Reflections on studies of gene expression in aneuploids

2010 ◽  
Vol 426 (2) ◽  
pp. 119-123 ◽  
Author(s):  
James A. Birchler
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
Gene Dosage ◽  
Gene Dosage Effects ◽  
Dosage Effects ◽  
Different Types ◽  
Chromosomal Copy Number ◽  
Cancerous Cells ◽  
Insight Into ◽  
Careful Documentation

Aneuploidy involves changes in chromosomal copy number compared with normal euploid genotypes. Studies of gene expression in aneuploids in a variety of species have claimed many different types of responses. Studies of individual genes suggest that there are both structural gene dosage effects and compensation in aneuploids, and that subtle trans-acting effects across the genome are quite prevalent. A discussion is presented concerning the normalization procedures for studying gene expression in aneuploids. A careful documentation of the modulations of gene expression in aneuploids should provide insight into the nature of cancerous cells and the basis of aneuploid syndromes.

Gene Dosage Effects in B-Chronic Lymphocytic Leukemia with Del 13q14.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2640-2640
Author(s):  
Ludger Sellmann ◽  
Rene Scholtysik ◽  
Holger Nueckel ◽  
Tanja Boes ◽  
Alexander Carpinteiro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chromosomal Abnormalities ◽  
Gene Dosage ◽  
Micro Rna ◽  
Lymphocytic Leukemia ◽  
Fish Analysis ◽  
Gene Dosage Effects ◽  
Dosage Effects ◽  
Bcl2 Protein ◽  
Rna Genes

Abstract Abstract 2640 Poster Board II-616 Introduction: Deletion of 13q14 (del13q14) is the most common abnormality of B-chronic lymphocytic leukemia (CLL). However, for a long time investigations of this region did not detect the relevant pathogenetic mechanism. Micro-RNA genes MIRN15a and MIRN16-1 located on 13q14.3 were postulated to close this gap. Down-regulated expression of these miRNAs was shown to increase the anti apoptotic B cell lymphoma 2 (Bcl2) proteins. However, relevance and frequency of deregulated micro-RNA genes was differentially described. To understand the influence of deletion of chromosomal region 13q14 on gene expression, chromosomal abnormalities detected by single nucleotide polymorphism (SNP) chips were compared with gene expression analyzed by gene expression profiling in CLL. Furthermore, impact of deletion 13q14 on MIRN15A and MIRN16-1 expression and correlation to BCL2 protein expression were investigated. Methods: 15 B-CLL cases harboring del 13q14 were investigated for the extend of deletion with the 50k Xbal SNP array. Gene expression of the genes located in the aberrant region evaluated by Affymetrix U133A gene chip of 13 of these cases was compared between cases with and without this aberration. FISH analysis was done to validate SNP-data. Expression of MIRN15a and MIRN16-1 was evaluated by real-time PCR from further 20 B-CLL with TaqMan MicroRNA assays. From the 25 cases Western blot analysis for Bcl2 was performed. Results: SNP-chip and FISH analysis with probes for regions RB1, D13S25 and D13S319 gave consistent results. The minimal deleted region of del13q14 reaches from physical position 49543165 to 50272626 and mostly includes the location of MIRN15a and 16-1. 10 gene probes were located in the aberrant chromosomal 13q14 region and entered statistical analysis. In 4 of 5 genes with monoallelic deletions gene expression was significantly reduced. In regions harbouring mono- and biallelic deletions in 4 of 5 genes the monoallelic deleted cases showed decreased expression compared to the normal cases. Evaluation of MIRN15a and MIRN16-1 revealed strong down-regulation of expression in CLL harbouring biallelic del13q14 compared to other CLL and healthy B-cells (p=0.002; p=0.002), whereas there were no statistically significant differences between CLL with or without monoallelic deletion or healthy B-cells (p=0.534; p=0.665). Bcl2 Western blot analysis revealed stronger Bcl2 expression in CLL harbouring del13q14 in contrast to CLL without this abnormality (p=0.002). However, no difference between cases with mono- or biallelic del13q14 was detected (p=0.400). Conclusion: SNP chip analysis is a helpful tool to detect chromosomal abnormalities on a high resolution. Although detailed genetic analyses failed to demonstrate the consistent involvement of any of the genes located in the deleted region of B-CLL harboring del13q14, reduced expression occurred in most of these genes indicating gene dosage effects. MIRN15a and MIRN16-1 expression are frequently reduced in B-CLL with biallelic but not monoallelic deletion of 13q14 without an influence on Bcl2 protein levels. Disclosures: Off Label Use: intrapleural and intraperitoneal use of rituximab.

