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Results: 1 to 10 of 149

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Local ancestry transitions modify snp-trait associations.
Fish AE, Crawford DC, Capra JA, Bush WS
(2018) Pac Symp Biocomput 23: 424-435
MeSH Terms: Adult, African Continental Ancestry Group, Chromosomes, Human, Computational Biology, Epistasis, Genetic, European Continental Ancestry Group, Evolution, Molecular, Gene Frequency, Genetics, Population, Genome-Wide Association Study, Haplotypes, Humans, Linear Models, Models, Genetic, Polymorphism, Single Nucleotide, Recombination, Genetic
Show Abstract · Added March 14, 2018
Genomic maps of local ancestry identify ancestry transitions - points on a chromosome where recent recombination events in admixed individuals have joined two different ancestral haplotypes. These events bring together alleles that evolved within separate continential populations, providing a unique opportunity to evaluate the joint effect of these alleles on health outcomes. In this work, we evaluate the impact of genetic variants in the context of nearby local ancestry transitions within a sample of nearly 10,000 adults of African ancestry with traits derived from electronic health records. Genetic data was located using the Metabochip, and used to derive local ancestry. We develop a model that captures the effect of both single variants and local ancestry, and use it to identify examples where local ancestry transitions significantly interact with nearby variants to influence metabolic traits. In our most compelling example, we find that the minor allele of rs16890640 occuring on a European background with a downstream local ancestry transition to African ancestry results in significantly lower mean corpuscular hemoglobin and volume. This finding represents a new way of discovering genetic interactions, and is supported by molecular data that suggest changes to local ancestry may impact local chromatin looping.
0 Communities
1 Members
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16 MeSH Terms
SMARCAL1 maintains telomere integrity during DNA replication.
Poole LA, Zhao R, Glick GG, Lovejoy CA, Eischen CM, Cortez D
(2015) Proc Natl Acad Sci U S A 112: 14864-9
MeSH Terms: Animals, Chromosomes, Human, DNA Damage, DNA Helicases, DNA Replication, HeLa Cells, Humans, Mice, Recombination, Genetic, Telomere, Telomere Homeostasis
Show Abstract · Added February 4, 2016
The SMARCAL1 (SWI/SNF related, matrix-associated, actin-dependent, regulator of chromatin, subfamily A-like 1) DNA translocase is one of several related enzymes, including ZRANB3 (zinc finger, RAN-binding domain containing 3) and HLTF (helicase-like transcription factor), that are recruited to stalled replication forks to promote repair and restart replication. These enzymes can perform similar biochemical reactions such as fork reversal; however, genetic studies indicate they must have unique cellular activities. Here, we present data showing that SMARCAL1 has an important function at telomeres, which present an endogenous source of replication stress. SMARCAL1-deficient cells accumulate telomere-associated DNA damage and have greatly elevated levels of extrachromosomal telomere DNA (C-circles). Although these telomere phenotypes are often found in tumor cells using the alternative lengthening of telomeres (ALT) pathway for telomere elongation, SMARCAL1 deficiency does not yield other ALT phenotypes such as elevated telomere recombination. The activity of SMARCAL1 at telomeres can be separated from its genome-maintenance activity in bulk chromosomal replication because it does not require interaction with replication protein A. Finally, this telomere-maintenance function is not shared by ZRANB3 or HLTF. Our results provide the first identification, to our knowledge, of an endogenous source of replication stress that requires SMARCAL1 for resolution and define differences between members of this class of replication fork-repair enzymes.
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11 MeSH Terms
Anaplastic Lymphoma Kinase as a Therapeutic Target in Non-Small Cell Lung Cancer.
Iams WT, Lovly CM
(2015) Cancer J 21: 378-82
MeSH Terms: Anaplastic Lymphoma Kinase, Antineoplastic Agents, Antineoplastic Combined Chemotherapy Protocols, Carcinoma, Non-Small-Cell Lung, Clinical Trials as Topic, Drug Resistance, Neoplasm, Humans, Lung Neoplasms, Molecular Targeted Therapy, Mutation, Protein Kinase Inhibitors, Receptor Protein-Tyrosine Kinases, Recombination, Genetic, Translocation, Genetic, Treatment Outcome
Show Abstract · Added January 26, 2016
The therapeutic targeting of anaplastic lymphoma kinase (ALK) has been a burgeoning area of research since 2007 when ALK fusions were initially identified in patients with non-small cell lung cancer. The field has rapidly progressed through development of the first-generation ALK inhibitor, crizotinib, to an understanding of mechanisms of acquired resistance to crizotinib and is currently witnessing an explosion in the development of next-generation ALK inhibitors such as ceritinib, alectinib, PF-06463922, AP26113, X-396, and TSR-011. As with most targeted therapies, acquired resistance appears to be an inevitable outcome. Current preclinical and clinical studies are focused on the development of rational therapeutic strategies, including novel ALK inhibitors, as well as rational combination therapies to maximize disease control by delaying or overcoming acquired therapeutic resistance. This review summarizes the existing clinical data and ongoing research pertaining to the clinical application of ALK inhibitors in patients with non-small cell lung cancer.
