scholarly journals Paralog dependency indirectly affects the robustness of human cells

2019 ◽  
Author(s):  
Rohan Dandage ◽  
Christian R Landry
Keyword(s):  
Gene Loss ◽  
Fitness Landscape ◽  
Human Cells ◽  
The Other ◽  
Gene Copy ◽  
Deleterious Mutations ◽  
Loss Of Function ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
Paralogous Proteins

SummaryGene duplicates provide protection against loss-of-function mutations. This protective redundancy partly relies on the fact that paralogs carry their functions independently, i.e. the inactivation of one gene copy does not impair the function of the other copy. However, a significant fraction of paralogous proteins may form functionally dependent pairs, for instance through heteromerization. As a consequence, one could expect these heteromeric paralogs to be less protective against deleterious mutations. To test this hypothesis, we examined the fitness landscape of gene loss-of-function by CRISPR-Cas9 in more than 450 human cell lines. Our analysis revealed a robustness landscape of human cells showing regions of higher vulnerability to gene inactivation as a function of key paralog properties. We find that heteromerizing paralogs are indeed less protective than non-heteromeric ones, but this association is largely due to their higher abundance and their larger number of protein-protein interaction partners.

scholarly journals Mutational robustness changes during long-term adaptation in laboratory budding yeast populations

2021 ◽  
Author(s):  
Milo Johnson ◽  
Michael M. Desai
Keyword(s):  
Gene Disruption ◽  
Fitness Landscape ◽  
Single Step ◽  
The Other ◽  
Specific Gene ◽  
Deleterious Mutations ◽  
Mutational Robustness ◽  
Fitness Effects ◽  
The Mean

As an adapting population traverses the fitness landscape, its local neighborhood (i.e., the collection of fitness effects of single-step mutations) can change shape because of interactions with mutations acquired during evolution. These changes to the distribution of fitness effects can affect both the rate of adaptation and the accumulation of deleterious mutations. However, while numerous models of fitness landscapes have been proposed in the literature, empirical data on how this distribution changes during evolution remains limited. In this study, we directly measure how the fitness landscape neighborhood changes during laboratory adaptation. Using a barcode-based mutagenesis system, we measure the fitness effects of 91 specific gene disruption mutations in genetic backgrounds spanning 8,000-10,000 generations of evolution in two constant environments. We find that the mean of the distribution of fitness effects decreases in one environment, indicating a reduction in mutational robustness, but does not change in the other. We show that these distribution-level patterns result from biases in variable patterns of epistasis at the level of individual mutations, including fitness-correlated and idiosyncratic epistasis.

A Screen for Dominant Modifiers of the irreC-rst Cell Death Phenotype in the Developing Drosophila Retina

Genetics ◽  
2000 ◽  
Vol 156 (1) ◽  
pp. 205-217
Author(s):  
Sara B Tanenbaum ◽  
Sharon M Gorski ◽  
Jamie C Rusconi ◽  
Ross L Cagan
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Cell Population ◽  
Gene Loss ◽  
Retinal Development ◽  
Genetic Screen ◽  
The Other ◽  
Loss Of Function ◽  
Cell Death Phenotype

Abstract Programmed cell death (PCD) in the Drosophila retina requires activity of the irregular chiasmC-roughest (irreC-rst) gene. Loss-of-function mutations in irreC-rst block PCD during retinal development and lead to a rough eye phenotype in the adult. To identify genes that interact with irreC-rst and may be involved in PCD, we conducted a genetic screen for dominant enhancers and suppressors of the adult rough eye phenotype. We screened 150,000 mutagenized flies and recovered 170 dominant modifiers that localized primarily to the second and third chromosomes. At least two allelic groups correspond to previously identified death regulators, Delta and dRas1. Examination of retinae from homozygous viable mutants indicated two major phenotypic classes. One class exhibited pleiotropic defects while the other class exhibited defects specific to the cell population that normally undergoes PCD.

