gene deletions
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Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 27
Author(s):  
Dabin Moon ◽  
Hye Won Park ◽  
Dongheon Surl ◽  
Dongju Won ◽  
Seung-Tae Lee ◽  
...  

In this study, we investigated medically or surgically actionable genes in inherited eye disease, based on clinical phenotype and genomic data. This retrospective consecutive case series included 149 patients with inherited eye diseases, seen by a single pediatric ophthalmologist, who underwent genetic testing between 1 March 2017 and 28 February 2018. Variants were detected using a target enrichment panel of 429 genes and known deep intronic variants associated with inherited eye disease. Among 149 patients, 38 (25.5%) had a family history, and this cohort includes heterogeneous phenotype including anterior segment dysgenesis, congenital cataract, infantile nystagmus syndrome, optic atrophy, and retinal dystrophy. Overall, 90 patients (60.4%) received a definite molecular diagnosis. Overall, NGS-guided precision care was provided to 8 patients (5.4%). The precision care included cryotherapy to prevent retinal detachment in COL2A1 Stickler syndrome, osteoporosis management in patients with LRP5-associated familial exudative vitreoretinopathy, and avoidance of unnecessary phlebotomy in hyperferritinemia-cataract syndrome. A revision of the initial clinical diagnosis was made in 22 patients (14.8%). Unexpected multi-gene deletions and dual diagnosis were noted in 4 patients (2.7%). We found that precision medical or surgical managements were provided for 8 of 149 patients (5.4%), and multiple locus variants were found in 2.7% of cases. These findings are important because individualized management of inherited eye diseases can be achieved through genetic testing.


2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Bin Zhang ◽  
Michel Liu ◽  
Chin-To Fong ◽  
M. Anwar Iqbal

AbstractMEIS2 (Meis homeobox 2) encodes a homeobox protein in the three amino acid loop extension (TALE) family of highly conserved homeodomain-containing transcription regulators important for development. MEIS2 deletions/mutations have been associated with cleft lip/palate, dysmorphic facial features, cardiac defects, as well as intellectual disability at a variable severity. Here we report on one familial case that two affected siblings carry the same non-mosaic ~ 423 kb genomic deletion at 15q14 encompassing the entirety of CDIN1 and the last three exons (ex. 10, 11, 12) of the MEIS2 gene, while their unaffected father is mosaic for the same deletion in about 10% lymphocytes. Both siblings presented with mild developmental delay and bifid uvula, while no congenital cardiac abnormalities were identified. The elder sister also showed syncopal episodes and mild speech delay and the father had atrial septal defects. This is the first report showing multiple family members inherit a genomic deletion resulting in a MEIS2 partial truncation from a mosaic parent. Taken all together, this study has important implications for genetic counseling regarding recurrence risk and also points to the importance of offering MEIS2 gene tests covering both point mutations and microdeletions to individuals with milder bifid uvula and developmental delay.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jessica N. McCaffery ◽  
Douglas Nace ◽  
Camelia Herman ◽  
Balwan Singh ◽  
Eric Mukomena Sompwe ◽  
...  

AbstractRapid diagnostic tests (RDTs) detecting histidine-rich protein 2 (HRP2) and HRP3 are widely used throughout sub-Saharan Africa (SSA) to diagnose Plasmodium falciparum malaria. However, multiple SSA countries have reported pfhrp2 and pfhrp3 (pfhrp2/3) gene deletions. Blood samples (n = 1109) collected from patients with P. falciparum infection from six health facilities throughout the Democratic Republic of the Congo (DRC) from March 2017 to January 2018 were evaluated for pfhrp2/3 deletions. Samples were assayed for HRP2, pan-Plasmodium LDH (pLDH) and aldolase (pAldolase) antigens by bead-based multiplex antigen assay. Samples with low HRP2 concentration compared to pLDH and pAldolase antigens were selected for further pfhrp2/3 genotyping PCRs. The majority of blood samples (93.3%, 1035/1109) had high concentrations of the HRP2 antigen. Single deletions of pfhrp2 were identified in 0.27% (3/1109) of screened samples, with one sample from each of the Kapolowe, Mikalayi, and Rutshuru study sites. A pfhrp3 single deletion (0.09%, 1/1109) was found in the Kapolowe site. Dual pfhrp2 and pfhrp3 deletions were not observed. Due to, the low numbers of pfhrp2 deletions and the sporadic locations of these deletions, the use of HRP2-based RDTs appears to still be appropriate for these locations in DRC.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Thoma Itoh ◽  
Takashi Makino

