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Use of deep whole-genome sequencing data to identify structure risk variants in breast cancer susceptibility genes.
Guo X, Shi J, Cai Q, Shu XO, He J, Wen W, Allen J, Pharoah P, Dunning A, Hunter DJ, Kraft P, Easton DF, Zheng W, Long J
(2018) Hum Mol Genet 27: 853-859
MeSH Terms: BRCA1 Protein, Breast Neoplasms, Fanconi Anemia Complementation Group N Protein, Female, Genetic Predisposition to Disease, Genome, Human, High-Throughput Nucleotide Sequencing, Humans, Membrane Proteins, PTEN Phosphohydrolase, Rad51 Recombinase, Sequence Deletion, Tumor Suppressor Protein p53
Show Abstract · Added April 3, 2018
Functional disruptions of susceptibility genes by large genomic structure variant (SV) deletions in germlines are known to be associated with cancer risk. However, few studies have been conducted to systematically search for SV deletions in breast cancer susceptibility genes. We analysed deep (> 30x) whole-genome sequencing (WGS) data generated in blood samples from 128 breast cancer patients of Asian and European descent with either a strong family history of breast cancer or early cancer onset disease. To identify SV deletions in known or suspected breast cancer susceptibility genes, we used multiple SV calling tools including Genome STRiP, Delly, Manta, BreakDancer and Pindel. SV deletions were detected by at least three of these bioinformatics tools in five genes. Specifically, we identified heterozygous deletions covering a fraction of the coding regions of BRCA1 (with approximately 80kb in two patients), and TP53 genes (with ∼1.6 kb in two patients), and of intronic regions (∼1 kb) of the PALB2 (one patient), PTEN (three patients) and RAD51C genes (one patient). We confirmed the presence of these deletions using real-time quantitative PCR (qPCR). Our study identified novel SV deletions in breast cancer susceptibility genes and the identification of such SV deletions may improve clinical testing.
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13 MeSH Terms
MybA, a transcription factor involved in conidiation and conidial viability of the human pathogen Aspergillus fumigatus.
Valsecchi I, Sarikaya-Bayram Ö, Wong Sak Hoi J, Muszkieta L, Gibbons J, Prevost MC, Mallet A, Krijnse-Locker J, Ibrahim-Granet O, Mouyna I, Carr P, Bromley M, Aimanianda V, Yu JH, Rokas A, Braus GH, Saveanu C, Bayram Ö, Latgé JP
(2017) Mol Microbiol 105: 880-900
MeSH Terms: Aspergillosis, Aspergillus fumigatus, Cell Wall, Fungal Proteins, Gene Deletion, Gene Expression Regulation, Fungal, Humans, Membrane Proteins, Sequence Deletion, Spores, Fungal, Transcription Factors, Virulence
Show Abstract · Added March 21, 2018
Aspergillus fumigatus, a ubiquitous human fungal pathogen, produces asexual spores (conidia), which are the main mode of propagation, survival and infection of this human pathogen. In this study, we present the molecular characterization of a novel regulator of conidiogenesis and conidial survival called MybA because the predicted protein contains a Myb DNA binding motif. Cellular localization of the MybA::Gfp fusion and immunoprecipitation of the MybA::Gfp or MybA::3xHa protein showed that MybA is localized to the nucleus. RNA sequencing data and a uidA reporter assay indicated that the MybA protein functions upstream of wetA, vosA and velB, the key regulators involved in conidial maturation. The deletion of mybA resulted in a very significant reduction in the number and viability of conidia. As a consequence, the ΔmybA strain has a reduced virulence in an experimental murine model of aspergillosis. RNA-sequencing and biochemical studies of the ΔmybA strain suggested that MybA protein controls the expression of enzymes involved in trehalose biosynthesis as well as other cell wall and membrane-associated proteins and ROS scavenging enzymes. In summary, MybA protein is a new key regulator of conidiogenesis and conidial maturation and survival, and plays a crucial role in propagation and virulence of A. fumigatus.