POPDC proteins and cardiac function

2019 ◽  
Vol 47 (5) ◽  
pp. 1393-1404 ◽  
Author(s):  
Thomas Brand
Keyword(s):  
Potential Role ◽  
Striated Muscle ◽  
Short Review ◽  
Effector Proteins ◽  
Muscle Disease ◽  
Disease Genes ◽  
Protein Protein Interaction ◽  
Interaction Partners ◽  
And Function

Abstract The Popeye domain-containing gene family encodes a novel class of cAMP effector proteins in striated muscle tissue. In this short review, we first introduce the protein family and discuss their structure and function with an emphasis on their role in cyclic AMP signalling. Another focus of this review is the recently discovered role of POPDC genes as striated muscle disease genes, which have been associated with cardiac arrhythmia and muscular dystrophy. The pathological phenotypes observed in patients will be compared with phenotypes present in null and knockin mutations in zebrafish and mouse. A number of protein–protein interaction partners have been discovered and the potential role of POPDC proteins to control the subcellular localization and function of these interacting proteins will be discussed. Finally, we outline several areas, where research is urgently needed.

scholarly journals act Operon Control of Developmental Gene Expression in Myxococcus xanthus

2002 ◽  
Vol 184 (4) ◽  
pp. 1172-1179 ◽  
Author(s):  
Thomas M. A. Gronewold ◽  
Dale Kaiser
Keyword(s):  
Fruiting Body ◽  
Myxococcus Xanthus ◽  
The Other ◽  
Loss Of Function ◽  
Wild Type ◽  
Developmental Gene ◽  
Developmental Gene Expression ◽  
Mutant Strains ◽  
Genes Encoding ◽  
Signal Production

ABSTRACT Cell-bound C-signal guides the building of a fruiting body and triggers the differentiation of myxospores. Earlier work has shown that transcription of the csgA gene, which encodes the C-signal, is directed by four genes of the act operon. To see how expression of the genes encoding components of the aggregation and sporulation processes depends on C-signaling, mutants with loss-of-function mutations in each of the act genes were investigated. These mutations were found to have no effect on genes that are normally expressed up to 3 h into development and are C-signal independent. Neither the time of first expression nor the rate of expression increase was changed in actA, actB, actC, or actD mutant strains. Also, there was no effect on A-signal production, which normally starts before 3 h. By contrast, the null act mutants have striking defects in C-signal production. These mutations changed the expression of four gene reporters that are related to aggregation and sporulation and are expressed at 6 h or later in development. The actA and actB null mutations substantially decreased the expression of all these reporters. The other act null mutations caused either premature expression to wild-type levels (actC) or delayed expression (actD), which ultimately rose to wild-type levels. The pattern of effects on these reporters shows how the C-signal differentially regulates the steps that together build a fruiting body and differentiate spores within it.

scholarly journals Target-Site Mutations and Expression of ALS Gene Copies Vary According to Echinochloa Species

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1841
Author(s):  
Silvia Panozzo ◽  
Elisa Mascanzoni ◽  
Laura Scarabel ◽  
Andrea Milani ◽  
Giliardi Dalazen ◽  
...  
Keyword(s):  
Cropping Systems ◽  
Point Mutations ◽  
Common Species ◽  
Target Site ◽  
The Other ◽  
Gene Copy ◽  
Resistance Level ◽  
Resistance Evolution ◽  
Gene Copies ◽  
Als Inhibitors

The sustainability of rice cropping systems is jeopardized by the large number and variety of populations of polyploid Echinochloa spp. resistant to ALS inhibitors. Better knowledge of the Echinochloa species present in Italian rice fields and the study of ALS genes involved in target-site resistance could significantly contribute to a better understanding of resistance evolution and management. Using a CAPS-rbcL molecular marker, two species, E. crus-galli (L.) P. Beauv. and E. oryzicola (Vasinger) Vasing., were identified as the most common species in rice in Italy. Mutations involved in ALS inhibitor resistance in the different species were identified and associated with the ALS homoeologs. The relative expression of the ALS gene copies was evaluated. Molecular characterization led to the identification of three ALS genes in E. crus-galli and two in E. oryzicola. The two species also carried different point mutations conferring resistance: Ala122Asn in E. crus-galli and Trp574Leu in E. oryzicola. Mutations were carried in the same gene copy (ALS1), which was significantly more expressed than the other copies (ALS2 and ALS3) in both species. These results explain the high resistance level of these populations and why mutations in the other ALS copies are not involved in herbicide resistance.

scholarly journals Characterization of an Unstable Allele of the Arabidopsis HY4 Locus

Genetics ◽  
1998 ◽  
Vol 149 (3) ◽  
pp. 1575-1585
Author(s):  
Edward P Bruggemann ◽  
Bernard Doan ◽  
Korie Handwerger ◽  
Gisela Storz
Keyword(s):  
Fast Neutron ◽  
Blue Light ◽  
Large Deletion ◽  
The Other ◽  
Epigenetic Mechanisms ◽  
Loss Of Function ◽  
Wild Type ◽  
Unusual Behavior ◽  
Recessive Lethal

