, characterized by slow growth coupled with an ability to survive antibiotic treatment. The phenotype is acquired via a spontaneous, reversible switch between normal and persister cells. These observations suggest that clonal bacterial populations may use persister cells, whose slow division rate under growth conditions leads to lower population fitness, as an “insurance policy” against antibiotic encounters. We present a model of Escherichia coli persistence, and using experimentally derived parameters for both wild type and a mutant strain (hipQ) with markedly different switching rates, we show how fitness loss due to slow persister growth pays off as a risk-reducing strategy. We demonstrate that wild-type persistence is suited for environments in which antibiotic stress is a rare event. The optimal rate of switching between normal and persister cells is found to depend strongly on the frequency of environmental changes and only weakly on the selective pressures of any given environment. In contrast to typical examples of adaptations to features of a single environment, persistence appears to constitute an adaptation that is tuned to the distribution of environmental change.
Genetics - Tập 169 Số 4 - Trang 1807-1814 - 2005
INBREEDING ESTIMATION FROM POPULATION DATA: MODELS, PROCEDURES AND IMPLICATIONS ABSTRACT
Four different estimation procedures for models of population structure are compared. The parameters of the models are shown to be equivalent and, in most cases, easily expressed in terms of the parameters Wright calls "F-statistics." We have estimated the parameters of each of these models with data on nine codominant allele pairs in 47 Yanomama villages, and we find that the different estimators for a given parameter all yield more or less equivalent results.
F-statistics are often equated to inbreeding coefficients that are defined as the probability of identity by descent from alleles taken to be unique in some founding population. However, we are led to infer from computer simulation and general historical considerations that all estimates from genotype frequencies greatly underestimate the inbreeding coefficient for alleles in the founding population of American Indians in the western hemisphere. We surmise that in the highly subdivided tribal populations which prevailed until the recent advent of civilization, the probability of identity by descent for homologous alleles was roughly 0.5. We consider some consequences of working with the customary, much lower, estimates—0.005 to 0.01—if, on the time scale of human evolution, these represent only a very recent departure from the inbreeding intensity that prevailed before civilization.
Genetics - Tập 85 Số 2 - Trang 355-371 - 1977
Genetic Screen for Postembryonic Development in the Zebrafish (<i>Danio rerio</i>): Dominant Mutations Affecting Adult Form Abstract Large-scale forward genetic screens have been instrumental for identifying genes that regulate development, homeostasis, and regeneration, as well as the mechanisms of disease. The zebrafish, Danio rerio, is an established genetic and developmental model used in genetic screens to uncover genes necessary for early development. However, the regulation of postembryonic development has received less attention as these screens are more labor intensive and require extensive resources. The lack of systematic interrogation of late development leaves large aspects of the genetic regulation of adult form and physiology unresolved. To understand the genetic control of postembryonic development, we performed a dominant screen for phenotypes affecting the adult zebrafish. In our screen, we identified 72 adult viable mutants showing changes in the shape of the skeleton as well as defects in pigmentation. For efficient mapping of these mutants and mutation identification, we devised a new mapping strategy based on identification of mutant-specific haplotypes. Using this method in combination with a candidate gene approach, we were able to identify linked mutations for 22 out of 25 mutants analyzed. Broadly, our mutational analysis suggests that there are key genes and pathways associated with late development. Many of these pathways are shared with humans and are affected in various disease conditions, suggesting constraint in the genetic pathways that can lead to change in adult form. Taken together, these results show that dominant screens are a feasible and productive means to identify mutations that can further our understanding of gene function during postembryonic development and in disease.
Genetics - Tập 207 Số 2 - Trang 609-623 - 2017
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