Journal articles on the topic 'Mutant Phenotype'
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von Eiff, Christof, Peter McNamara, Karsten Becker, Donna Bates, Xiang-He Lei, Michael Ziman, Barry R. Bochner, Georg Peters, and Richard A. Proctor. "Phenotype Microarray Profiling of Staphylococcus aureus menD and hemB Mutants with the Small-Colony-Variant Phenotype." Journal of Bacteriology 188, no. 2 (January 15, 2006): 687–93. http://dx.doi.org/10.1128/jb.188.2.687-693.2006.
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ABSTRACT Standard biochemical tests have revealed that hemin and menadione auxotrophic Staphylococcus aureus small-colony variants (SCVs) exhibit multiple phenotypic changes. To provide a more complete analysis of the SCV phenotype, two genetically defined mutants with a stable SCV phenotype were comprehensively tested. These mutants, generated via mutations in menD or hemB that yielded menadione and hemin auxotrophs, were subjected to phenotype microarray (PM) analysis of over 1,500 phenotypes (including utilization of different carbon, nitrogen, phosphate, and sulfur sources; growth stimulation or inhibition by amino acids and other nutrients, osmolytes, and metabolic inhibitors; and susceptibility to antibiotics). Compared to parent strain COL, the hemB mutant was defective in utilization of a variety of carbon sources, including Krebs cycle intermediates and compounds that ultimately generate ATP via electron transport. The phenotype of the menD mutant was similar to that of the hemB mutant, but the defects in carbon metabolism were more pronounced than those seen with the hemB mutant. In both mutant strains, hexose phosphates and other carbohydrates that provide ATP in the absence of electron transport stimulated growth. Other phenotypes of SCV mutants, such as hypersensitivity to sodium selenite, sodium tellurite, and sodium nitrite, were also uncovered by the PM analysis. Key results of the PM analysis were confirmed in independent growth studies and by using Etest strips for susceptibility testing. PM technology is a new and efficient technology for assessing cellular phenotypes in S. aureus.
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McKenzie, Calen, Ivette Guzman, Ciro Velasco-Cruz, and Paul W. Bosland. "Photosynthetic Pigments Profiled in Capsicum Lutescens Mutants." Journal of the American Society for Horticultural Science 146, no. 4 (July 2021): 233–40. http://dx.doi.org/10.21273/jashs05025-20.
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Lutescens, or lutescent, plant mutants produce leaves that are abnormally light yellow-green compared with normal plants, and are observed in multiple species of Capsicum as well as other genera such as Zea, Oryza, and Oenothera. Previous investigations into the lutescent phenotype in Capsicum have focused on genetic and transcriptomic analyses, and comparatively little is known about the phytochemical constituents of the lutescent leaf phenotype. Previous research in similar lutescent mutants in Capsicum and Oryza species has attributed their pale yellow-green leaf color and poor vigor to deficient chloroplast development. A total of 25 accessions of Capsicum lutescens mutants were phenotyped and analyzed based on a multivariate approach, using ‘Jupiter’ bell pepper (Capsicum annuum) with normal green leaves as a contextual benchmark. Photosynthetic pigments from mutant leaves were extracted and analyzed using high-performance liquid chromatography (HPLC); reflectance of the leaf material was measured with a chromameter using the L*a*b* color space. The chlorophyll a (Chl a)/b (Chl b) ratio was greater in leaves of lutescens mutants than in ‘Jupiter’. Multivariate statistical analyses revealed all lutescent mutant accessions could be distinguished from the ‘Jupiter’ contextual benchmark by variables indicating poor chloroplast development and increased photooxidative stress in lutescent mutant accessions. The lutescent leaf phenotype was not found to be caused by elevated xanthophyll or decreased chlorophyll concentrations. Furthermore, multivariate analysis revealed the lutescent mutant phenotype to be variable, with a wide range of phenotypes clustered into four major groups.
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Alvarez-Ortega, Carolina, Irith Wiegand, Jorge Olivares, Robert E. W. Hancock, and José Luis Martínez. "Genetic Determinants Involved in the Susceptibility of Pseudomonas aeruginosa to β-Lactam Antibiotics." Antimicrobial Agents and Chemotherapy 54, no. 10 (August 2, 2010): 4159–67. http://dx.doi.org/10.1128/aac.00257-10.
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ABSTRACT The resistome of P. aeruginosa for three β-lactam antibiotics, namely, ceftazidime, imipenem, and meropenem, was deciphered by screening a comprehensive PA14 mutant library for mutants with increased or reduced susceptibility to these antimicrobials. Confirmation of the phenotypes of all selected mutants was performed by Etest. Of the total of 78 confirmed mutants, 41 demonstrated a reduced susceptibility phenotype and 37 a supersusceptibility (i.e., altered intrinsic resistance) phenotype, with 6 mutants demonstrating a mixed phenotype, depending on the antibiotic. Only three mutants demonstrated reduced (PA0908) or increased (glnK and ftsK) susceptibility to all three antibiotics. Overall, the mutant profiles of susceptibility suggested distinct mechanisms of action and resistance for the three antibiotics despite their similar structures. More detailed analysis indicated important roles for novel and known β-lactamase regulatory genes, for genes with likely involvement in barrier function, and for a range of regulators of alginate biosynthesis.
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Yu, I.-ching, Kevin A. Fengler, Steven J. Clough, and Andrew F. Bent. "Identification of Arabidopsis Mutants Exhibiting an Altered Hypersensitive Response in Gene-for-Gene Disease Resistance." Molecular Plant-Microbe Interactions® 13, no. 3 (March 2000): 277–86. http://dx.doi.org/10.1094/mpmi.2000.13.3.277.
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A mutational study was carried out to isolate Arabidopsis thaliana plants that exhibit full or partial disruption of the RPS2-mediated hypersensitive response (HR) to Pseudomonas syringae that express avrRpt2. Five classes of mutants were identified including mutations at RPS2, dnd mutations causing a “defense, no death” loss-of-HR phenotype, a lesion-mimic mutant that also exhibited an HR¯phenotype, and a number of intermediate or partial-loss-of-HR mutants. Surprisingly, many of these mutants displayed elevated resistance to virulent P. syringae and, in some cases, to Peronospora parasitica. Constitutively elevated levels of pathogenesis-related (PR) gene expression and salicylic acid were also observed. In the lesion-mimic mutant, appearance of elevated resistance was temporally correlated with appearance of lesions. For one of the intermediate lines, resistance was shown to be dependent on elevated levels of salicylic acid. A new locus was identified and named IHR1, after the mutant phenotype of “intermediate HR.” Genetic analysis of the intermediate-HR plant lines was difficult due to uncertainties in distinguishing the partial/intermediate mutant phenotypes from wild type. Despite this difficulty, the intermediate-HR mutants remain of interest because they reveal potential new defense-related loci and because many of these lines exhibit partially elevated disease resistance without dwarfing or other apparent growth defects.
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Zhang, Xingping, Bill Rhodes, Vance Baird, and Halina Skorupska. "A Tendrilless Mutant in Watermelon: Phenotype and Development." HortScience 31, no. 4 (August 1996): 602e—602. http://dx.doi.org/10.21273/hortsci.31.4.602e.
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A spontaneous watermelon mutant, previously named branch less, was re-evaluated in this study. The mutant watermelon plants from genetic stock Bl-91 and derived from F2 and BC1 populations, did not produce tendrils under field or greenhouse conditions. The mutants stopped producing branches after the fifth or sixth node. Leaf shape changed during development of the mutants. Early leaves were normal, but later leaves had fewer and fewer lobes, finally becoming triangular toward the end of the shoot. The most distinct effect of the mutant gene was to convert vegetative meristems into floral meristems; tendrils and axillary buds were replaced by flowers at the node. The mutant plants were determinate. A grafting experiment showed that the rootstock had no effect on the mutant phenotype. Genetic analysis of F1, F2, and BC1 populations suggested that the mutant is inherited as a single, recessive nuclear gene. Based on the phenotype, a new name is suggested for this mutant: tendrilless, with a new gene symbol tl.
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Waddell, D. R., K. Duffy, and G. Vogel. "Cytokinesis is defective in Dictyostelium mutants with altered phagocytic recognition, adhesion, and vegetative cell cohesion properties." Journal of Cell Biology 105, no. 5 (November 1, 1987): 2293–300. http://dx.doi.org/10.1083/jcb.105.5.2293.
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Mutants that have been selected for defects in phagocytic recognition, adhesion, and vegetative cell-cell cohesion were found to be larger and more highly multinucleate than their parent strain. This defect is associated with the complex mutant phenotype of these mutants since revertants of the mutants coordinately acquire the wild-type phenotype for all of the defects. The larger size and multinuclearity were due to a high frequency of failure of cytokinesis in cells of wild-type size. This was shown by purifying the small cells in mutant populations and observing their growth and cell division. The mutant phenotype is more penetrant during axenic growth. Most of the mutants are not multinucleate when grown on bacteria. Recently, new mutants have been isolated that are also multinucleate when grown on bacteria by a strong selection procedure for non-adhesion to tissue culture dishes. The pleiotropic mutant phenotype and the greater penetrance of the mutant phenotype in axenic culture can be explained by hypothesizing a deficiency in a membrane component of the actomyosin motor that is involved in all of the processes defective in the mutants.
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DeLaurier, April, Douglas G. Howe, Leyla Ruzicka, Adam N. Carte, Lacie Mishoe Hernandez, Kali J. Wiggins, Mika M. Gallati, et al. "ZebraShare: a new venue for rapid dissemination of zebrafish mutant data." PeerJ 9 (April 13, 2021): e11007. http://dx.doi.org/10.7717/peerj.11007.