Abstract The Arabidopsis HY4 gene encodes the nonessential blue light photoreceptor CRY1. Loss-of-function hy4 mutants have an elongated hypocotyl phenotype after germination under blue light. We previously analyzed 20 independent hy4 alleles produced by fast neutron mutagenesis. These alleles were grouped into two classes based on their genetic behavior and corresponding deletion size: (1) null hy4 alleles that were semidominant over wild type and contained small or moderate-sized deletions at HY4 and (2) null hy4 alleles that were recessive lethal and contained large HY4 deletions. Here we describe one additional fast neutron hy4 mutant, B144, that did not fall into either of these two classes. Mutant B144 was isolated as a heterozygote with an intermediate hy4 phenotype. One allele from this mutant, hy4-B144Δ, contains a large deletion at HY4 and is recessive lethal. The other allele from this mutant, HY4-B144*, appears to be intact and functional but is unstable and spontaneously converts to a nonfunctional hy4 allele. In addition, HY4-B144* is lethal in homozygotes and suppresses local recombination. We discuss genetic and epigenetic mechanisms that may account for the unusual behavior of the HY4-B144* allele.

scholarly journals Integrated genomic and transcriptomic analysis revealed mutation patterns of de-differentiated liposarcoma and leiomyosarcoma

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Wenshuai Liu ◽  
Hanxing Tong ◽  
Chenlu Zhang ◽  
Rongyuan Zhuang ◽  
He Guo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sanger Sequencing ◽  
Immune Cell ◽  
Gene Copy Number ◽  
Gene Copy ◽  
Rna Seq ◽  
Loss Of Function ◽  
Rt Pcr ◽  
The Difference ◽  
Histologic Types

Abstract Background Treating patients with advanced sarcomas is challenging due to great histologic diversity among its subtypes. Leiomyosarcoma (LMS) and de-differentiated liposarcoma (DDLPS) are two common and aggressive subtypes of soft tissue sarcoma (STS). They differ significantly in histology and clinical behaviors. However, the molecular driving force behind the difference is unclear. Methods We collected 20 LMS and 12 DDLPS samples and performed whole exome sequencing (WES) to obtain their somatic mutation profiles. We also performed RNA-Seq to analyze the transcriptomes of 8 each of the LMS and DDLPS samples and obtained information about differential gene expression, pathway enrichment, immune cell infiltration in tumor microenvironment, and chromosomal rearrangement including gene fusions. Selected gene fusion events from the RNA-seq prediction were checked by RT-PCR in tandem with Sanger sequencing. Results We detected loss of function mutation and deletion of tumor suppressors mostly in LMS, and oncogene amplification mostly in DDLPS. A focal amplification affecting chromosome 12q13–15 region which encodes MDM2, CDK4 and HMGA2 is notable in DDLPS. Mutations in TP53, ATRX, PTEN, and RB1 are identified in LMS but not DDLPS, while mutation of HERC2 is only identified in DDLPS but not LMS. RNA-seq revealed overexpression of MDM2, CDK4 and HMGA2 in DDLPS and down-regulation of TP53 and RB1 in LMS. It also detected more fusion events in DDLPS than LMS (4.5 vs. 1, p = 0.0195), and the ones involving chromosome 12 in DDLPS stand out. RT-PCR and Sanger sequencing verified the majority of the fusion events in DDLPS but only one event in LMS selected to be tested. The tumor microenvironmental signatures are highly correlated with histologic types. DDLPS has more endothelial cells and fibroblasts content than LMS. Conclusions Our analysis revealed different recurrent genetic variations in LMS and DDLPS including simultaneous upregulation of gene expression and gene copy number amplification of MDM2 and CDK4. Up-regulation of tumor related genes is favored in DDLPS, while loss of suppressor function is favored in LMS. DDLPS harbors more frequent fusion events which can generate neoepitopes and potentially targeted by personalized immune treatment.

scholarly journals The two cytochrome c species, DC3 and DC4, are not required for caspase activation and apoptosis in Drosophila cells

2004 ◽  
Vol 167 (3) ◽  
pp. 405-410 ◽  
Author(s):  
Loretta Dorstyn ◽  
Kathryn Mills ◽  
Yuri Lazebnik ◽  
Sharad Kumar
Keyword(s):  
Cytochrome C ◽  
Ectopic Expression ◽  
Human Cells ◽  
Loss Of Function ◽  
Caspase Activation ◽  
Drosophila Cell ◽  
Drosophila Development ◽  
Cell Lysates ◽  
C Proteins ◽  
Drosophila Cells