© 2017 John Wiley & Sons Ltd.
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A common deletion in the haptoglobin gene associated with blood cholesterol levels among Chinese women.
Zheng NS, Bastarache LA, Bastarache JA, Lu Y, Ware LB, Shu XO, Denny JC, Long J
(2017) J Hum Genet 62: 911-914
MeSH Terms: Adult, Aged, Alleles, Asian Continental Ancestry Group, Case-Control Studies, Cholesterol, DNA Copy Number Variations, Female, Gene Frequency, Genetic Association Studies, Genotype, Haptoglobins, Humans, Middle Aged, Population Surveillance, Sequence Deletion, Young Adult
Show Abstract · Added March 14, 2018
Haptoglobin (HP) protein plays a critical role in binding and removing free hemoglobin from blood. A deletion in the HP gene affects the protein structure and function. A recent study developed a novel method to impute this variant and discovered significant association of this variant with low-density lipoprotein (LDL) and total cholesterol levels among European descendants. In the present study, we investigated this variant among 3608 Chinese women. Consistent with findings from Europeans, we found significant associations between the deletion with lower cholesterol levels; women homozygous for the deletion allele (HP1-HP1), had a lower level of total cholesterol (-4.24 mg dl, P=0.02) and LDL cholesterol (-3.43 mg dl, P=0.03) than those not carrying the deletion allele (HP2-HP2). Especially, women carrying the HP1S-HP1S, had an even lower level of total cholesterol (-5.59 mg dl, P=7.0 × 10) and LDL cholesterol (-4.68 mg dl, P=8.0 × 10) compared to those carrying HP2-HP2. These associations remained significant after an adjustment for an established cholesterol level-related variant, rs2000999. Our study extends the previous findings regarding the association of HP structure variant with blood cholesterol levels to East Asians and affirms the validity of the new methodology for assessing HP structure variation.
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17 MeSH Terms
A patient with multisystem dysfunction carries a truncation mutation in human , the gene encoding the Na-K-2Cl cotransporter, NKCC1.
Delpire E, Wolfe L, Flores B, Koumangoye R, Schornak CC, Omer S, Pusey B, Lau C, Markello T, Adams DR
(2016) Cold Spring Harb Mol Case Stud 2: a001289
MeSH Terms: Adolescent, Alleles, Carrier Proteins, Cell Membrane, Chlorides, Female, Fibroblasts, Humans, Mutation, Sequence Deletion, Sodium, Sodium, Dietary, Sodium-Potassium-Chloride Symporters, Solute Carrier Family 12, Member 2, Whole Exome Sequencing
Show Abstract · Added April 26, 2017
This study describes a 13-yr-old girl with orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency, and multiorgan failure involving the gut and bladder. Exome sequencing revealed a de novo, loss-of-function allele in , the gene encoding the Na-K-2Cl cotransporter-1. The 11-bp deletion in exon 22 results in frameshift (p.Val1026Phe*2) and truncation of the carboxy-terminal tail of the cotransporter. Preliminary studies in heterologous expression systems demonstrate that the mutation leads to a nonfunctional transporter, which is expressed and trafficked to the plasma membrane alongside wild-type NKCC1. The truncated protein, visible at higher molecular sizes, indicates either enhanced dimerization or misfolded aggregate. No significant dominant-negative effect was observed. K transport experiments performed in fibroblasts from the patient showed reduced total and NKCC1-mediated K influx. The absence of a bumetanide effect on K influx in patient fibroblasts only under hypertonic conditions suggests a deficit in NKCC1 regulation. We propose that disruption in NKCC1 function might affect sensory afferents and/or smooth muscle cells, as their functions depend on NKCC1 creating a Cl gradient across the plasma membrane. This Cl gradient allows the γ-aminobutyric acid (GABA) receptor or other Cl channels to depolarize the membrane affecting processes such as neurotransmission or cell contraction. Under this hypothesis, disrupted sensory and smooth muscle function in a diverse set of tissues could explain the patient's phenotype.