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Background In the past decade, the zebrafish community has widely embraced targeted mutagenesis technologies, resulting in an abundance of mutant lines. While many lines have proven to be useful for investigating gene function, many have also shown no apparent phenotype, or phenotypes not of interest to the originating lab. In order for labs to document and share information about these lines, we have created ZebraShare as a new resource offered within ZFIN. Methods ZebraShare involves a form-based submission process generated by ZFIN. The ZebraShare interface (https://zfin.org/action/zebrashare) can be accessed on ZFIN under “Submit Data”. Users download the Submission Workbook and complete the required fields, then submit the completed workbook with associated images and captions, generating a new ZFIN publication record. ZFIN curators add the submitted phenotype and mutant information to the ZFIN database, provide mapping information about mutations, and cross reference this information across the appropriate ZFIN databases. We present here examples of ZebraShare submissions, including phf21aa, kdm1a, ctnnd1, snu13a, and snu13b mutant lines. Results Users can find ZebraShare submissions by searching ZFIN for specific alleles or line designations, just as for alleles submitted through the normal process. We present several potential examples of submission types to ZebraShare including a phenotypic mutants, mildly phenotypic, and early lethal mutants. Mutants for kdm1a show no apparent skeletal phenotype, and phf21aa mutants show only a mild skeletal phenotype, yet these genes have specific human disease relevance and therefore may be useful for further studies. The p120-catenin encoding gene, ctnnd1, was knocked out to investigate a potential role in brain development or function. The homozygous ctnnd1 mutant disintegrates during early somitogenesis and the heterozygote has localized defects, revealing vital roles in early development. Two snu13 genes were knocked out to investigate a role in muscle formation. The snu13a;snu13b double mutant has an early embryonic lethal phenotype, potentially related to a proposed role in the core splicing complex. In each example, the mutants submitted to ZebraShare display phenotypes that are not ideally suited to their originating lab’s project directions but may be of great relevance to other researchers. Conclusion ZebraShare provides an opportunity for researchers to directly share information about mutant lines within ZFIN, which is widely used by the community as a central database of information about zebrafish lines. Submissions of alleles with a phenotypic or unexpected phenotypes is encouraged to promote collaborations, disseminate lines, reduce redundancy of effort and to promote efficient use of time and resources. We anticipate that as submissions to ZebraShare increase, they will help build an ultimately more complete picture of zebrafish genetics and development.
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Larsson, Annika Sundås, Katarina Landberg, and D. R. Meeks-Wagner. "The TERMINAL FLOWER2 (TFL2) Gene Controls the Reproductive Transition and Meristem Identity in Arabidopsis thaliana." Genetics 149, no. 2 (June 1, 1998): 597–605. http://dx.doi.org/10.1093/genetics/149.2.597.
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Abstract A new mutant of Arabidopsis thaliana that initiates flowering early and terminates the inflorescence with floral structures has been identified and named terminal flower2 (tfl2). While these phenotypes are similar to that of the terminal flower1 (tfl1) mutant, tfl2 mutant plants are also dwarfed in appearance, have reduced photoperiod sensitivity and have a more variable terminal flower structure. Under long-day and short-day growth conditions tfl1 tfl2 double mutants terminate the inflorescence without development of lateral flowers; thus, unlike tfl1 single mutants the double mutant inflorescence morphology is not affected by day length. The enhanced phenotype of the double mutant suggests that TFL2 acts in a developmental pathway distinct from TFL1. The complex nature of the tfl2 single mutant phenotype suggests that TFL2 has a regulatory role more global than that of TFL1. Double mutant analysis of tfl2 in combination with mutant alleles of the floral meristem identity genes LEAFY and APETALA1 demonstrates that TFL2 function influences developmental processes controlled by APETALA1, but not those regulated by LEAFY. Thus, the TFL2 gene product appears to have a dual role in regulating meristem activity, one being to regulate the meristem response to light signals affecting the development of the plant and the other being the maintenance of inflorescence meristem identity.
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Koerniati, Sri. "UNTAGGED MUTATION IN RICE GAL4/VP16 TRANSCRIPTIONAL ACTIVATOR FACILITATED-ENHANCER TRAP LINES." Indonesian Journal of Agricultural Science 14, no. 1 (April 21, 2013): 27. http://dx.doi.org/10.21082/ijas.v14n1.2013.27-35.
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An enhancer trap system is an insertional mutagenesis based upon gene expression, instead of gene knock-out, so its insertion in genome is expected not linked to any dramatic changes in plant phenotypes. Gene knock-out, leading to lossof- function (LoF) mutation, is a dominant approach for rice functional genomic studies. The objective of this study was to find out whether Transcriptional Activator-Facilitated Enhancer Trap (TAFET) T-DNA insertion inducing mutant phenotypes in rice TAFET population. Materials used in this experiment were T1 generation of 270 rice TAFET lines. Eight plants of each were grown in the greenhouse and observed for any mutant phenotypes. Phenotypic, histochemical, Southern<br />blot analyses were carried out to define a mutant of pSKC66.1- 8e. Result showed that about 10% of the 270 lines produced chlorophyll-deficient leaves, ranged from yellowish green (viridis), white stripe green zebra-like stripe) to completely white (albino). Albino plants died after two weeks, whilst white stripe or viridis mutants became normal in the next generation<br />(T2). Another mutant was pSKC66.1-8e line which had floral dramatic phenotype change with various spikelet shapes and number of organs, and had a single twisted culm. The flower of mutant also had gus gene expression. Plants with wild type did not express gus gene and had six or more straight culms. Molecular, histochemical and phenotypic analyses of this particular line for three generations indicated that mutant phenotype was not due to the T-DNA insertion. Since there was approved that Tos17 is activated during tissue culture and induced mutant phenotype, this line might relate to Tos17 insertion, but it needs further investigation to gain such conclusion.
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Koerniati, Sri. "UNTAGGED MUTATION IN RICE GAL4/VP16 TRANSCRIPTIONAL ACTIVATOR FACILITATED-ENHANCER TRAP LINES." Indonesian Journal of Agricultural Science 14, no. 1 (April 21, 2013): 27. http://dx.doi.org/10.21082/ijas.v14n1.2013.p27-35.
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An enhancer trap system is an insertional mutagenesis based upon gene expression, instead of gene knock-out, so its insertion in genome is expected not linked to any dramatic changes in plant phenotypes. Gene knock-out, leading to lossof- function (LoF) mutation, is a dominant approach for rice functional genomic studies. The objective of this study was to find out whether Transcriptional Activator-Facilitated Enhancer Trap (TAFET) T-DNA insertion inducing mutant phenotypes in rice TAFET population. Materials used in this experiment were T1 generation of 270 rice TAFET lines. Eight plants of each were grown in the greenhouse and observed for any mutant phenotypes. Phenotypic, histochemical, Southern<br />blot analyses were carried out to define a mutant of pSKC66.1- 8e. Result showed that about 10% of the 270 lines produced chlorophyll-deficient leaves, ranged from yellowish green (viridis), white stripe green zebra-like stripe) to completely white (albino). Albino plants died after two weeks, whilst white stripe or viridis mutants became normal in the next generation<br />(T2). Another mutant was pSKC66.1-8e line which had floral dramatic phenotype change with various spikelet shapes and number of organs, and had a single twisted culm. The flower of mutant also had gus gene expression. Plants with wild type did not express gus gene and had six or more straight culms. Molecular, histochemical and phenotypic analyses of this particular line for three generations indicated that mutant phenotype was not due to the T-DNA insertion. Since there was approved that Tos17 is activated during tissue culture and induced mutant phenotype, this line might relate to Tos17 insertion, but it needs further investigation to gain such conclusion.
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Chistoserdova, Ludmila, Gregory J. Crowther, Julia A. Vorholt, Elizabeth Skovran, Jean-Charles Portais, and Mary E. Lidstrom. "Identification of a Fourth Formate Dehydrogenase in Methylobacterium extorquens AM1 and Confirmation of the Essential Role of Formate Oxidation in Methylotrophy." Journal of Bacteriology 189, no. 24 (October 5, 2007): 9076–81. http://dx.doi.org/10.1128/jb.01229-07.
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ABSTRACT A mutant of Methylobacterium extorquens AM1 with lesions in genes for three formate dehydrogenase (FDH) enzymes was previously described by us (L. Chistoserdova, M. Laukel, J.-C. Portais, J. A. Vorholt, and M. E. Lidstrom, J. Bacteriol. 186:22-28, 2004). This mutant had lost its ability to grow on formate but still maintained the ability to grow on methanol. In this work, we further investigated the phenotype of this mutant. Nuclear magnetic resonance experiments with [13C]formate, as well as 14C-labeling experiments, demonstrated production of labeled CO2 in the mutant, pointing to the presence of an additional enzyme or a pathway for formate oxidation. The tungsten-sensitive phenotype of the mutant suggested the involvement of a molybdenum-dependent enzyme. Whole-genome array experiments were conducted to test for genes overexpressed in the triple-FDH mutant compared to the wild type, and a gene (fdh4A) was identified whose translated product carried similarity to an uncharacterized putative molybdopterin-binding oxidoreductase-like protein sharing relatively low similarity with known formate dehydrogenase alpha subunits. Mutation of this gene in the triple-FDH mutant background resulted in a methanol-negative phenotype. When the gene was deleted in the wild-type background, the mutant revealed diminished growth on methanol with accumulation of high levels of formate in the medium, pointing to an important role of FDH4 in methanol metabolism. The identity of FDH4 as a novel FDH was also confirmed by labeling experiments that revealed strongly reduced CO2 formation in growing cultures. Mutation of a small open reading frame (fdh4B) downstream of fdh4A resulted in mutant phenotypes similar to the phenotypes of fdh4A mutants, suggesting that fdh4B is also involved in formate oxidation.
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DeRyckere, Deborah, Cheryl L. Smith, and G. Steven Martin. "The Role of Nucleotide Binding and Hydrolysis in the Function of the Fission Yeast cdc18+ Gene Product." Genetics 151, no. 4 (April 1, 1999): 1445–57. http://dx.doi.org/10.1093/genetics/151.4.1445.