AbstractRecent progress in high throughput single cell RNA-seq (scRNA-seq) has activated the development of data-driven inferring methods of gene regulatory networks. Most network estimations assume that perturbations produce downstream effects. However, the effects of gene perturbations are sometimes compensated by a gene with redundant functionality (functional compensation). In order to avoid functional compensation, previous studies constructed double gene deletions, but its vast nature of gene combinations was not suitable for comprehensive network estimation. We hypothesized that functional compensation may emerge as a noise change without mean change (noise-only change) due to varying physical properties and strong compensation effects. Here, we show compensated interactions, which are not detected by mean change, are captured by noise-only change quantified from scRNA-seq. We investigated whether noise-only change genes caused by a single deletion of STP1 and STP2, which have strong functional compensation, are enriched in redundantly regulated genes. As a result, noise-only change genes are enriched in their redundantly regulated genes. Furthermore, novel downstream genes detected from noise change are enriched in “transport”, which is related to known downstream genes. Herein, we suggest the noise difference comparison has the potential to be applied as a new strategy for network estimation that capture even compensated interaction.


2021 ◽  
Author(s):  
◽  
Ploi Yibmantasiri

<p>One of the major problems in biology is to identify genes that are involved in specific processes. Classical genetics and biochemistry, although powerful and informative, can be very labour intensive and do not necessarily characterise networked genes in processes that may overarch numerous biochemical pathways. Here we utilised genomic tools that are capable of defining networks to identify genes involved the complex target mode-of-action of a novel antifungal compound, neothyonidioside and in regulating specific stress processes and the PDR phenotype. The first part of this study investigated the mode-of-action of the antifungal compound, neothyonidioside (neo). We developed a neo resistant mutant strain then utilising a modification of SGAM, a genetic mapping tool, and application of genome-wide chemical-genetic profiling, we identified the neo resistant locus NCP1. This gene acts at a late step in ergosterol biosynthesis but is not the target of neo. The finding that many of the component genes in the ESCRT complex were necessary for neo resistance allowed us to predict and verify by high-content fluorescence microcopy that interruptions in the endosome-multivesicular body pathway were involved. From the known function of the ESCRT proteins and that neo binds ergosterol only above threshold concentrations of ergosterol (explaining the mutant phenotype) we concluded that neo disruption of membrane curvature and fusion capability in the endosome-vacuole pathway is its target. In the second part of this study we identified genes in a genome-wide fashion that modulate the pleiotropic drug resistance (PDR) phenotype and oxidative stress response. Many PDR targets are well studied ABC transporters (e.g. PDR5 , YOR1), but the modulating events between xenobiotic sensing and transcription factor activation, and possible crosstalk between PDR and other stress responses such as oxidative stress are not well characterised. To identify specific genes involved in the PDR and oxidative stress processes, we developed a fluorescent reporter screen for effects on the PDR-target ABC-transporters, Pdr5p and Yor1p tagged with GFP. For the oxidative stress response, the oxidative stress (OS) transcription factor Yap1p tagged with GFP was used. Each reporter was placed in the yeast non-essential gene deletion background of ~4800 strains which were then subjected to either xenobiotic treatments (PDR –GFP reporters) or oxidant treatments (Yap1p-GFP). We then screened for gene deletions which prevented the normal upregulation of PDR reporters in the presence of xenobiotics. Controls were included in the screens that assured we were assessing genes that must contribute to or act before the transcription of the ABC-transporters. A similar screening strategy was pursued for identifying gene deletions that prevent the normal nuclear re-localisation of Yap1p in the presence of oxidants. A major finding in this study was identification of genes contributing to the PDR phenotype that involved signalling (Rho-GTPase, MAPK), that were involved in RNA polymerase II mediator complexes and chromatin modification (subunits of ADA and SAGA histone acetyltransferase complexes), and that were involved in sphingo/phosphorlipids biosynthesis. Secondary screens comprising spot dilution growth assays and Western blots of Pdr5p abundance confirmed key genes of the primary screen and showed that these were specific and not global transcriptional effects.For some of the gene-dependencies, our results can only be construed to indicate the existence of alternative pathways underpinning the PDR phenotype in a Pdr1p/Pdr3p independent manner. We then supposed that if in fact PDR phenotypes are the result of genetic networks, then genes known to interact with the most highly connected hubs from our PDR screen results should also to some extent contribute to the PDR phenotype (spot dilution growth assays, Western blot abundance). A selection of 18 such genes that also appeared in our primary screen but were deemed to be below the cut-off point were phenotype tested and in 60% of the cases showed similar phenotypes to the genes already identified. This result not only proved the validity of the screening methods but validated the original supposition, i.e. that PDR phenotypes can be affected, through gene networks.</p>