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C-terminal motif of human neuropeptide Y receptor determines internalization and arrestin recruitment.
Wanka L, Babilon S, Burkert K, Mörl K, Gurevich VV, Beck-Sickinger AG
(2017) Cell Signal 29: 233-239
MeSH Terms: Amino Acid Motifs, Amino Acid Sequence, Amino Acids, Animals, COS Cells, Cercopithecus aethiops, Endocytosis, HEK293 Cells, Humans, Mutant Proteins, Receptors, Neuropeptide Y, Reproducibility of Results, Sequence Alignment, Sequence Deletion, Structure-Activity Relationship, beta-Arrestin 2
Show Abstract · Added March 14, 2018
The human neuropeptide Y receptor is a rhodopsin-like G protein-coupled receptor (GPCR), which contributes to anorexigenic signals. Thus, this receptor is a highly interesting target for metabolic diseases. As GPCR internalization and trafficking affect receptor signaling and vice versa, we aimed to investigate the molecular mechanism of hYR desensitization and endocytosis. The role of distinct segments of the hYR carboxyl terminus was investigated by fluorescence microscopy, binding assays, inositol turnover experiments and bioluminescence resonance energy transfer assays to examine the internalization behavior of hYR and its interaction with arrestin-3. Based on results of C-terminal deletion mutants and substitution of single amino acids, the motif EESEHLPLSTVHTEVSKGS was identified, with glutamate, threonine and serine residues playing key roles, based on site-directed mutagenesis. Thus, we identified the internalization motif for the human neuropeptide Y receptor, which regulates arrestin-3 recruitment and receptor endocytosis.
Copyright © 2016 Elsevier Inc. All rights reserved.
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16 MeSH Terms
Induction of HIV Neutralizing Antibody Lineages in Mice with Diverse Precursor Repertoires.
Tian M, Cheng C, Chen X, Duan H, Cheng HL, Dao M, Sheng Z, Kimble M, Wang L, Lin S, Schmidt SD, Du Z, Joyce MG, Chen Y, DeKosky BJ, Chen Y, Normandin E, Cantor E, Chen RE, Doria-Rose NA, Zhang Y, Shi W, Kong WP, Choe M, Henry AR, Laboune F, Georgiev IS, Huang PY, Jain S, McGuire AT, Georgeson E, Menis S, Douek DC, Schief WR, Stamatatos L, Kwong PD, Shapiro L, Haynes BF, Mascola JR, Alt FW
(2016) Cell 166: 1471-1484.e18
MeSH Terms: Animals, Antibodies, Monoclonal, Antibodies, Neutralizing, B-Lymphocytes, Cell Line, Disease Models, Animal, Gene Expression Regulation, HIV-1, Immunization, Immunoglobulin Heavy Chains, Inhibitory Concentration 50, Mice, Precursor Cells, B-Lymphoid, Sequence Deletion, T-Lymphocytes
Show Abstract · Added May 3, 2017
The design of immunogens that elicit broadly reactive neutralizing antibodies (bnAbs) has been a major obstacle to HIV-1 vaccine development. One approach to assess potential immunogens is to use mice expressing precursors of human bnAbs as vaccination models. The bnAbs of the VRC01-class derive from the IGHV1-2 immunoglobulin heavy chain and neutralize a wide spectrum of HIV-1 strains via targeting the CD4 binding site of the envelope glycoprotein gp120. We now describe a mouse vaccination model that allows a germline human IGHV1-2(∗)02 segment to undergo normal V(D)J recombination and, thereby, leads to the generation of peripheral B cells that express a highly diverse repertoire of VRC01-related receptors. When sequentially immunized with modified gp120 glycoproteins designed to engage VRC01 germline and intermediate antibodies, IGHV1-2(∗)02-rearranging mice, which also express a VRC01-antibody precursor light chain, can support the affinity maturation of VRC01 precursor antibodies into HIV-neutralizing antibody lineages.