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Abstract The fission yeast cdc18+ gene is required for both initiation of DNA replication and the mitotic checkpoint that normally inhibits mitosis in the absence of DNA replication. The cdc18+ gene product contains conserved Walker A and B box motifs. Studies of other ATPases have shown that these motifs are required for nucleotide binding and hydrolysis, respectively. We have observed that mutant strains in which either of these motifs is disrupted are inviable. The effects of these mutations were examined by determining the phenotypes of mutant strains following depletion of complementing wild-type Cdc18. In both synchronous and asynchronous cultures, the nucleotide-hydrolysis motif mutant (DE286AA) arrests with a 1C–2C DNA content, and thus exhibits no obvious defects in entry into S phase or in the mitotic checkpoint. In contrast, in cultures synchronized by hydroxyurea arrest and release, the nucleotide-binding motif mutant (K205A) exhibits the null phenotype, with 1C and <1C DNA content, indicating a block in entry into S phase and loss of checkpoint control. In asynchronous cultures this mutant exhibits a mixed phenotype: a percentage of the population displays the null phenotype, while the remaining fraction arrests with a 2C DNA content. Thus, the phenotype exhibited by the K205A mutant is dependent on the cell-cycle position at which wild-type Cdc18 is depleted. These data indicate that both nucleotide binding and hydrolysis are required for Cdc18 function. In addition, the difference in the phenotypes exhibited by the nucleotide-binding and hydrolysis motif mutants is consistent with a two-step model for Cdc18 function in which nucleotide binding and hydrolysis are required for distinct aspects of Cdc18 function that may be executed at different points in the cell cycle.
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White, E., B. Faha, and B. Stillman. "Regulation of adenovirus gene expression in human WI38 cells by an E1B-encoded tumor antigen." Molecular and Cellular Biology 6, no. 11 (November 1986): 3763–73. http://dx.doi.org/10.1128/mcb.6.11.3763-3773.1986.
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Adenovirus mutants carrying alterations in the gene encoding the E1B 19-kilodalton tumor antigen (19K protein) cause enhanced cytopathic effect (cyt phenotype) and the degradation of host-cell chromosomal DNA (deg phenotype) upon infection of human HeLa or KB cells. Furthermore, E1B 19K gene mutant viruses are defective for cellular transformation. We report that these mutant viruses possess a host-range phenotype for growth in human cells. In human HeLa cells the mutant viruses grew to the same levels as the wild-type virus, but they were severely defective for growth in KB cells. In human WI38 cells, the E1B 19K gene mutant viruses had a substantial growth advantage over the wild-type virus, yielding 500-fold-higher titers. Viral DNA synthesis was reduced 10- to 20-fold in WI38 cells infected with the wild-type virus relative to that synthesized by the E1B mutant viruses. Viral early and late protein synthesis was similarly reduced in wild type- relative to mutant-infected cells. These reduced levels of early gene expression in wild-type virus-infected cells were paralleled by comparably reduced levels of early cytoplasmic mRNA. The primary cause of this host-range phenotype appeared at the level of early gene transcription, since transcription of viral early genes in the mutant-infected cells was substantially greater than levels found in cells infected with the wild-type virus. These results implicate the E1B 19K tumor antigen in the regulation of adenovirus early gene expression. Specifically, the E1B 19K protein directly or indirectly exerts a negative effect on early gene transcription accounting for efficient gene expression from the E1B mutant viruses in WI38 cells. Based on these findings it is probable that the cyt and deg phenotypes observed in mutant-infected HeLa and KB cells are the result of the pleiotropic effect of this altered gene regulation.
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White, E., B. Faha, and B. Stillman. "Regulation of adenovirus gene expression in human WI38 cells by an E1B-encoded tumor antigen." Molecular and Cellular Biology 6, no. 11 (November 1986): 3763–73. http://dx.doi.org/10.1128/mcb.6.11.3763.
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Adenovirus mutants carrying alterations in the gene encoding the E1B 19-kilodalton tumor antigen (19K protein) cause enhanced cytopathic effect (cyt phenotype) and the degradation of host-cell chromosomal DNA (deg phenotype) upon infection of human HeLa or KB cells. Furthermore, E1B 19K gene mutant viruses are defective for cellular transformation. We report that these mutant viruses possess a host-range phenotype for growth in human cells. In human HeLa cells the mutant viruses grew to the same levels as the wild-type virus, but they were severely defective for growth in KB cells. In human WI38 cells, the E1B 19K gene mutant viruses had a substantial growth advantage over the wild-type virus, yielding 500-fold-higher titers. Viral DNA synthesis was reduced 10- to 20-fold in WI38 cells infected with the wild-type virus relative to that synthesized by the E1B mutant viruses. Viral early and late protein synthesis was similarly reduced in wild type- relative to mutant-infected cells. These reduced levels of early gene expression in wild-type virus-infected cells were paralleled by comparably reduced levels of early cytoplasmic mRNA. The primary cause of this host-range phenotype appeared at the level of early gene transcription, since transcription of viral early genes in the mutant-infected cells was substantially greater than levels found in cells infected with the wild-type virus. These results implicate the E1B 19K tumor antigen in the regulation of adenovirus early gene expression. Specifically, the E1B 19K protein directly or indirectly exerts a negative effect on early gene transcription accounting for efficient gene expression from the E1B mutant viruses in WI38 cells. Based on these findings it is probable that the cyt and deg phenotypes observed in mutant-infected HeLa and KB cells are the result of the pleiotropic effect of this altered gene regulation.
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Welshons, W. J., and H. J. Welshons. "SUPPRESSION OF THE FACET-STRAWBERRY POSITION EFFECT IN DROSOPHILA BY LESIONS ADJACENT TO NOTCH." Genetics 110, no. 3 (July 1, 1985): 465–77. http://dx.doi.org/10.1093/genetics/110.3.465.
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ABSTRACT The recessive visible rough eye mutant effect of faswb, a small deletion at the 5' end of the Notch locus, is suppressed when faswb is coupled to five different closely linked deficiencies distal to salivary band 3C7. In addition, an inversion with a proximal breakpoint between 3C3 and 3C5 similarly suppresses the mutant effect. The data support the position effect interpretation of faswb: The small deletion allows functions distal to Notch to interfere with functions at Notch, and when the interference is eliminated, the faswb-mutant effect disappears.—The faswb deletion also interacts with another recessive visible rough-eye mutant at Notch called fag. In the cis condition, faswb fag double mutants have a mutant-eye phenotype like fag (similar to the mutant effect of faswb) and, in addition, express an accessory phenotype (thickened wing veins). Although the mutant-eye effect of faswb can be suppressed by lesions adjacent to Notch, the accessory phenotype of the coupled mutants is not suppressed. It is suggested that the faswb deletion has two observable effects: One is a modifiable position effect causing the faswb rough-eye phenotype; the other is a stable effect exerted upon a 5-kb insertion that is the probable cause of the fag mutant expression, thus resulting in a wing effect that accompanies the eye effect of fag.
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Bang, A. G., V. Hartenstein, and J. W. Posakony. "Hairless is required for the development of adult sensory organ precursor cells in Drosophila." Development 111, no. 1 (January 1, 1991): 89–104. http://dx.doi.org/10.1242/dev.111.1.89.
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Reduction of the wild-type activity of the gene Hairless (H) results in two major phenotypic effects on the mechanosensory bristles of adult Drosophila. Bristles are either ‘lost’ (i.e. the shaft and socket fail to appear) or they exhibit a ‘double socket’ phenotype, in which the shaft is apparently transformed into a second socket. Analysis of the phenotypes conferred by a series of H mutant genotypes demonstrates (1) that different sensilla exhibit different patterns of response to decreasing levels of H+ function, and (2) that the ‘bristle loss’ phenotype results from greater loss of H+ function than the ‘double socket’ phenotype. The systematic study of H allelic combinations enabled us to identify genotypes that reliably produce specific mutant defects in particular positions on the bodies of adult flies. This permitted us to investigate the cellular development of sensilla in these same positions in larvae and pupae and thereby establish the developmental basis for the mutant phenotypes. We have found that H is required for at least two steps of adult sensillum development. In positions where ‘double socket’ microchaetes appear on the notum of H mutant flies, sensillum precursor cells are present in the developing pupa and divide normally, but their progeny adopt an aberrant spatial arrangement and fail to differentiate correctly. In regions of the notum exhibiting ‘bristle loss’ in adult H mutants, we were unable at the appropriate stages of development to detect sensillum-specific cell types, the precursor cell divisions that generate them, or the primary precursor cells themselves. Thus, the H ‘bristle loss’ phenotype appears to reflect a very early defect in sensillum development, namely the failure to specify and/or execute the sensory organ precursor cell fate. This finding indicates that H is one of a small number of identified genes for which the loss-of-function phenotype is the failure of sensillum precursor cell development.
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van Mullem, Alies, Ramona van Heerebeek, Dionisios Chrysis, Edward Visser, Marco Medici, Maria Andrikoula, Agathocles Tsatsoulis, Robin Peeters, and Theo J. Visser. "Clinical Phenotype and Mutant TRα1." New England Journal of Medicine 366, no. 15 (April 12, 2012): 1451–53. http://dx.doi.org/10.1056/nejmc1113940.
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Hawkins, Justin P., Barney A. Geddes, and Ivan J. Oresnik. "Common dyes used to determine bacterial polysaccharides on agar are affected by medium acidification." Canadian Journal of Microbiology 63, no. 6 (June 2017): 559–62. http://dx.doi.org/10.1139/cjm-2016-0743.