scholarly journals Use of Gene Dosage Effects for a Whole-Genome Screen To Identify Mycobacterium marinum Macrophage Infection Loci

2008 ◽  
Vol 76 (7) ◽  
pp. 3100-3115 ◽  
Author(s):  
Bonggoo Park ◽  
Selvakumar Subbian ◽  
Sahar H. El-Etr ◽  
Suat L. G. Cirillo ◽  
Jeffrey D. Cirillo
Keyword(s):  
Gene Dosage ◽  
Mycobacterium Marinum ◽  
Macrophage Infection ◽  
Entire Genome ◽  
Dna Library ◽  
Gene Dosage Effects ◽  
Physical Maps ◽  
Dosage Effects ◽  
In Trans ◽  
Insight Into

ABSTRACT We recently identified two loci, mel1 and mel2, that affect macrophage infection by Mycobacterium marinum. The ability of these loci to confer enhanced infection in trans is presumably due to gene dosage effects since their presence on plasmids increases expression from five- to eightfold. Reasoning that this phenomenon would allow identification of other mycobacterial genes involved in macrophage infection, we conducted a screen of an M. marinum DNA library that provides 2.6-fold coverage of the entire genome for clones that affect macrophage infection. Our preliminary screen identified 76 plasmids that carry loci affecting macrophage infection. We eliminated plasmids that do not confer the expected phenotype when retransformed (70%), that have identical physical maps (5%), or that carry either of the mel1 or mel2 loci (14%) from further consideration. Four loci that confer enhanced infection (mel) and four that confer repressed infection (mrl) of macrophages were identified, and two of each group were chosen for detailed analysis. Saturating transposon mutagenesis was used to identify the loci responsible, and M. marinum mutants were constructed in the genes involved. We expect these genes to provide insight into how mycobacteria parasitize macrophages, an important component of innate immunity.

scholarly journals Oligogenic effects of 16p11.2 copy number variation on craniofacial development

2019 ◽  
Author(s):  
Yuqi Qiu ◽  
Thomas Arbogast ◽  
Sandra Martin Lorenzo ◽  
Honying Li ◽  
Shih C. Tang ◽  
...  
Keyword(s):  
Copy Number ◽  
Gene Dosage ◽  
Copy Number Variant ◽  
Craniofacial Development ◽  
Model Organisms ◽  
List Type ◽  
Gene Dosage Effects ◽  
Dosage Effects ◽  
Craniofacial Structure ◽  
Mirror Effects

AbstractA copy number variant (CNV) of 16p11.2, which encompasses 30 genes, is associated with developmental and psychiatric disorders, head size and body mass. The genetic mechanisms that underlie these associations are not understood. To elucidate the effects of genes on development, we exploited the quantitative effects of CNV on craniofacial structure in humans and model organisms. We show that reciprocal deletion and duplication of 16p11.2 have characteristic “mirror” effects on craniofacial features that are conserved in human, rat and mouse. By testing gene dosage effects on the shape of the mandible in zebrafish, we show that the distribution of effects for all individual genes is consistent with that of the CNV, and some combinations have non-additive effects. Our results suggest that, at minimum, one third of genes within the 16p11.2 region influence craniofacial development, and the facial gestalt of each CNV represents a product of 30 dosage effects.HighlightsReciprocal CNVs of 16p11.2 have mirror effects on craniofacial structure. Copy number is associated with a positive effect on nasal and mandibular regions and a negative effect on frontal regions of the face.Effects of CNV on craniofacial development in human are well conserved in rat and mouse models of 16p11.2 deletion and duplication.7/30 genes each independently have significant effects on the shape of the mandible in zebrafish; these include SPN, C16orf54, SEZ6L2, ASPHD1, TAOK2, INO80E and FAM57B. Others (MAPK3, MVP, KCTD13) have detectable effects only in combination.Overexpression of 30 genes individually showed a distribution of effects that was skewed in the same direction as that of the full duplication, suggesting that specific facial features represent the net of all individual effects combined.