Copyright © 2016 Elsevier Inc. All rights reserved.
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A Novel Saccharomyces cerevisiae FG Nucleoporin Mutant Collection for Use in Nuclear Pore Complex Functional Experiments.
Adams RL, Terry LJ, Wente SR
(2015) G3 (Bethesda) 6: 51-8
MeSH Terms: Gene Expression, Genetic Association Studies, Mutation, Nuclear Pore Complex Proteins, Phenotype, Plasmids, Protein Interaction Domains and Motifs, Saccharomyces cerevisiae, Sequence Deletion
Show Abstract · Added February 15, 2016
FG nucleoporins (Nups) are the class of proteins that both generate the permeability barrier and mediate selective transport through the nuclear pore complex (NPC). The FG Nup family has 11 members in Saccharomyces cerevisiae, and the study of mutants lacking different FG domains has been instrumental in testing transport models. To continue analyzing the distinct functional roles of FG Nups in vivo, additional robust genetic tools are required. Here, we describe a novel collection of S. cerevisiae mutant strains in which the FG domains of different groups of Nups are absent (Δ) in the greatest number documented to date. Using this plasmid-based ΔFG strategy, we find that a GLFG domain-only pore is sufficient for viability. The resulting extensive plasmid and strain resources are available to the scientific community for future in-depth in vivo studies of NPC transport.
Copyright © 2016 Adams et al.
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9 MeSH Terms
Reduction of thalamic and cortical Ih by deletion of TRIP8b produces a mouse model of human absence epilepsy.
Heuermann RJ, Jaramillo TC, Ying SW, Suter BA, Lyman KA, Han Y, Lewis AS, Hampton TG, Shepherd GMG, Goldstein PA, Chetkovich DM
(2016) Neurobiol Dis 85: 81-92
MeSH Terms: Animals, Blotting, Western, Cerebral Cortex, Disease Models, Animal, Electrocardiography, Electrocorticography, Electrodes, Implanted, Epilepsy, Absence, Immunohistochemistry, Male, Membrane Potentials, Membrane Proteins, Mice, Knockout, Motor Activity, Neurons, Patch-Clamp Techniques, Peroxins, Rotarod Performance Test, Sequence Deletion, Thalamus, Tissue Culture Techniques
Show Abstract · Added April 2, 2019
Absence seizures occur in several types of human epilepsy and result from widespread, synchronous feedback between the cortex and thalamus that produces brief episodes of loss of consciousness. Genetic rodent models have been invaluable for investigating the pathophysiological basis of these seizures. Here, we identify tetratricopeptide-containing Rab8b-interacting protein (TRIP8b) knockout mice as a new model of absence epilepsy, featuring spontaneous spike-wave discharges on electroencephalography (EEG) that are the electrographic hallmark of absence seizures. TRIP8b is an auxiliary subunit of the hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels, which have previously been implicated in the pathogenesis of absence seizures. In contrast to mice lacking the pore-forming HCN channel subunit HCN2, TRIP8b knockout mice exhibited normal cardiac and motor function and a less severe seizure phenotype. Evaluating the circuit that underlies absence seizures, we found that TRIP8b knockout mice had significantly reduced HCN channel expression and function in thalamic-projecting cortical layer 5b neurons and thalamic relay neurons, but preserved function in inhibitory neurons of the reticular thalamic nucleus. Our results expand the known roles of TRIP8b and provide new insight into the region-specific functions of TRIP8b and HCN channels in constraining cortico-thalamo-cortical excitability.
Copyright © 2015 Elsevier Inc. All rights reserved.
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High-throughput gene targeting and phenotyping in zebrafish using CRISPR/Cas9.