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In this work, we highlight effects of pH on bacterial phenotypes when using the bacteriological dyes Aniline blue, Congo red, and Calcofluor white to analyze polysaccharide production. A study of galactose catabolism in Sinorhizobium meliloti led to the isolation of a mutation in dgoK1, which was observed to overproduce exopolysaccharides when grown in the presence of galactose. When this mutant strain was spotted onto plates containing Aniline blue, Congo red, or Calcofluor white, the intensity of the associated staining was strikingly different from that of the wild type. Additionally, a Calcofluor dull phenotype was observed, suggesting production of a polysaccharide other than succinoglycan. Further investigation of this phenotype revealed that these results were dependent on medium acidification, as buffering at pH 6 had no effect on these phenotypes, while medium buffered at pH 6.5 resulted in a reversal of the phenotypes. Screening for mutants of the dgoK1 strain that were negative for the Aniline blue phenotype yielded a strain carrying a mutation in tkt2, which is annotated as a putative transketolase. Consistent with the plate phenotypes, when this mutant was grown in broth cultures, it did not acidify its growth medium. Overall, this work shows that caution should be exercised in evaluating polysaccharide phenotypes based strictly on the use of dyes.
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Biondi, Emanuele G., Francesca Marini, Fabio Altieri, Laura Bonzi, Marco Bazzicalupo, and Maddalena del Gallo. "Extended phenotype of an mreB-like mutant in Azospirillum brasilense." Microbiology 150, no. 7 (July 1, 2004): 2465–74. http://dx.doi.org/10.1099/mic.0.26904-0.
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Tn5 mutagenesis was used to generate an Azospirillum brasilense SPF94 mutant. Genetic analysis of this mutant revealed that a homologue of the mreB gene, which controls cell shape in Bacillus subtilis and Escherichia coli, was inactivated. The cell-surface properties of the mutant were different from those of the parental strain. The mutant colonies were highly fluorescent when grown on plates containing Calcofluor White. Light and electron microscopy revealed that the mutant cells were round and had thicker capsules than the spiral parental strain. The mutants contained up to ten times more capsule protein than the parental strain, but lacked a 40 kDa protein that is abundant in the parental strain. The phenotype of the isolated mutant resembled that of the cyst-like differentiated forms of Azospirillum, suggesting that the mreB homologue could be involved in differentiation.
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Fine, Alexander D., Robyn L. Ball, Yasuhiro Fujiwara, Mary Ann Handel, and Gregory W. Carter. "Uncoupling of transcriptomic and cytological differentiation in mouse spermatocytes with impaired meiosis." Molecular Biology of the Cell 30, no. 5 (March 2019): 717–28. http://dx.doi.org/10.1091/mbc.e18-10-0681.
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Cell differentiation is driven by changes in gene expression that manifest as changes in cellular phenotype or function. Altered cellular phenotypes, stemming from genetic mutations or other perturbations, are widely assumed to directly correspond to changes in the transcriptome and vice versa. Here, we exploited the cytologically well-defined Prdm9 mutant mouse as a model of developmental arrest to test whether parallel programs of cellular differentiation and gene expression are tightly coordinated, or can be disassociated. By comparing cytological phenotype markers and transcriptomes in wild-type and mutant spermatocytes, we identified multiple instances of cellular and molecular uncoupling in Prdm9–/– mutants. Most notably, although Prdm9–/– germ cells undergo cytological arrest in a late-leptotene/zygotene stage, they nevertheless develop gene expression signatures characteristic of later developmental substages. These findings suggest that transcriptomic changes may not reliably map to cellular phenotypes in developmentally perturbed systems.
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Murray, Jeremy, Bogumil Karas, Loretta Ross, Andreas Brachmann, Cameron Wagg, Ryan Geil, Jillian Perry, et al. "Genetic Suppressors of the Lotus japonicus har1-1 Hypernodulation Phenotype." Molecular Plant-Microbe Interactions® 19, no. 10 (October 2006): 1082–91. http://dx.doi.org/10.1094/mpmi-19-1082.
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Lotus japonicus har1 mutants respond to inoculation with Mesorhizobium loti by forming an excessive number of nodules due to genetic lesions in the HAR1 autoregulatory receptor kinase gene. In order to expand the repertoire of mutants available for the genetic dissection of the root nodule symbiosis (RNS), a screen for suppressors of the L. japonicus har1-1 hypernodulation phenotype was performed. Of 150,000 M2 plants analyzed, 61 stable L. japonicus double-mutant lines were isolated. In the context of the har1-1 mutation, 26 mutant lines were unable to form RNS, whereas the remaining 35 mutant lines carried more subtle symbiotic phenotypes, either forming white ineffective nodules or showing reduced nodulation capacity. When challenged with Glomus intraradices, 18 of the 61 suppressor lines were unable to establish a symbiosis with this arbuscular mycorrhiza fungus. Using a combined approach of genetic mapping, targeting induced local lesions in genomics, and sequencing, all non-nodulating mutant lines were characterized and shown to represent new alleles of at least nine independent symbiotic loci. The class of mutants with reduced nodulation capacity was of particular interest because some of them may specify novel plant functions that regulate nodule development in L. japonicus. To facilitate mapping of the latter class of mutants, an introgression line, in which the har1-1 allele was introduced into a polymorphic background of L. japonicus ecotype MG20, was constructed.
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Ferraioli, Simona, Rosarita Tatè, Michele Cermola, Renée Favre, Maurizio Iaccarino, and Eduardo J. Patriarca. "Auxotrophic Mutant Strains of Rhizobium etli Reveal New Nodule Development Phenotypes." Molecular Plant-Microbe Interactions® 15, no. 5 (May 2002): 501–10. http://dx.doi.org/10.1094/mpmi.2002.15.5.501.
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We report here the isolation and characterization of amino acid-requiring mutant strains of Rhizobium etli. We observe that the phenotype of most mutations, even when causing a strict auxotrophy, is overcome by cross-feeding from the host plant Phaseolus vulgaris, thereby allowing bacterial production of Nod factors and, consequently, nodule induction. Conversely, light and electron microscopy analysis reveals that the nodules induced by all mutants, including those with normal external morphology, are halted or strongly altered at intermediate or late stages of development. Moreover, some mutants induce nodules that display novel symbiotic phenotypes, such as specific alterations of the invaded cells or the presence of a reduced number of abnormally shaped uninvaded cells. Other mutants induce nodules showing an early and vast necrosis of the central tissue, a phenotype not previously observed in bean nodules, not even in nodules induced by a Fix¯ mutant. These observations indicate that amino acid auxotrophs represent a powerful tool to study the development of globose determinate-type nodules and emphasize the importance of establishing their histology and citology before considerations of metabolic exchange are made.
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Tam, L. W., and P. A. Lefebvre. "Cloning of flagellar genes in Chlamydomonas reinhardtii by DNA insertional mutagenesis." Genetics 135, no. 2 (October 1, 1993): 375–84. http://dx.doi.org/10.1093/genetics/135.2.375.
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Abstract Chlamydomonas is a popular genetic model system for studying many cellular processes. In this report, we describe a new approach to isolate Chlamydomonas genes using the cloned nitrate reductase gene (NIT1) as an insertional mutagen. A linearized plasmid containing the NIT1 gene was introduced into nit1 mutant cells by glass-bead transformation. Of 3000 Nit+ transformants examined, 74 showed motility defects of a wide range of phenotypes, suggesting that DNA transformation is an effective method for mutagenizing cells. For 13 of 15 such motility mutants backcrossed to nit- mutant strains, the motility phenotype cosegregated with the Nit+ phenotype, indicating that the motility defects of these 13 mutants may be caused by integration of the plasmid. Further genetic analysis indicated that three of these mutants contained alleles of previously identified loci: mbo2 (move backward only), pf13 (paralyzed flagella) and vfl1 (variable flagellar number). Three other abnormal-flagellar-number mutants did not map to any previously described loci at which mutations produce similar phenotypes. Genomic sequences flanking the integrated plasmid in the mbo2 and vfl1 mutants were isolated and used as probes to obtain wild-type genomic clones, which complemented the motility defects upon transformation into cells. Our results demonstrate the potential of this new approach for cloning genes identified by mutation in Chlamydomonas.
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Becraft, P. W., and M. Freeling. "Genetic analysis of Rough sheath1 developmental mutants of maize." Genetics 136, no. 1 (January 1, 1994): 295–311. http://dx.doi.org/10.1093/genetics/136.1.295.
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Abstract Maize Rough sheath1 (Rs1) mutants are dominant and cause a proliferation of sheath-like tissue at the base of the blade and throughout the ligular region. They also cause ligule displacement, a chaotic pattern of vasculature and abnormal cellular structure of vascular bundles. The affected region of Rs1-O leaves displays genetic and morphological attributes of both sheath and auricle, suggesting an overlap of these genetic programs. The rs1 locus maps approximately 26 map units distal to opaque2 (o2) on chromosome 7S, defining a new distal-most locus on the genetic map. Three mutant alleles, Rs1-O, Rs1-1025 and Rs1-Z, all display similar phenotypes. The mutations are completely dominant and the Rs1-O phenotype is not affected by dosage of the chromosome arm carrying the rs1+ allele, indicating that these alleles are neomorphic. Analysis of genetic mosaics showed that the Rs1-O phenotype is non-cell-autonomous, suggesting that intercellular signals convey the phenotype. Rs1 mutant phenotypes are affected by modifiers present in particular genetic backgrounds. An enhancer of Rs1-O was identified; segregation data imply a single recessive gene, ers1. Rs1 mutants were also found to enhance the expression of unlinked rs2 and Rs4 mutants, suggesting that these mutations affect similar developmental processes. We discuss the phenotypic and genetic similarities between Rs1 and Knotted 1 (Kn1) mutants that led to the identification of rs1 as a kn1-like homeobox gene (unpublished data).
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Yan, Wei-Ming, Mei-Zhu Chen, Dong-Yu Wei, Jian-Cong Wang, Zuo-Ming Zhang, Lei Zhang, and Tao Chen. "Retinal neovascularization induced by mutant Vldlr gene inhibited in an inherited retinitis pigmentosa mouse model: an in-vivo study." International Journal of Ophthalmology 14, no. 7 (July 18, 2021): 990–97. http://dx.doi.org/10.18240/ijo.2021.07.05.