Regulation of MAL gene expression in yeast: Gene dosage effects

1987 ◽  
Vol 209 (3) ◽  
pp. 508-517 ◽  
Author(s):  
Michael J. Goldenthal ◽  
Marco Vanoni ◽  
Barbara Buchferer ◽  
Julius Marmur
Keyword(s):  
Gene Expression ◽  
Gene Dosage ◽  
Yeast Gene ◽  
Gene Dosage Effects ◽  
Dosage Effects

scholarly journals Evolutionary Rescue and Drug Resistance on Multicopy Plasmids

Genetics ◽  
2020 ◽  
Vol 215 (3) ◽  
pp. 847-868
Author(s):  
Mario Santer ◽  
Hildegard Uecker
Keyword(s):  
Copy Number ◽  
Gene Dosage ◽  
Branching Processes ◽  
Plasmid Copy Number ◽  
Wild Type ◽  
Plasmid Copy ◽  
Gene Dosage Effects ◽  
Dosage Effects ◽  
Evolutionary Rescue ◽  
Establishment Probability

Bacteria often carry “extra DNA” in the form of plasmids in addition to their chromosome. Many plasmids have a copy number greater than one such that the genes encoded on these plasmids are present in multiple copies per cell. This has evolutionary consequences by increasing the mutational target size, by prompting the (transitory) co-occurrence of mutant and wild-type alleles within the same cell, and by allowing for gene dosage effects. We develop and analyze a mathematical model for bacterial adaptation to harsh environmental change if adaptation is driven by beneficial alleles on multicopy plasmids. Successful adaptation depends on the availability of advantageous alleles and on their establishment probability. The establishment process involves the segregation of mutant and wild-type plasmids to the two daughter cells, allowing for the emergence of mutant homozygous cells over the course of several generations. To model this process, we use the theory of multitype branching processes, where a type is defined by the genetic composition of the cell. Both factors—the availability of advantageous alleles and their establishment probability—depend on the plasmid copy number, and they often do so antagonistically. We find that in the interplay of various effects, a lower or higher copy number may maximize the probability of evolutionary rescue. The decisive factor is the dominance relationship between mutant and wild-type plasmids and potential gene dosage effects. Results from a simple model of antibiotic degradation indicate that the optimal plasmid copy number may depend on the specific environment encountered by the population.

scholarly journals Evolutionary rescue and drug resistance on multicopy plasmids

2019 ◽  
Author(s):  
Mario Santer ◽  
Hildegard Uecker
Keyword(s):  
Copy Number ◽  
Gene Dosage ◽  
Branching Processes ◽  
Plasmid Copy Number ◽  
Wild Type ◽  
Plasmid Copy ◽  
Gene Dosage Effects ◽  
Dosage Effects ◽  
Evolutionary Rescue ◽  
Establishment Probability

AbstractBacteria often carry “extra DNA” in form of plasmids in addition to their chromosome. Many plasmids have a copy number greater than one such that the genes encoded on these plasmids are present in multiple copies per cell. This has evolutionary consequences by increasing the mutational target size, by prompting the (transitory) co-occurrence of mutant and wild-type alleles within the same cell, and by allowing for gene dosage effects. We develop and analyze a mathematical model for bacterial adaptation to harsh environmental change if adaptation is driven by beneficial alleles on multicopy plasmids. Successful adaptation depends on the availability of advantageous alleles and on their establishment probability. The establishment process involves the segregation of mutant and wild-type plasmids to the two daughter cells, allowing for the emergence of mutant-homozygous cells over the course of several generations. To model this process, we use the theory of multi-type branching processes, where a type is defined by the genetic composition of the cell. Both factors – the number of adaptive alleles and their establishment probability – depend on the plasmid copy number, and they often do so antagonistically. We find that in the interplay of various effects, a lower or higher copy number may maximize the probability of evolutionary rescue. The decisive factor is the dominance relationship between mutant and wild-type plasmids and potential gene dosage effects. Results from a simple model of antibiotic degradation indicate that the optimal plasmid copy number may depend on the specific environment encountered by the population.