Varshney GK, Pei W, LaFave MC, Idol J, Xu L, Gallardo V, Carrington B, Bishop K, Jones M, Li M, Harper U, Huang SC, Prakash A, Chen W, Sood R, Ledin J, Burgess SM
(2015) Genome Res 25: 1030-42
MeSH Terms: Alleles, Animals, CRISPR-Cas Systems, Gene Knockout Techniques, Gene Targeting, Genome-Wide Association Study, Genomics, Germ Cells, High-Throughput Screening Assays, Humans, Mutagenesis, Phenotype, Quantitative Trait Loci, RNA, Guide, Sequence Deletion, Zebrafish
Show Abstract · Added July 23, 2015
The use of CRISPR/Cas9 as a genome-editing tool in various model organisms has radically changed targeted mutagenesis. Here, we present a high-throughput targeted mutagenesis pipeline using CRISPR/Cas9 technology in zebrafish that will make possible both saturation mutagenesis of the genome and large-scale phenotyping efforts. We describe a cloning-free single-guide RNA (sgRNA) synthesis, coupled with streamlined mutant identification methods utilizing fluorescent PCR and multiplexed, high-throughput sequencing. We report germline transmission data from 162 loci targeting 83 genes in the zebrafish genome, in which we obtained a 99% success rate for generating mutations and an average germline transmission rate of 28%. We verified 678 unique alleles from 58 genes by high-throughput sequencing. We demonstrate that our method can be used for efficient multiplexed gene targeting. We also demonstrate that phenotyping can be done in the F1 generation by inbreeding two injected founder fish, significantly reducing animal husbandry and time. This study compares germline transmission data from CRISPR/Cas9 with those of TALENs and ZFNs and shows that efficiency of CRISPR/Cas9 is sixfold more efficient than other techniques. We show that the majority of published "rules" for efficient sgRNA design do not effectively predict germline transmission rates in zebrafish, with the exception of a GG or GA dinucleotide genomic match at the 5' end of the sgRNA. Finally, we show that predicted off-target mutagenesis is of low concern for in vivo genetic studies.
© 2015 Varshney et al.; Published by Cold Spring Harbor Laboratory Press.
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Next-generation sequencing reveals the biological significance of the N(2),3-ethenoguanine lesion in vivo.
Chang SC, Fedeles BI, Wu J, Delaney JC, Li D, Zhao L, Christov PP, Yau E, Singh V, Jost M, Drennan CL, Marnett LJ, Rizzo CJ, Levine SS, Guengerich FP, Essigmann JM
(2015) Nucleic Acids Res 43: 5489-500
MeSH Terms: DNA Adducts, DNA Damage, DNA Polymerase beta, DNA Repair, DNA Repair Enzymes, Dioxygenases, Guanine, High-Throughput Nucleotide Sequencing, Mutagenesis, Mutation, Sequence Analysis, DNA, Sequence Deletion
Show Abstract · Added January 7, 2016
Etheno DNA adducts are a prevalent type of DNA damage caused by vinyl chloride (VC) exposure and oxidative stress. Etheno adducts are mutagenic and may contribute to the initiation of several pathologies; thus, elucidating the pathways by which they induce cellular transformation is critical. Although N(2),3-ethenoguanine (N(2),3-εG) is the most abundant etheno adduct, its biological consequences have not been well characterized in cells due to its labile glycosidic bond. Here, a stabilized 2'-fluoro-2'-deoxyribose analog of N(2),3-εG was used to quantify directly its genotoxicity and mutagenicity. A multiplex method involving next-generation sequencing enabled a large-scale in vivo analysis, in which both N(2),3-εG and its isomer 1,N(2)-ethenoguanine (1,N(2)-εG) were evaluated in various repair and replication backgrounds. We found that N(2),3-εG potently induces G to A transitions, the same mutation previously observed in VC-associated tumors. By contrast, 1,N(2)-εG induces various substitutions and frameshifts. We also found that N(2),3-εG is the only etheno lesion that cannot be repaired by AlkB, which partially explains its persistence. Both εG lesions are strong replication blocks and DinB, a translesion polymerase, facilitates the mutagenic bypass of both lesions. Collectively, our results indicate that N(2),3-εG is a biologically important lesion and may have a functional role in VC-induced or inflammation-driven carcinogenesis.
© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.
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