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AIM: To explore whether the retinal neovascularization (NV) in a genetic mutant mice model could be ameliorated in an inherited retinitis pigmentosa (RP) mouse, which would help to elucidate the possible mechanism and prevention of retinal NV diseases in clinic. METHODS: The Vldlr-/- mice, the genetic mutant mouse model of retinal NV caused by the homozygous mutation of Vldlr gene, with the rd1 mice, the inherited RP mouse caused by homozygous mutation of Pde6b gene were bred. Intercrossing of the above two mice led to the birth of the F1 hybrids, further inbreeding of which gave birth to the F2 offspring. The ocular genotypes and phenotypes of the mice from all generations were examined, with the F2 offspring grouped according to the genotypes. RESULTS: The rd1 mice exhibited the RP phenotype of outer retinal degeneration and loss of retinal function. The Vldlr-/- mice exhibited the phenotype of retinal NV obviously shown by the fundus fluorescein angiography. The F1 hydrides, with the heterozygote genotype, exhibited no phenotypes of RP or retinal NV. The F2 offspring with homozygous genotypes were grouped into four subgroups. They were the F2-I mice with the wild-type Pde6b and Vldlr genes (Pde6b+/+-Vldlr+/+), which had normal ocular phenotypes; the F2-II mice with homozygous mutant Vldlr gene (Pde6b+/+-Vldlr-/-), which exhibited the retinal NV phenotype; the F2-III mice with homozygous mutant Pde6b gene (Pde6b-/--Vldlr+/+), which exhibited the RP phenotype. Specifically, the F2-IV mice with homozygous mutant Vldlr and Pde6b gene (Pde6b-/--Vldlr-/-) showed only the RP phenotype, without the signs of retinal NV. CONCLUSION: The retinal NV can be inhibited by the RP phenotype, which implies the role of a hyperoxic state in treating retinal NV diseases.
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Shanks, Robert M. Q., Nicholas A. Stella, Eric J. Kalivoda, Megan R. Doe, Dawn M. O'Dee, Kira L. Lathrop, Feng Li Guo, and Gerard J. Nau. "A Serratia marcescens OxyR Homolog Mediates Surface Attachment and Biofilm Formation." Journal of Bacteriology 189, no. 20 (August 3, 2007): 7262–72. http://dx.doi.org/10.1128/jb.00859-07.
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ABSTRACT OxyR is a conserved bacterial transcription factor with a regulatory role in oxidative stress response. From a genetic screen for genes that modulate biofilm formation in the opportunistic pathogen Serratia marcescens, mutations in an oxyR homolog and predicted fimbria structural genes were identified. S. marcescens oxyR mutants were severely impaired in biofilm formation, in contrast to the hyperbiofilm phenotype exhibited by oxyR mutants of Escherichia coli and Burkholderia pseudomallei. Further analysis revealed that OxyR plays a role in the primary attachment of cells to a surface. Similar to what is observed in other bacterial species, S. marcescens OxyR is required for oxidative stress resistance. Mutations in oxyR and type I fimbrial genes resulted in severe defects in fimbria-associated phenotypes, revealing roles in cell-cell and cell-biotic surface interactions. Transmission electron microscopy revealed the absence of fimbria-like surface structures on an OxyR-deficient strain and an enhanced fimbrial phenotype in strains bearing oxyR on a multicopy plasmid. The hyperfimbriated phenotype conferred by the multicopy oxyR plasmid was absent in a type I fimbrial mutant background. Real-time reverse transcriptase PCR indicated an absence of transcripts from a fimbrial operon in an oxyR mutant that were present in the wild type and a complemented oxyR mutant strain. Lastly, chromosomal Plac -mediated expression of fimABCD was sufficient to restore wild-type levels of yeast agglutination and biofilm formation to an oxyR mutant. Together, these data support a model in which OxyR contributes to early stages of S. marcescens biofilm formation by influencing fimbrial gene expression.
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Stone, Elisa M., Cheryl Reifsnyder, Mitch McVey, Brandy Gazo, and Lorraine Pillus. "Two Classes of sir3 Mutants Enhance the sir1 Mutant Mating Defect and Abolish Telomeric Silencing in Saccharomyces cerevisiae." Genetics 155, no. 2 (June 1, 2000): 509–22. http://dx.doi.org/10.1093/genetics/155.2.509.
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Abstract Silent information regulators, or Sir proteins, play distinct roles in chromatin-mediated transcriptional control at the silent mating-type loci, telomeres, and within the rDNA repeats of Saccharomyces cerevisiae. An unusual collection of sir3 mutant alleles was identified in a genetic screen for enhancers of the sir1 mutant mating-defective phenotype. These sir3-eso mutants, like the sir1 mutant, exhibit little or no mating defects alone, but the sir1 sir3-eso double mutants are essentially nonmating. All of the sir3-eso mutants are defective in telomeric silencing. In some mutants, this phenotype is suppressed by tethering Sir1p to telomeres; other mutants are dominant for mating and telomeric silencing defects. Additionally, several sir3-eso mutants are nonmating in combination with the nat1 N-terminal acetyltransferase mutant. The temperature-sensitive allele sir3-8 has an eso phenotype at permissive temperature, yet acts as a null allele at restrictive temperature due to loss of sir3-8 protein. Sequence analysis showed that eight of the nine sir3-eso alleles have mutations within the N-terminal region that is highly similar to the DNA replication initiation protein Orc1p. Together, these data reveal modular domains for Sir3p and further define its function in silencing chromatin.
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Hanekamp, Theodor, Mary K. Thorsness, Indrani Rebbapragada, Elizabeth M. Fisher, Corrine Seebart, Monica R. Darland, Jennifer A. Coxbill, Dustin L. Updike, and Peter E. Thorsness. "Maintenance of Mitochondrial Morphology Is Linked to Maintenance of the Mitochondrial Genome in Saccharomyces cerevisiae." Genetics 162, no. 3 (November 1, 2002): 1147–56. http://dx.doi.org/10.1093/genetics/162.3.1147.
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Abstract In the yeast Saccharomyces cerevisiae, certain mutant alleles of YME4, YME6, and MDM10 cause an increased rate of mitochondrial DNA migration to the nucleus, carbon-source-dependent alterations in mitochondrial morphology, and increased rates of mitochondrial DNA loss. While single mutants grow on media requiring mitochondrial respiration, any pairwise combination of these mutations causes a respiratory-deficient phenotype. This double-mutant phenotype allowed cloning of YME6, which is identical to MMM1 and encodes an outer mitochondrial membrane protein essential for maintaining normal mitochondrial morphology. Yeast strains bearing null mutations of MMM1 have altered mitochondrial morphology and a slow growth rate on all carbon sources and quantitatively lack mitochondrial DNA. Extragenic suppressors of MMM1 deletion mutants partially restore mitochondrial morphology to the wild-type state and have a corresponding increase in growth rate and mitochondrial DNA stability. A dominant suppressor also suppresses the phenotypes caused by a point mutation in MMM1, as well as by specific mutations in YME4 and MDM10.
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Shima, Naoko, Robert J. Munroe, and John C. Schimenti. "The Mouse Genomic Instability Mutation chaos1 Is an Allele of Polq That Exhibits Genetic Interaction with Atm." Molecular and Cellular Biology 24, no. 23 (December 1, 2004): 10381–89. http://dx.doi.org/10.1128/mcb.24.23.10381-10389.2004.
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ABSTRACT chaos1 (for chromosome aberrations occurring spontaneously 1) is a recessive mutation that was originally identified in a phenotype-based screen for chromosome instability mutants in mice. Mutant animals exhibit significantly higher frequencies of spontaneous and radiation- or mitomycin C-induced micronucleated erythrocytes, indicating a potential defect in homologous recombination or interstrand cross-link repair. The chaos1 allele was genetically associated with a missense mutation in Polq, which encodes DNA polymerase θ. We demonstrate here that chaos1 is a mutant allele of Polq by using two genetic approaches: chaos1 mutant phenotype correction by a bacterial artificial chromosome carrying wild-type Polq and a failed complementation test between chaos1 and a Polq-disrupted allele generated by gene targeting. To investigate the potential involvement of Polq in DNA double-strand break repair, we introduced chaos1 into an Atm (for ataxia telangiectasia mutated)-deficient background. The majority (∼90%) of double-homozygous mice died during the neonatal period. Surviving double mutants exhibited synergistic phenotypes such as severe growth retardation and enhanced chromosome instability. However, remarkably, double mutants had delayed onset of thymic lymphoma, significantly increasing life span. These data suggest a unique role of Polq in maintaining genomic integrity, which is probably distinctive from the major homologous recombination pathway regulated by ATM.
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Jurkowski, Grace I., Roger K. Smith, I.-ching Yu, Jong Hyun Ham, Shashi B. Sharma, Daniel F. Klessig, Kevin A. Fengler, and Andrew F. Bent. "Arabidopsis DND2, a Second Cyclic Nucleotide-Gated Ion Channel Gene for Which Mutation Causes the “Defense, No Death” Phenotype." Molecular Plant-Microbe Interactions® 17, no. 5 (May 2004): 511–20. http://dx.doi.org/10.1094/mpmi.2004.17.5.511.