scholarly journals Selection of SHV Extended-Spectrum-β-Lactamase-Dependent Cefotaxime and Ceftazidime Resistance in Klebsiella pneumoniae Requires a Plasmid-Borne blaSHV Gene

2007 ◽  
Vol 52 (2) ◽  
pp. 441-445 ◽  
Author(s):  
David S. Hammond ◽  
Tegan Harris ◽  
Jan Bell ◽  
John Turnidge ◽  
Philip M. Giffard
Keyword(s):  
Klebsiella Pneumoniae ◽  
Copy Number ◽  
Gene Dosage ◽  
Single Cells ◽  
The Other ◽  
Gene Dosage Effects ◽  
Dosage Effects ◽  
Extended Spectrum ◽  
Copy Number Amplification ◽  
Selection Of

ABSTRACT In Klebsiella pneumoniae, it is common for plasmid-located and chromosome-located bla SHV copies to coexist within single cells. The plasmid-borne genes are mainly derived from two separate IS26-mediated mobilizations of bla SHV. The objective of this study was to test the hypothesis that the presence of a non-extended-spectrum β-lactamase (non-ESBL) encoding plasmid-borne form of bla SHV facilitates the cefotaxime (CTX)-mediated selection of ESBL-expressing mutants, even when there is a chromosomal copy of the same gene. Twenty-one diverse ESBL-negative, bla TEM-negative K. pneumoniae clinical isolates were tested for the IS26 insertions characteristic of the two mobilization events. The isolates were then tested for their ability to be selected for ESBL-mediated CTX resistance by serial subculturing with a doubling of the CTX concentration at every subculture. Fourteen isolates possessed neither of the IS26 insertions. None of these became ESBL positive, and all died during the course of the experiment, despite possessing chromosomal bla SHV copies. The other isolates all became ESBL positive and grew abundantly up to a CTX concentration of 128 μg/ml. Similar results were obtained with ceftazidime. ESBL expression was associated with the appearance of the expected G→A mutation at position 1 of codon 238 and also with bla SHV copy number amplification. It was concluded that plasmid-borne bla SHV greatly facilitates the selection of ESBL expression, even when the same gene is on the chromosome, and that gene dosage effects are likely to contribute to this phenomenon.

scholarly journals Genetics advances and learning disability

2000 ◽  
Vol 176 (1) ◽  
pp. 12-19 ◽  
Author(s):  
Walter J. Muir
Keyword(s):  
Learning Disability ◽  
Gene Dosage ◽  
Genetic Disorders ◽  
Molecular Medicine ◽  
Gene Dosage Effects ◽  
Dosage Effects ◽  
Rapid Changes ◽  
Basic Understanding ◽  
Genetic Mechanisms ◽  
Dynamic Mutations

BackgroundMedicine is rapidly becoming molecular medicine, and little escapes the grasp of modern genetics. Most disorders associated with learning disability have at least a genetic component influencing their expression; in many disorders, disturbances of genetic mechanisms play a pivotal role.AimsDynamic mutations, imprinting mechanisms and gene-dosage effects are explained with reference to genetic disorders that lead to learning disability.MethodA review of recent important studies in the genetics of learning disability.ResultsA host of new genetic connections to conditions associated with learning disability have been made.ConclusionsA basic understanding of these genetic connections is important for all learning disability psychiatrists if they are to follow the rapid changes – already beginning to influence our practice – that hold immense promise for the future.

Sign in / Sign up

Export Citation Format

Share Document