2021 ◽  
Author(s):  
◽  
Ploi Yibmantasiri

<p>One of the major problems in biology is to identify genes that are involved in specific processes. Classical genetics and biochemistry, although powerful and informative, can be very labour intensive and do not necessarily characterise networked genes in processes that may overarch numerous biochemical pathways. Here we utilised genomic tools that are capable of defining networks to identify genes involved the complex target mode-of-action of a novel antifungal compound, neothyonidioside and in regulating specific stress processes and the PDR phenotype. The first part of this study investigated the mode-of-action of the antifungal compound, neothyonidioside (neo). We developed a neo resistant mutant strain then utilising a modification of SGAM, a genetic mapping tool, and application of genome-wide chemical-genetic profiling, we identified the neo resistant locus NCP1. This gene acts at a late step in ergosterol biosynthesis but is not the target of neo. The finding that many of the component genes in the ESCRT complex were necessary for neo resistance allowed us to predict and verify by high-content fluorescence microcopy that interruptions in the endosome-multivesicular body pathway were involved. From the known function of the ESCRT proteins and that neo binds ergosterol only above threshold concentrations of ergosterol (explaining the mutant phenotype) we concluded that neo disruption of membrane curvature and fusion capability in the endosome-vacuole pathway is its target. In the second part of this study we identified genes in a genome-wide fashion that modulate the pleiotropic drug resistance (PDR) phenotype and oxidative stress response. Many PDR targets are well studied ABC transporters (e.g. PDR5 , YOR1), but the modulating events between xenobiotic sensing and transcription factor activation, and possible crosstalk between PDR and other stress responses such as oxidative stress are not well characterised. To identify specific genes involved in the PDR and oxidative stress processes, we developed a fluorescent reporter screen for effects on the PDR-target ABC-transporters, Pdr5p and Yor1p tagged with GFP. For the oxidative stress response, the oxidative stress (OS) transcription factor Yap1p tagged with GFP was used. Each reporter was placed in the yeast non-essential gene deletion background of ~4800 strains which were then subjected to either xenobiotic treatments (PDR –GFP reporters) or oxidant treatments (Yap1p-GFP). We then screened for gene deletions which prevented the normal upregulation of PDR reporters in the presence of xenobiotics. Controls were included in the screens that assured we were assessing genes that must contribute to or act before the transcription of the ABC-transporters. A similar screening strategy was pursued for identifying gene deletions that prevent the normal nuclear re-localisation of Yap1p in the presence of oxidants. A major finding in this study was identification of genes contributing to the PDR phenotype that involved signalling (Rho-GTPase, MAPK), that were involved in RNA polymerase II mediator complexes and chromatin modification (subunits of ADA and SAGA histone acetyltransferase complexes), and that were involved in sphingo/phosphorlipids biosynthesis. Secondary screens comprising spot dilution growth assays and Western blots of Pdr5p abundance confirmed key genes of the primary screen and showed that these were specific and not global transcriptional effects.For some of the gene-dependencies, our results can only be construed to indicate the existence of alternative pathways underpinning the PDR phenotype in a Pdr1p/Pdr3p independent manner. We then supposed that if in fact PDR phenotypes are the result of genetic networks, then genes known to interact with the most highly connected hubs from our PDR screen results should also to some extent contribute to the PDR phenotype (spot dilution growth assays, Western blot abundance). A selection of 18 such genes that also appeared in our primary screen but were deemed to be below the cut-off point were phenotype tested and in 60% of the cases showed similar phenotypes to the genes already identified. This result not only proved the validity of the screening methods but validated the original supposition, i.e. that PDR phenotypes can be affected, through gene networks.</p>


2021 ◽  
Author(s):  
Sabin Nundu ◽  
Hiroaki Arima ◽  
Shirley Simpson ◽  
Ben-Yeddy Abel Chitama ◽  
Yannick Bazitama Munyeku ◽  
...  