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A previous mutant screen identified Arabidopsis dnd1 and dnd2 “defense, no death” mutants, which exhibit loss of hypersensitive response (HR) cell death without loss of gene-for-gene resistance. The dnd1 phenotype is caused by mutation of the gene encoding cyclic nucleotide-gated (CNG) ion channel AtCNGC2. This study characterizes dnd2 plants. Even in the presence of high titers of Pseudomonas syringae expressing avrRpt2, most leaf mesophyll cells in the dnd2 mutant exhibited no HR. These plants retained strong RPS2-, RPM1-, or RPS4-mediated restriction of P. syringae pathogen growth. Mutant dnd2 plants also exhibited enhanced broad-spectrum resistance against virulent P. syringae and constitutively elevated levels of salicylic acid, and pathogenesis-related (PR) gene expression. Unlike the wild type, dnd2 plants responding to virulent and avirulent P. syringae exhibited elevated expression of both salicylatedependent PR-1 and jasmonate and ethylene—dependent PDF1.2. Introduction of nahG+ (salicylate hydroxylase) into the dnd2 background, which removes salicylic acid and causes other defense alterations, eliminated constitutive disease resistance and PR gene expression but only weakly impacted the HR¯ phenotype. Map-based cloning revealed that dnd2 phenotypes are caused by mutation of a second CNG ion channel gene, AtCNGC4. Hence, loss of either of two functionally nonredundant CNG ion channels can cause dnd phenotypes. The dnd mutants provide a unique genetic background for dissection of defense signaling.
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Boucherat, Olivier, Séverine Montaron, Félix-Antoine Bérubé-Simard, Josée Aubin, Polyxeni Philippidou, Deneen M. Wellik, Jeremy S. Dasen, and Lucie Jeannotte. "Partial functional redundancy between Hoxa5 and Hoxb5 paralog genes during lung morphogenesis." American Journal of Physiology-Lung Cellular and Molecular Physiology 304, no. 12 (June 15, 2013): L817—L830. http://dx.doi.org/10.1152/ajplung.00006.2013.
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Hox genes encode transcription factors governing complex developmental processes in several organs. A subset of Hox genes are expressed in the developing lung. Except for Hoxa5, the lack of overt lung phenotype in single mutants suggests that Hox genes may not play a predominant role in lung ontogeny or that functional redundancy may mask anomalies. In the Hox5 paralog group, both Hoxa5 and Hoxb5 genes are expressed in the lung mesenchyme whereas Hoxa5 is also expressed in the tracheal mesenchyme. Herein, we generated Hoxa5; Hoxb5 compound mutant mice to evaluate the relative contribution of each gene to lung development. Hoxa5; Hoxb5 mutants carrying the four mutated alleles displayed an aggravated lung phenotype, resulting in the death of the mutant pups at birth. Characterization of the phenotype highlighted the role of Hoxb5 in lung formation, the latter being involved in branching morphogenesis, goblet cell specification, and postnatal air space structure, revealing partial functional redundancy with Hoxa5. However, the Hoxb5 lung phenotypes were less severe than those seen in Hoxa5 mutants, likely because of Hoxa5 compensation. New specific roles for Hoxa5 were also unveiled, demonstrating the extensive contribution of Hoxa5 to the developing respiratory system. The exclusive expression of Hoxa5 in the trachea and the phrenic motor column likely underlies the Hoxa5-specific trachea and diaphragm phenotypes. Altogether, our observations establish that the Hoxa5 and Hoxb5 paralog genes shared some functions during lung morphogenesis, Hoxa5 playing a predominant role.
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Maduro, M., and D. Pilgrim. "Identification and cloning of unc-119, a gene expressed in the Caenorhabditis elegans nervous system." Genetics 141, no. 3 (November 1, 1995): 977–88. http://dx.doi.org/10.1093/genetics/141.3.977.
Full textAbstract:
Abstract A spontaneous mutation affecting locomotion of the nematode Caenorhabditis elegans has been mapped to a new gene, unc-119. Phenotypic characterization of the mutants suggests the defect does not lie in the musculature and that the animals also have defects in feeding behavior and chemosensation. unc-119 has been physically mapped relative to a previously identified chromosomal break in linkage group III, and DNA clones covering the region can rescue the mutant phenotype in transgenic animals. Three more alleles at the locus, with identical phenotypes, have been induced and characterized, all of which are putative null alleles. The predicted UNC-119 protein has no significant similarity to other known proteins. Expression of an unc-119/lacZ fusion in transgenic animals is seen in many neurons, suggesting that the unc-119 mutant phenotype is due to a defect in the nervous system.
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Gibson, S. I., R. T. Surosky, and B. K. Tye. "The phenotype of the minichromosome maintenance mutant mcm3 is characteristic of mutants defective in DNA replication." Molecular and Cellular Biology 10, no. 11 (November 1990): 5707–20. http://dx.doi.org/10.1128/mcb.10.11.5707-5720.1990.
Full textAbstract:
MCM3 is an essential gene involved in the maintenance of minichromosomes in yeast cells. It encodes a protein of 971 amino acids that shows striking homology to the Mcm2 protein. We have mapped the mcm3-1 mutation of the left arm of chromosome V approximately 3 kb centromere proximal of anp1. The mcm3-1 mutant was found to be thermosensitive for growth. Under permissive growth conditions, it was defective in minichromosome maintenance in an autonomously replicating sequence-specific manner and showed an increase in chromosome loss and recombination. Under nonpermissive conditions, mcm3-1 exhibited a cell cycle arrest phenotype, arresting at the large-bud stage with an undivided nucleus that had a DNA content of nearly 2n. These phenotypes are consistent with incomplete replication of the genome of the mcm3-1 mutant, possibly as a result of limited replication initiation at selective autonomously replicating sequences leading to cell cycle arrest before mitosis. The phenotype exhibited by the mcm3 mutant is very similar to that of mcm2, suggesting that the Mcm2 and Mcm3 protein may play interacting roles in DNA replication.
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Gibson, S. I., R. T. Surosky, and B. K. Tye. "The phenotype of the minichromosome maintenance mutant mcm3 is characteristic of mutants defective in DNA replication." Molecular and Cellular Biology 10, no. 11 (November 1990): 5707–20. http://dx.doi.org/10.1128/mcb.10.11.5707.
Full textAbstract:
MCM3 is an essential gene involved in the maintenance of minichromosomes in yeast cells. It encodes a protein of 971 amino acids that shows striking homology to the Mcm2 protein. We have mapped the mcm3-1 mutation of the left arm of chromosome V approximately 3 kb centromere proximal of anp1. The mcm3-1 mutant was found to be thermosensitive for growth. Under permissive growth conditions, it was defective in minichromosome maintenance in an autonomously replicating sequence-specific manner and showed an increase in chromosome loss and recombination. Under nonpermissive conditions, mcm3-1 exhibited a cell cycle arrest phenotype, arresting at the large-bud stage with an undivided nucleus that had a DNA content of nearly 2n. These phenotypes are consistent with incomplete replication of the genome of the mcm3-1 mutant, possibly as a result of limited replication initiation at selective autonomously replicating sequences leading to cell cycle arrest before mitosis. The phenotype exhibited by the mcm3 mutant is very similar to that of mcm2, suggesting that the Mcm2 and Mcm3 protein may play interacting roles in DNA replication.
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Delgado-Requerey, Víctor, Francisco Javier Cejudo, and María-Cruz González. "The Functional Relationship between NADPH Thioredoxin Reductase C, 2-Cys Peroxiredoxins, and m-Type Thioredoxins in the Regulation of Calvin–Benson Cycle and Malate-Valve Enzymes in Arabidopsis." Antioxidants 12, no. 5 (May 3, 2023): 1041. http://dx.doi.org/10.3390/antiox12051041.
Full textAbstract:
The concerted regulation of chloroplast biosynthetic pathways and NADPH extrusion via malate valve depends on f and m thioredoxins (Trxs). The finding that decreased levels of the thiol-peroxidase 2-Cys peroxiredoxin (Prx) suppress the severe phenotype of Arabidopsis mutants lacking NADPH-dependent Trx reductase C (NTRC) and Trxs f uncovered the central function of the NTRC-2-Cys-Prx redox system in chloroplast performance. These results suggest that Trxs m is also regulated by this system; however, the functional relationship between NTRC, 2-Cys Prxs, and m-type Trxs is unknown. To address this issue, we generated Arabidopsis thaliana mutants combining deficiencies in NTRC, 2-Cys Prx B, Trxs m1, and m4. The single trxm1 and trxm4 mutants showed a wild-type phenotype, with growth retardation noticed only in the trxm1m4 double mutant. Moreover, the ntrc-trxm1m4 mutant displayed a more severe phenotype than the ntrc mutant, as shown by the impaired photosynthetic performance, altered chloroplast structure, and defective light-dependent reduction in the Calvin–Benson cycle and malate-valve enzymes. These effects were suppressed by the decreased contents of 2-Cys Prx, since the quadruple ntrc-trxm1m4-2cpb mutant displayed a wild-type-like phenotype. These results show that the activity of m-type Trxs in the light-dependent regulation of biosynthetic enzymes and malate valve is controlled by the NTRC-2-Cys-Prx system.
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Singleton, Belinda K., Winnie Lau, Victoria S. S. Fairweather, Nicholas M. Burton, Marieangela C. Wilson, Steve F. Parsons, Ben M. Richardson, et al. "Mutations in the second zinc finger of human EKLF reduce promoter affinity but give rise to benign and disease phenotypes." Blood 118, no. 11 (September 15, 2011): 3137–45. http://dx.doi.org/10.1182/blood-2011-04-349985.
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Abstract Mutations in the human erythroid Krüppel-like factor (EKLF) can lead to either anemia or the benign InLu phenotype. To elucidate the relationship between these mutations and the differing phenotypes, we prepared recombinant forms of wild-type and 5 mutant EKLF proteins and quantitated their binding affinity to a range of EKLF-regulated genes. Missense mutants (R328H, R328L, and R331G) from persons with InLu phenotype did not bind DNA. Hence, as with the heterozygous loss of function nonsense (L127X, S270X, and K292X) and frameshift (P190Lfs and R319Efs) EKLF mutations, monoallelic loss of EKLF does not result in haploinsufficiency at all loci. In contrast, K332Q has a slightly reduced DNA binding affinity (∼ 2-fold) for all promoters examined but exhibits a phenotype only in a compound heterozygote with a nonfunctional allele. E325K also has a reduced, but significant, binding affinity, particularly for the β-globin gene but results in a disease phenotype even with the wild-type allele expressed, although not as a classic dominant-negative mutant. E325K protein may therefore actively interfere with EKLF-dependent processes by destabilizing transcription complexes, providing a rational explanation for the severity of the disease phenotype. Our study highlights the critical role of residues within the second EKLF zinc finger domain.