In Drosophila, activation of the apical caspase DRONC requires the apoptotic protease-activating factor homologue, DARK. However, unlike caspase activation in mammals, DRONC activation is not accompanied by the release of cytochrome c from mitochondria. Drosophila encodes two cytochrome c proteins, Cytc-p (DC4) the predominantly expressed species, and Cytc-d (DC3), which is implicated in caspase activation during spermatogenesis. Here, we report that silencing expression of either or both DC3 and DC4 had no effect on apoptosis or activation of DRONC and DRICE in Drosophila cells. We find that loss of function mutations in dc3 and dc4, do not affect caspase activation during Drosophila development and that ectopic expression of DC3 or DC4 in Drosophila cells does not induce caspase activation. In cell-free studies, recombinant DC3 or DC4 failed to activate caspases in Drosophila cell lysates, but remarkably induced caspase activation in extracts from human cells. Overall, our results argue that DARK-mediated DRONC activation occurs independently of cytochrome c.

scholarly journals The sex with the reduced sex chromosome dies earlier: a comparison across the tree of life

2020 ◽  
Vol 16 (3) ◽  
pp. 20190867 ◽  
Author(s):  
Zoe A. Xirocostas ◽  
Susan E. Everingham ◽  
Angela T. Moles
Keyword(s):  
Sex Chromosome ◽  
Meta Analysis ◽  
Chromosome Morphology ◽  
Tree Of Life ◽  
The Other ◽  
Deleterious Mutations ◽  
Male And Female ◽  
Fundamental Understanding ◽  
Female Longevity ◽  
Heterogametic Sex

Many taxa show substantial differences in lifespan between the sexes. However, these differences are not always in the same direction. In mammals, females tend to live longer than males, while in birds, males tend to live longer than females. One possible explanation for these differences in lifespan is the unguarded X hypothesis, which suggests that the reduced or absent chromosome in the heterogametic sex (e.g. the Y chromosome in mammals and the W chromosome in birds) exposes recessive deleterious mutations on the other sex chromosome. While the unguarded X hypothesis is intuitively appealing, it had never been subject to a broad test. We compiled male and female longevity data for 229 species spanning 99 families, 38 orders and eight classes across the tree of life. Consistent with the unguarded X hypothesis, a meta-analysis showed that the homogametic sex, on average, lives 17.6% longer than the heterogametic sex. Surprisingly, we found substantial differences in lifespan dimorphism between female heterogametic species (in which the homogametic sex lives 7.1% longer) and male heterogametic species (in which the homogametic sex lives 20.9% longer). Our findings demonstrate the importance of considering chromosome morphology in addition to sexual selection and environment as potential drivers of sexual dimorphism, and advance our fundamental understanding of the mechanisms that shape an organism's lifespan.

scholarly journals Dysbindin deficiency Alters Cardiac BLOC-1 Complex and Myozap Levels in Mice

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2390
Author(s):  
Ankush Borlepawar ◽  
Nesrin Schmiedel ◽  
Matthias Eden ◽  
Lynn Christen ◽  
Alexandra Rosskopf ◽  
...  
Keyword(s):  
Direct Interaction ◽  
Cardiomyocyte Hypertrophy ◽  
Loss Of Function ◽  
Interaction Partners ◽  
Lysosome Related Organelles ◽  
The Stability ◽  
Schizophrenia Susceptibility

Dysbindin, a schizophrenia susceptibility marker and an essential constituent of BLOC-1 (biogenesis of lysosome-related organelles complex-1), has recently been associated with cardiomyocyte hypertrophy through the activation of Myozap-RhoA-mediated SRF signaling. We employed sandy mice (Dtnbp1_KO), which completely lack Dysbindin protein because of a spontaneous deletion of introns 5–7 of the Dtnbp1 gene, for pathophysiological characterization of the heart. Unlike in vitro, the loss-of-function of Dysbindin did not attenuate cardiac hypertrophy, either in response to transverse aortic constriction stress or upon phenylephrine treatment. Interestingly, however, the levels of hypertrophy-inducing interaction partner Myozap as well as the BLOC-1 partners of Dysbindin like Muted and Pallidin were dramatically reduced in Dtnbp1_KO mouse hearts. Taken together, our data suggest that Dysbindin’s role in cardiomyocyte hypertrophy is redundant in vivo, yet essential to maintain the stability of its direct interaction partners like Myozap, Pallidin and Muted.

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