Abstract Background. Loss of efficacy of malaria diagnostic tests may lead to untreated or mistreated cases, compromising case management and control. There is an increasing reliance on rapid diagnostic tests (RDTs), with the most widely used of these targeting the Plasmodium falciparum histidine-rich protein 2 gene. There are numerous reports of the deletion of this gene in P. falciparum parasites in some populations, rendering them undetectable by PfHRP2 RDTs. We aimed to identify P. falciparum parasites lacking the P. falciparum histidine rich protein 2 and 3 genes isolated from asymptomatic and symptomatic school-age children in Kinshasa, Democratic Republic of Congo. Methods. We assessed the performance of PfHRP2-based RDTs in comparison to microscopy and PCR. PCR was then used to identify parasite isolates lacking pfhrp2/3 genes. Results. Of 462 DNA samples analysed, deletions of the pfhrp2 and pfhrp3 genes were found in only three (2%) samples and one (1%) sample in the RDT positive subgroup, respectively. No parasites lacking the pfhrp2/3 genes were found in the RDT negative subgroup. Conclusion. Plasmodium falciparum histidine-rich protein 2/3 gene deletions are uncommon in the surveyed population, and do not result in diagnostic failure. We encourage the use of rigorous PCR methods to identify pfhrp2/3 gene deletions in order to minimize the overestimation of their prevalence.


2021 ◽  
Author(s):  
Stephanie L Brumwell ◽  
Katherine D Van Belois ◽  
Daniel J Giguere ◽  
David R Edgell ◽  
Bogumil J Karas

D. radiodurans has become an attractive microbial platform for the study of extremophile biology and industrial bioproduction. To improve the genomic manipulation and tractability of this species, the development of tools for whole genome engineering and design is necessary. Here, we report the development of a simple and robust conjugation-based transformation system from E. coli to D. radiodurans allowing for the introduction of stable, replicating plasmids expressing antibiotic resistance markers. Using this method with nonreplicating plasmids, we developed a protocol for creating sequential gene deletions in D. radiodurans by target-ing restriction-modification system genes. Importantly, we demonstrated a conjugation-based method for cloning the large (178 kb), high G+C content MP1 megaplasmid from D. radiodurans in E. coli. The conjugation-based tools described here will facili-tate the development of D. radiodurans strains with synthetic genomes for biological studies and industrial applications.


2021 ◽  
Author(s):  
Jane Hawkey ◽  
Ben Vezina ◽  
Jonathan Monk ◽  
Louise M Judd ◽  
Taylor Harshegyi ◽  
...  

The Klebsiella pneumoniae species complex (KpSC) is a set of seven Klebsiella taxa which are found in a variety of niches, and are an important cause of opportunistic healthcare- associated infections in humans. Due to increasing rates of multi-drug resistance within the KpSC, there is a growing interest in better understanding the biology and metabolism of these organisms to inform novel control strategies. We collated 37 sequenced KpSC isolates isolated from a variety of niches, representing all seven taxa. We generated strain-specific genome scale metabolic models (GEMs) for all 37 isolates and simulated growth phenotypes on 511 distinct carbon, nitrogen, sulphur and phosphorus substrates. Models were curated and their accuracy assessed using matched phenotypic growth data for 94 substrates (median accuracy of 96%). We explored species-specific growth capabilities and examined the impact of all possible single gene deletions on growth in 145 core carbon substrates. These analyses revealed multiple strain-specific differences, within and between species and highlight the importance of selecting a diverse range of strains when exploring KpSC metabolism. This diverse set of highly accurate GEMs could be used to inform novel drug design, enhance genomic analyses, and identify novel virulence and resistance determinants. We envisage that these 37 curated strain-specific GEMs, covering all seven taxa of the KpSC, provide a valuable resource to the Klebsiella research community.


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