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Ferguson, E. L., and K. V. Anderson. "Localized enhancement and repression of the activity of the TGF-beta family member, decapentaplegic, is necessary for dorsal-ventral pattern formation in the Drosophila embryo." Development 114, no. 3 (March 1, 1992): 583–97. http://dx.doi.org/10.1242/dev.114.3.583.
Full textAbstract:
Seven zygotically active genes are required for normal patterning of the dorsal 40% of the Drosophila embryo. Among these genes, decapentaplegic (dpp) has the strongest mutant phenotype: in the absence of dpp, all cells in the dorsal and dorsolateral regions of the embryo adopt fates characteristic of more ventrally derived cells (Irish and Gelbart (1987) Genes Dev. 1, 868–879). Here we describe the phenotypes caused by alleles of another of this set of genes, tolloid, and show that tolloid is required for dorsal, but not dorsolateral, pattern. Extragenic suppressors of tolloid mutations were isolated that proved to be mutations that elevate dpp activity. We studied the relationship between tolloid and dpp by analyzing the phenotypes of tolloid embryos with elevated numbers of the dpp gene and found that doubling the dpp+ gene dosage completely suppressed weak tolloid mutants and partially suppressed the phenotypes of tolloid null mutants. We conclude that the function of tolloid is to increase dpp activity. We also examined the effect of doubling dpp+ gene dosage on the phenotypes caused by other mutations affecting dorsal development. Like tolloid, the phenotypes of mutant embryos lacking shrew gene function were suppressed by elevated dpp, indicating that shrew also acts upstream of dpp to increase dpp activity. In contrast, increasing the number of copies of the dpp gene enhanced the short gastrulation (sog) mutant phenotype, causing ventrolateral cells to adopt dorsal fates. This indicates that sog gene product normally blocks dpp activity ventrally. We propose that the tolloid, shrew and sog genes are required to generate a gradient of dpp activity, which directly specifies the pattern of the dorsal 40% of the embryo.
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Díaz-Troya, Sandra, Miguel Roldán, Manuel J. Mallén-Ponce, Pablo Ortega-Martínez, and Francisco J. Florencio. "Lethality caused by ADP-glucose accumulation is suppressed by salt-induced carbon flux redirection in cyanobacteria." Journal of Experimental Botany 71, no. 6 (December 20, 2019): 2005–17. http://dx.doi.org/10.1093/jxb/erz559.
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Abstract Cyanobacteria are widely distributed photosynthetic organisms. During the day they store carbon, mainly as glycogen, to provide the energy and carbon source they require for maintenance during the night. Here, we generate a mutant strain of the freshwater cyanobacterium Synechocystis sp. PCC 6803 lacking both glycogen synthases. This mutant has a lethal phenotype due to massive accumulation of ADP-glucose, the substrate of glycogen synthases. This accumulation leads to alterations in its photosynthetic capacity and a dramatic decrease in the adenylate energy charge of the cell to values as low as 0.1. Lack of ADP-glucose pyrophosphorylase, the enzyme responsible for ADP-glucose synthesis, or reintroduction of any of the glycogen synthases abolishes the lethal phenotype. Viability of the glycogen synthase mutant is also fully recovered in NaCl-supplemented medium, which redirects the surplus of ADP-glucose to synthesize the osmolite glucosylglycerol. This alternative metabolic sink also suppresses phenotypes associated with the defective response to nitrogen deprivation characteristic of glycogen-less mutants, restoring the capacity to degrade phycobiliproteins. Thus, our system is an excellent example of how inadequate management of the adenine nucleotide pools results in a lethal phenotype, and the influence of metabolic carbon flux in cell viability and fitness.
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Ziman, M., J. M. O'Brien, L. A. Ouellette, W. R. Church, and D. I. Johnson. "Mutational analysis of CDC42Sc, a Saccharomyces cerevisiae gene that encodes a putative GTP-binding protein involved in the control of cell polarity." Molecular and Cellular Biology 11, no. 7 (July 1991): 3537–44. http://dx.doi.org/10.1128/mcb.11.7.3537-3544.1991.
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The Saccharomyces cerevisiae CDC42 gene product, a member of the ras superfamily of low-molecular-weight GTP-binding proteins, is involved in the control of cell polarity. We have analyzed the effects of three CDC42 mutations (Gly to Val-12, Gln to Leu-61, and Asp to Ala-118) in the putative GTP-binding and hydrolysis domains and one mutation (Cys to Ser-188) in the putative isoprenylation site. The first three mutations resulted in either a dominant-lethal or dose-dependent dominant-lethal phenotype when present on plasmids in haploid cdc42-1ts or wild-type strains. Both wild-type and cdc42-1ts cells carrying plasmids (pGAL) with either the CDC42Val-12 or CDC42Leu-61 alleles under the control of a GAL promoter were arrested with a novel phenotype of large cells with elongated or multiple buds. Cells carrying pGAL-CDC42Ala-118 were arrested as large, round, unbudded cells reminiscent of cdc42-1ts arrested cells. The different phenotype of the CDC42Ala-118 mutant versus the CDC42Val-12 and CDC42Leu-61 mutants was unexpected since the phenotypes of all three analogous ras mutants were similar to each other. This suggests that aspects of the biochemical properties of the Cdc42 protein differ from those of the Ras protein. The cdc42Ser-188 mutant gene was incapable of complementing the cdc42-1ts mutation and was recessive to both wild-type and cdc42-1ts. In double-mutant alleles, the cdc42Ser-188 mutation was capable of suppressing the dominant lethality associated with the three putative GTP-binding and hydrolysis mutations, suggesting that isoprenylation is necessary for the activity of the wild-type and mutant proteins.
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Ziman, M., J. M. O'Brien, L. A. Ouellette, W. R. Church, and D. I. Johnson. "Mutational analysis of CDC42Sc, a Saccharomyces cerevisiae gene that encodes a putative GTP-binding protein involved in the control of cell polarity." Molecular and Cellular Biology 11, no. 7 (July 1991): 3537–44. http://dx.doi.org/10.1128/mcb.11.7.3537.
Full textAbstract:
The Saccharomyces cerevisiae CDC42 gene product, a member of the ras superfamily of low-molecular-weight GTP-binding proteins, is involved in the control of cell polarity. We have analyzed the effects of three CDC42 mutations (Gly to Val-12, Gln to Leu-61, and Asp to Ala-118) in the putative GTP-binding and hydrolysis domains and one mutation (Cys to Ser-188) in the putative isoprenylation site. The first three mutations resulted in either a dominant-lethal or dose-dependent dominant-lethal phenotype when present on plasmids in haploid cdc42-1ts or wild-type strains. Both wild-type and cdc42-1ts cells carrying plasmids (pGAL) with either the CDC42Val-12 or CDC42Leu-61 alleles under the control of a GAL promoter were arrested with a novel phenotype of large cells with elongated or multiple buds. Cells carrying pGAL-CDC42Ala-118 were arrested as large, round, unbudded cells reminiscent of cdc42-1ts arrested cells. The different phenotype of the CDC42Ala-118 mutant versus the CDC42Val-12 and CDC42Leu-61 mutants was unexpected since the phenotypes of all three analogous ras mutants were similar to each other. This suggests that aspects of the biochemical properties of the Cdc42 protein differ from those of the Ras protein. The cdc42Ser-188 mutant gene was incapable of complementing the cdc42-1ts mutation and was recessive to both wild-type and cdc42-1ts. In double-mutant alleles, the cdc42Ser-188 mutation was capable of suppressing the dominant lethality associated with the three putative GTP-binding and hydrolysis mutations, suggesting that isoprenylation is necessary for the activity of the wild-type and mutant proteins.
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Wen, Kuo-Kuang, Melissa McKane, Ema Stokasimov, and Peter A. Rubenstein. "Mutant profilin suppresses mutant actin-dependent mitochondrial phenotype inSaccharomyces cerevisiae." Journal of Biological Chemistry 287, no. 16 (April 13, 2012): 13048. http://dx.doi.org/10.1074/jbc.a110.217661.
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Wen, Kuo-Kuang, Melissa McKane, Ema Stokasimov, and Peter A. Rubenstein. "Mutant Profilin Suppresses Mutant Actin-dependent Mitochondrial Phenotype inSaccharomyces cerevisiae." Journal of Biological Chemistry 286, no. 48 (September 28, 2011): 41745–57. http://dx.doi.org/10.1074/jbc.m110.217661.
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Kar, Ranjeet D., and Johann K. Eberhart. "Predicting Modifiers of Genotype-Phenotype Correlations in Craniofacial Development." International Journal of Molecular Sciences 24, no. 2 (January 8, 2023): 1222. http://dx.doi.org/10.3390/ijms24021222.