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15 MeSH Terms
LRIG1 Regulates Ontogeny of Smooth Muscle-Derived Subsets of Interstitial Cells of Cajal in Mice.
Kondo J, Powell AE, Wang Y, Musser MA, Southard-Smith EM, Franklin JL, Coffey RJ
(2015) Gastroenterology 149: 407-19.e8
MeSH Terms: Animals, Fluorescent Antibody Technique, Homozygote, Integrases, Interstitial Cells of Cajal, Intestine, Small, Membrane Glycoproteins, Mice, Mice, Knockout, Muscle, Smooth, Myenteric Plexus, Nerve Tissue Proteins, Recombination, Genetic, Submucous Plexus
Show Abstract · Added July 28, 2015
BACKGROUND & AIMS - Interstitial cells of Cajal (ICC) control intestinal smooth muscle contraction to regulate gut motility. ICC within the plane of the myenteric plexus (ICC-MY) arise from KIT-positive progenitor cells during mouse embryogenesis. However, little is known about the ontogeny of ICC associated with the deep muscular plexus (ICC-DMP) in the small intestine and ICC associated with the submucosal plexus (ICC-SMP) in the colon. Leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) marks intestinal epithelial stem cells, but the role of LRIG1 in nonepithelial intestinal cells has not been identified. We sought to determine the ontogeny of ICC-DMP and ICC-SMP, and whether LRIG1 has a role in their development.
METHODS - Lrig1-null mice (homozygous Lrig1-CreERT2) and wild-type mice were analyzed by immunofluorescence and transit assays. Transit was evaluated by passage of orally administered rhodamine B-conjugated dextran. Lrig1-CreERT2 mice or mice with CreERT2 under control of an inducible smooth muscle promoter (Myh11-CreERT2) were crossed with Rosa26-LSL-YFP mice for lineage tracing analysis.
RESULTS - In immunofluorescence assays, ICC-DMP and ICC-SMP were found to express LRIG1. Based on lineage tracing, ICC-DMP and ICC-SMP each arose from LRIG1-positive smooth muscle progenitors. In Lrig1-null mice, there was loss of staining for KIT in DMP and SMP regions, as well as for 2 additional ICC markers (anoctamin-1 and neurokinin 1 receptor). Lrig1-null mice had significant delays in small intestinal transit compared with control mice.
CONCLUSIONS - LRIG1 regulates the postnatal development of ICC-DMP and ICC-SMP from smooth muscle progenitors in mice. Slowed small intestinal transit observed in Lrig1-null mice may be due, at least in part, to loss of the ICC-DMP population.
Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
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14 MeSH Terms
Global deletion of Ankrd1 results in a wound-healing phenotype associated with dermal fibroblast dysfunction.
Samaras SE, Almodóvar-García K, Wu N, Yu F, Davidson JM
(2015) Am J Pathol 185: 96-109
MeSH Terms: Adenoviridae, Animals, Cell Movement, Collagen, Crosses, Genetic, Exons, Female, Fibroblasts, Gels, Gene Deletion, Gene Expression Profiling, Genotype, Green Fluorescent Proteins, MAP Kinase Signaling System, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Muscle Proteins, Necrosis, Nuclear Proteins, Organ Size, Phenotype, Promoter Regions, Genetic, RNA, Recombination, Genetic, Repressor Proteins, Skin, Wound Healing
Show Abstract · Added January 20, 2015
The expression of ankyrin repeat domain protein 1 (Ankrd1), a transcriptional cofactor and sarcomeric component, is strongly elevated by wounding and tissue injury. We developed a conditional Ankrd1(fl/fl) mouse, performed global deletion with Sox2-cre, and assessed the role of this protein in cutaneous wound healing. Although global deletion of Ankrd1 did not affect mouse viability or development, Ankrd1(-/-) mice had at least two significant wound-healing phenotypes: extensive necrosis of ischemic skin flaps, which was reversed by adenoviral expression of ANKRD1, and delayed excisional wound closure, which was characterized by decreased contraction and reduced granulation tissue thickness. Skin fibroblasts isolated from Ankrd1(-/-) mice did not spread or migrate on collagen- or fibronectin-coated surfaces as efficiently as fibroblasts isolated from Ankrd1(fl/fl) mice. More important, Ankrd1(-/-) fibroblasts failed to contract three-dimensional floating collagen gels. Reconstitution of ANKRD1 by adenoviral infection stimulated both collagen gel contraction and actin fiber organization. These in vitro data were consistent with in vivo wound closure studies, and suggest that ANKRD1 is important for the proper interaction of fibroblasts with a compliant collagenous matrix both in vitro and in vivo.
Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
1 Communities
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30 MeSH Terms
Multiple requirements of the focal dermal hypoplasia gene porcupine during ocular morphogenesis.
Bankhead EJ, Colasanto MP, Dyorich KM, Jamrich M, Murtaugh LC, Fuhrmann S
(2015) Am J Pathol 185: 197-213
MeSH Terms: Acyltransferases, Alleles, Animals, Disease Models, Animal, Eye, Female, Focal Dermal Hypoplasia, Gene Expression Regulation, Developmental, Genotype, Glycoproteins, Hemizygote, In Situ Hybridization, Ligands, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Mutation, Recombination, Genetic, Retinal Pigment Epithelium, Wnt Proteins
Show Abstract · Added November 19, 2015
Wnt glycoproteins control key processes during development and disease by activating various downstream pathways. Wnt secretion requires post-translational modification mediated by the O-acyltransferase encoded by the Drosophila porcupine homolog gene (PORCN). In humans, PORCN mutations cause focal dermal hypoplasia (FDH, or Goltz syndrome), an X-linked dominant multisystem birth defect that is frequently accompanied by ocular abnormalities such as coloboma, microphthalmia, or even anophthalmia. Although genetic ablation of Porcn in mouse has provided insight into the etiology of defects caused by ectomesodermal dysplasia in FDH, the requirement for Porcn and the actual Wnt ligands during eye development have been unknown. In this study, Porcn hemizygosity occasionally caused ocular defects reminiscent of FDH. Conditional inactivation of Porcn in periocular mesenchyme led to defects in mid- and hindbrain and in craniofacial development, but was insufficient to cause ocular abnormalities. However, a combination of conditional Porcn depletion in optic vesicle neuroectoderm, lens, and neural crest-derived periocular mesenchyme induced severe eye abnormalities with high penetrance. In particular, we observed coloboma, transdifferentiation of the dorsal and ventral retinal pigment epithelium, defective optic cup periphery, and closure defects of the eyelid, as well as defective corneal morphogenesis. Thus, Porcn is required in both extraocular and neuroectodermal tissues to regulate distinct Wnt-dependent processes during morphogenesis of the posterior and anterior segments of the eye.
Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
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21 MeSH Terms
Control of gene expression in Helicobacter pylori using the Tet repressor.
McClain MS, Duncan SS, Gaddy JA, Cover TL
(2013) J Microbiol Methods 95: 336-41
MeSH Terms: Bacterial Proteins, Blotting, Western, Gene Expression Regulation, Bacterial, Genetics, Microbial, Helicobacter pylori, Molecular Biology, Operator Regions, Genetic, Recombination, Genetic, Repressor Proteins, Tetracyclines, Transcriptional Activation
Show Abstract · Added January 13, 2014
The lack of a versatile system to control gene expression in Helicobacter pylori has hampered efforts to study H. pylori physiology and pathogenesis. To overcome these limitations, we evaluated the utility of an inducible system based on the well-characterized Tet repressor (TetR) and Tet operator (tetO). As validation of this system, we introduced three copies of tetO into the promoter region upstream of the cagUT operon (encoding two virulence factors required for function of the H. pylori Cag type IV secretion system) and expressed tetR by introducing a codon-optimized gene into the chromosomal ureA locus. Introduction of the tetO copies upstream of cagUT did not disrupt promoter activity, as determined by immunoblotting for CagT. The subsequent introduction of tetR, however, did repress CagT synthesis. Production of CagT was restored when strains were cultured in the presence of the inducer, anhydrotetracycline. To demonstrate one potential application of this new tool, we analyzed the function of the Cag type IV secretion system. When the modified H. pylori strains were co-cultured with AGS cells, activity of the Cag type IV secretion system was dependent on the presence of anhydrotetracycline as evidenced by inducer-dependent induction of IL-8 secretion, CagA translocation, and appearance of type IV secretion system pili at the bacteria-host interface. These studies demonstrate the effectiveness of the tetR-tetO system to control gene expression in H. pylori and provide an improved system for studying H. pylori physiology and pathogenesis.
© 2013.
1 Communities
3 Members
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11 MeSH Terms
A model-based analysis of GC-biased gene conversion in the human and chimpanzee genomes.