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Most human birth defects are phenotypically variable even when they share a common genetic basis. Our understanding of the mechanisms of this variation is limited, but they are thought to be due to complex gene-environment interactions. Loss of the transcription factor Gata3 associates with the highly variable human birth defects HDR syndrome and microsomia, and can lead to disruption of the neural crest-derived facial skeleton. We have demonstrated that zebrafish gata3 mutants model the variability seen in humans, with genetic background and candidate pathways modifying the resulting phenotype. In this study, we sought to use an unbiased bioinformatic approach to identify environmental modifiers of gata3 mutant craniofacial phenotypes. The LINCs L1000 dataset identifies chemicals that generate differential gene expression that either positively or negatively correlates with an input gene list. These chemicals are predicted to worsen or lessen the mutant phenotype, respectively. We performed RNA-seq on neural crest cells isolated from zebrafish across control, Gata3 loss-of-function, and Gata3 rescue groups. Differential expression analyses revealed 551 potential targets of gata3. We queried the LINCs database with the 100 most upregulated and 100 most downregulated genes. We tested the top eight available chemicals predicted to worsen the mutant phenotype and the top eight predicted to lessen the phenotype. Of these, we found that vinblastine, a microtubule inhibitor, and clofibric acid, a PPAR-alpha agonist, did indeed worsen the gata3 phenotype. The Topoisomerase II and RNA-pol II inhibitors daunorubicin and triptolide, respectively, lessened the phenotype. GO analysis identified Wnt signaling and RNA polymerase function as being enriched in our RNA-seq data, consistent with the mechanism of action of some of the chemicals. Our study illustrates multiple potential pathways for Gata3 function, and demonstrates a systematic, unbiased process to identify modifiers of genotype-phenotype correlations.
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Mikkola, Riitta, and C. G. Kurland. "Media dependence of translational mutant phenotype." FEMS Microbiology Letters 56, no. 3 (December 1988): 265–69. http://dx.doi.org/10.1111/j.1574-6968.1988.tb03189.x.
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Balciunas, Darius. "Fish mutant, where is thy phenotype?" PLOS Genetics 14, no. 2 (February 22, 2018): e1007197. http://dx.doi.org/10.1371/journal.pgen.1007197.
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Glover, Kathleen K. M., Danica M. Sutherland, Terence S. Dermody, and Kevin M. Coombs. "A Single Point Mutation, Asn16→Lys, Dictates the Temperature-Sensitivity of the Reovirus tsG453 Mutant." Viruses 13, no. 2 (February 12, 2021): 289. http://dx.doi.org/10.3390/v13020289.
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Studies of conditionally lethal mutants can help delineate the structure-function relationships of biomolecules. Temperature-sensitive (ts) mammalian reovirus (MRV) mutants were isolated and characterized many years ago. Two of the most well-defined MRV ts mutants are tsC447, which contains mutations in the S2 gene encoding viral core protein σ2, and tsG453, which contains mutations in the S4 gene encoding major outer-capsid protein σ3. Because many MRV ts mutants, including both tsC447 and tsG453, encode multiple amino acid substitutions, the specific amino acid substitutions responsible for the ts phenotype are unknown. We used reverse genetics to recover recombinant reoviruses containing the single amino acid polymorphisms present in ts mutants tsC447 and tsG453 and assessed the recombinant viruses for temperature-sensitivity by efficiency-of-plating assays. Of the three amino acid substitutions in the tsG453 S4 gene, Asn16-Lys was solely responsible for the tsG453ts phenotype. Additionally, the mutant tsC447 Ala188-Val mutation did not induce a temperature-sensitive phenotype. This study is the first to employ reverse genetics to identify the dominant amino acid substitutions responsible for the tsC447 and tsG453 mutations and relate these substitutions to respective phenotypes. Further studies of other MRV ts mutants are warranted to define the sequence polymorphisms responsible for temperature sensitivity.
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Gems, D. H., and A. J. Clutterbuck. "Enhancers of conidiation mutants in Aspergillus nidulans." Genetics 137, no. 1 (May 1, 1994): 79–85. http://dx.doi.org/10.1093/genetics/137.1.79.
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Abstract Mutants at a number of loci, designated sthenyo, have been isolated as enhancers of the oligoconidial mutations at the medA locus. Two loci have been mapped: sthA on linkage group I, and sthB on linkage group V. Two probable alleles have been identified at each locus but two further mutants were unlinked to either sthA or sthB. Neither sthA nor sthB mutants have conspicuous effects on morphology on their own, nor could the sthA1 sthB2 double mutant be distinguished from wild type. Mutants at both loci also interact with the temperature-sensitive brlA42 mutant at the permissive temperature to give a phenotype described as "Abacoid." sthA1 also induces a slight modification of the phenotype of an abaA mutant. We conclude that sthenyo genes act mainly at the phialide stage of conidiation. We also describe the isolation of new medA mutants arising spontaneously as outgrowths on brlA42 colonies.
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Ohya, Y., and D. Botstein. "Structure-based systematic isolation of conditional-lethal mutations in the single yeast calmodulin gene." Genetics 138, no. 4 (December 1, 1994): 1041–54. http://dx.doi.org/10.1093/genetics/138.4.1041.
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Abstract Conditional-lethal mutations of the single calmodulin gene in Saccharomyces cerevisiae have been very difficult to isolate by random and systematic methods, despite the fact that deletions cause recessive lethality. We report here the isolation of numerous conditional-lethal mutants that were recovered by systematically altering phenylalanine residues. The phenylalanine residues of calmodulin were implicated in function both by structural studies of calmodulin bound to target peptides and by their extraordinary conservation in evolution. Seven single and 26 multiple Phe-->Ala mutations were constructed. Mutant phenotypes were examined in a haploid cmd1 disrupted strain under three conditions: single copy, low copy, and overexpressed. Whereas all but one of the single mutations caused no obvious phenotype, most of the multiple mutations caused obvious growth phenotypes. Five were lethal, 6 were lethal only in synthetic medium 13 were temperature-sensitive lethal and 2 had no discernible phenotypic consequences. Overexpression of some of the mutant genes restored the phenotype to nearly wild type. Several temperature-sensitive calmodulin mutations were suppressed by elevated concentration of CaCl2 in the medium. Mutant calmodulin protein was detected at normal levels in extracts of most of the lethal mutant cells, suggesting that the deleterious phenotypes were due to loss of the calmodulin function and not protein instability. Analysis of diploid strains heterozygous for all combinations of cmd 1-ts alleles revealed four intragenic complementation groups. The contributions of individual phe-->ala changes to mutant phenotypes support the idea of internal functional redundancy in the symmetrical calmodulin protein molecule. These results suggest that the several phenylalanine residues in calmodulin are required to different extents in different combinations in order to carry out each of the several essential tasks.
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Liao, Ben-Yang, and Meng-Pin Weng. "Unraveling the association between mRNA expressions and mutant phenotypes in a genome-wide assessment of mice." Proceedings of the National Academy of Sciences 112, no. 15 (March 30, 2015): 4707–12. http://dx.doi.org/10.1073/pnas.1415046112.
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High-throughput gene expression profiling has revealed substantial leaky and extraneous transcription of eukaryotic genes, challenging the perceptions that transcription is strictly regulated and that changes in transcription have phenotypic consequences. To assess the functional implications of mRNA transcription directly, we analyzed mRNA expression data derived from microarrays, RNA-sequencing, and in situ hybridization, together with phenotype data of mouse mutants as a proxy of gene function at the tissue level. The results indicated that despite the presence of widespread ectopic transcription, mRNA expression and mutant phenotypes of mammalian genes or tissues remain associated. The expression-phenotype association at the gene level was particularly strong for tissue-specific genes, and the association could be underestimated due to data insufficiency and incomprehensive phenotyping of mouse mutants; the strength of expression-phenotype association at the tissue level depended on tissue functions. Mutations on genes expressed at higher levels or expressed at earlier embryonic stages more often result in abnormal phenotypes in the tissues where they are expressed. The mRNA expression profiles that have stronger associations with their phenotype profiles tend to be more evolutionarily conserved, indicating that the evolution of transcriptome and the evolution of phenome are coupled. Therefore, mutations resulting in phenotypic aberrations in expressed tissues are more likely to occur in highly transcribed genes, tissue-specific genes, genes expressed during early embryonic stages, or genes with evolutionarily conserved mRNA expression profiles.
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Leib, David A., Travis E. Harrison, Kathleen M. Laslo, Michael A. Machalek, Nathaniel J. Moorman, and Herbert W. Virgin. "Interferons Regulate the Phenotype of Wild-type and Mutant Herpes Simplex Viruses In Vivo." Journal of Experimental Medicine 189, no. 4 (February 15, 1999): 663–72. http://dx.doi.org/10.1084/jem.189.4.663.
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Mechanisms responsible for neuroattenuation of herpes simplex virus (HSV) have been defined previously by studies of mutant viruses in cultured cells. The hypothesis that null mutations in host genes can override the attenuated phenotype of null mutations in certain viral genes was tested. Mutants such as those in infected cell protein (ICP) 0, thymidine kinase, ribonucleotide reductase, virion host shutoff, and ICP34.5 are reduced in their capacity to replicate in nondividing cells in culture and in vivo. The replication of these viruses was examined in eyes and trigeminal ganglia for 1–7 d after corneal inoculation in mice with null mutations (−/−) in interferon receptors (IFNR) for type I IFNs (IFN-α/βR), type II IFN (IFN-γR), and both type I and type II IFNs (IFN-α/β/γR). Viral titers in eyes and ganglia of IFN-γR−/− mice were not significantly different from congenic controls. However, in IFN-α/βR−/− or IFN-α/β/γR−/− mice, growth of all mutants, including those with significantly impaired growth in cell culture, was enhanced by up to 1,000-fold in eyes and trigeminal ganglia. Blepharitis and clinical signs of infection were evident in IFN-α/βR−/− and IFN-α/β/γR−/− but not control mice for all viruses. Also, IFNs were shown to significantly reduce productive infection of, and spread from intact, but not scarified, corneas. Particularly striking was restoration of near-normal trigeminal ganglion replication and neurovirulence of an ICP34.5 mutant in IFN-α/βR−/− mice. These data show that IFNs play a major role in limiting mutant and wild-type HSV replication in the cornea and in the nervous system. In addition, the in vivo target of ICP34.5 may be host IFN responses. These experiments demonstrate an unsuspected role for host factors in defining the phenotypes of some HSV mutants in vivo. The phenotypes of mutant viruses therefore cannot be interpreted based solely upon studies in cell culture but must be considered carefully in the context of host factors that may define the in vivo phenotype.