Capra JA, Hubisz MJ, Kostka D, Pollard KS, Siepel A
(2013) PLoS Genet 9: e1003684
MeSH Terms: Animals, Base Sequence, Chromosome Mapping, Evolution, Molecular, Gene Conversion, Genome, Humans, Mammals, Models, Theoretical, Pan troglodytes, Phylogeny, Recombination, Genetic, Selection, Genetic, Sequence Alignment
Show Abstract · Added April 18, 2017
GC-biased gene conversion (gBGC) is a recombination-associated process that favors the fixation of G/C alleles over A/T alleles. In mammals, gBGC is hypothesized to contribute to variation in GC content, rapidly evolving sequences, and the fixation of deleterious mutations, but its prevalence and general functional consequences remain poorly understood. gBGC is difficult to incorporate into models of molecular evolution and so far has primarily been studied using summary statistics from genomic comparisons. Here, we introduce a new probabilistic model that captures the joint effects of natural selection and gBGC on nucleotide substitution patterns, while allowing for correlations along the genome in these effects. We implemented our model in a computer program, called phastBias, that can accurately detect gBGC tracts about 1 kilobase or longer in simulated sequence alignments. When applied to real primate genome sequences, phastBias predicts gBGC tracts that cover roughly 0.3% of the human and chimpanzee genomes and account for 1.2% of human-chimpanzee nucleotide differences. These tracts fall in clusters, particularly in subtelomeric regions; they are enriched for recombination hotspots and fast-evolving sequences; and they display an ongoing fixation preference for G and C alleles. They are also significantly enriched for disease-associated polymorphisms, suggesting that they contribute to the fixation of deleterious alleles. The gBGC tracts provide a unique window into historical recombination processes along the human and chimpanzee lineages. They supply additional evidence of long-term conservation of megabase-scale recombination rates accompanied by rapid turnover of hotspots. Together, these findings shed new light on the evolutionary, functional, and disease implications of gBGC. The phastBias program and our predicted tracts are freely available.
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14 MeSH Terms
Pancreas-specific Cre driver lines and considerations for their prudent use.
Magnuson MA, Osipovich AB
(2013) Cell Metab 18: 9-20
MeSH Terms: Animals, DNA Nucleotidyltransferases, Extracellular Matrix Proteins, Integrases, Mice, Mice, Knockout, Mice, Transgenic, Models, Animal, Pancreas, Pancreatic Hormones, Protein-Lysine 6-Oxidase, Rats, Rats, Transgenic, Recombination, Genetic, Transgenes
Show Abstract · Added August 1, 2013
Cre/LoxP has broad utility for studying the function, development, and oncogenic transformation of pancreatic cells in mice. Here we provide an overview of the Cre driver lines that are available for such studies. We discuss how variegated expression, transgene silencing, and recombination in undesired cell types have conspired to limit the performance of these lines, sometimes leading to serious experimental concerns. We also discuss preferred strategies for achieving high-fidelity driver lines and remind investigators of the continuing need for caution when interpreting results obtained from any Cre/LoxP-based experiment performed in mice.
Copyright © 2013 Elsevier Inc. All rights reserved.
2 Communities
2 Members
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15 MeSH Terms
The transcriptional repressor NKAP is required for the development of iNKT cells.
Thapa P, Das J, McWilliams D, Shapiro M, Sundsbak R, Nelson-Holte M, Tangen S, Anderson J, Desiderio S, Hiebert S, Sant'angelo DB, Shapiro VS
(2013) Nat Commun 4: 1582
MeSH Terms: Animals, Cell Survival, Gene Deletion, Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor, Histone Deacetylases, Mice, Mice, Knockout, Natural Killer T-Cells, Organ Specificity, Receptors, Antigen, T-Cell, alpha-beta, Receptors, Notch, Recombination, Genetic, Repressor Proteins, Thymocytes
Show Abstract · Added March 26, 2014
Invariant natural killer T cells have a distinct developmental pathway from conventional αβ T cells. Here we demonstrate that the transcriptional repressor NKAP is required for invariant natural killer T cell but not conventional T cell development. In CD4-cre NKAP conditional knockout mice, invariant natural killer T cell development is blocked at the double-positive stage. This cell-intrinsic block is not due to decreased survival or failure to rearrange the invariant Vα14-Jα18 T cell receptor-α chain, but is rescued by overexpression of a rec-Vα14-Jα18 transgene at the double-positive stage, thus defining a role for NKAP in selection into the invariant natural killer T cell lineage. Importantly, deletion of the NKAP-associated protein histone deacetylase 3 causes a similar block in the invariant natural killer T cell development, indicating that NKAP and histone deacetylase 3 functionally interact to control invariant natural killer T cell development.
1 Communities
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14 MeSH Terms