Abstract:
:Host variation in Toll-like receptors and other innate immune signaling molecules alters infection susceptibility. However, only a portion of the variability observed in the innate immune response is accounted for by known genes in these pathways. Thus, the identification of additional genes that regulate the response to Gram positive bacteria is warranted. Bone marrow-derived macrophages (BMMs) from 43 inbred mouse strains were stimulated with lipotechoic acid (LTA), a major component of the Gram positive bacterial cell wall. Concentrations of the proinflammatory cytokines IL-6, IL-12, and TNF-α were measured. In silico whole genome association (WGA) mapping was performed using cytokine responses followed by network analysis to prioritize candidate genes. To determine which candidate genes could be responsible for regulating the LTA response, candidate genes were inhibited using RNA interference (RNAi) and were overexpressed in RAW264.7 macrophages. BMMs from Bdkrb1-deficient mice were used to assess the effect of Bdkrb1 gene deletion on the response to LTA, heat-killed Streptococcus pneumoniae, and heat-killed Staphylococcus aureus WGA mapping identified 117 loci: IL-6 analysis yielded 20 loci (average locus size = 0.133 Mb; 18 genes), IL-12 analysis produced 5 loci (0.201 Mb average; 7 genes), and TNF-α analysis yielded 92 loci (0.464 Mb average; 186 genes of which 46 were prioritized by network analysis). The follow-up small interfering RNA screen of 71 target genes identified four genes (Bdkrb1, Blnk, Fbxo17, and Nkx6-1) whose inhibition resulted in significantly reduced cytokine production following LTA stimulation. Overexpression of these four genes resulted in significantly increased cytokine production in response to LTA. Bdkrb1-deficient macrophages were less responsive to LTA and heat-killed S. aureus, validating the genetic and RNAi approach to identify novel regulators of the response to LTA. We have identified four innate immune response genes that may contribute to Gram positive bacterial susceptibility.
journal_name
Geneticsjournal_title
Geneticsauthors
Alper S,Warg LA,De Arras L,Flatley BR,Davidson EJ,Adams J,Smith K,Wohlford-Lenane CL,McCray PB Jr,Pedersen BS,Schwartz DA,Yang IVdoi
10.1534/genetics.115.185314subject
Has Abstractpub_date
2016-09-01 00:00:00pages
327-36issue
1eissn
0016-6731issn
1943-2631pii
genetics.115.185314journal_volume
204pub_type
杂志文章相关文献
GENETICS文献大全abstract::All living organisms require nutrient minerals for growth and have developed mechanisms to acquire, utilize, and store nutrient minerals effectively. In the aqueous cellular environment, these elements exist as charged ions that, together with protons and hydroxide ions, facilitate biochemical reactions and establish ...
journal_title:Genetics
pub_type: 杂志文章,评审
doi:10.1534/genetics.112.147207
更新日期:2013-03-01 00:00:00
abstract::The rate of adaptive evolution of a population ultimately depends on the rate of incorporation of beneficial mutations. Even beneficial mutations may, however, be lost from a population since mutant individuals may, by chance, fail to reproduce. In this paper, we calculate the probability of fixation of beneficial mut...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1997-06-01 00:00:00
abstract::Zinc plays many critical roles in biological systems: zinc bound to proteins has structural and catalytic functions, and zinc is proposed to act as a signaling molecule. Because zinc deficiency and excess result in toxicity, animals have evolved sophisticated mechanisms for zinc metabolism and homeostasis. However, th...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.107.084384
更新日期:2008-06-01 00:00:00
abstract::Antisuppressor mutations in the eEF1A gene of Podospora anserina were previously shown to impair ascospore formation, to drastically increase life span, and to permit the development of the Crippled Growth degenerative process. Here, we show that eEF1A controls ascospore formation through accuracy level maintenance. E...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:2001-08-01 00:00:00
abstract::We show by molecular analysis of behavioral and physiological mutants that the Drosophila Dmca1A calcium-channel alpha1 subunit is encoded by the cacophony (cac) gene and that nightblind-A and lethal(1)L13 mutations are allelic to cac with respect to an expanded array of behavioral and physiological phenotypes associa...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1998-07-01 00:00:00
abstract::A scheme for rapidly mapping chromosome rearrangements relative to the physical map of Caenorhabditis elegans is described that is based on hybridization patterns of cloned DNA on meiotic nuclei, as visualized by fluorescent in situ hybridization. From the nearly complete physical map, DNA clones, in yeast artificial ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1993-05-01 00:00:00
abstract::Extensive Monte Carlo simulations are conducted of spatial distributions of two-locus genotypes in large, continuous populations under isolation by distance models. The results show that substantial patches of double homozygotes are present in the spatial structures, even when loci are unlinked. The stochastic spread ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1995-05-01 00:00:00
abstract::Damaged DNA-binding proteins 1 and 2 (DDB1 and DDB2) are subunits of the damaged DNA-binding protein complex (DDB). DDB1 is also found in the same complex as DE-ETIOLATED 1 (DET1), a negative regulator of light-mediated responses in plants. Arabidopsis has two DDB1 homologs, DDB1A and DDB1B. ddb1a single mutants have ...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.107.070359
更新日期:2007-05-01 00:00:00
abstract::The SMK1 mitogen-activated protein kinase is required for spore morphogenesis in Saccharomyces cerevisiae. In contrast to the multiple aberrant spore wall assembly patterns seen even within a single smk1 null ascus, different smk1 missense mutants block in a coordinated fashion at intermediate stages. One smk1 mutant ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1999-04-01 00:00:00
abstract::The uaY gene encodes the transcriptional activator of purine catabolism genes in Aspergillus nidulans. uaY12 results in strongly defective growth on purines as nitrogen sources and in strongly diminished transcription of UaY-regulated genes. This mutation introduces an ATG codon 64 bp upstream of the uaY ATG, generati...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.108.099515
更新日期:2009-04-01 00:00:00
abstract::Two replications of a complete diallel cross experiment were performed among four partially inbred lines of mice. These inbred lines originated from a random-bred ICR strain and were produced by 12 generations of full sibbing (F congruent to 92%). Individual body weight was recorded for each animal at 12, 21, 42 and 5...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1975-10-01 00:00:00
abstract::Four species of the Hawaiian Drosophila planitibia subgroup which are homosequential in their polytene chromosomes are resident on the islands of Molokai, Maui and Hawaii. Comparisons of DNA sequence divergence in these four have been made by hybridization of total single-copy radiolabeled tracer DNA from each of the ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1983-06-01 00:00:00
abstract::The T-box genes comprise an ancient family of putative transcription factors conserved across species as divergent as Mus musculus and Caenorhabditis elegans. All T-box gene products are characterized by a novel 174-186-amino acid DNA binding domain called the T-box that was first discovered in the polypeptide product...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1996-09-01 00:00:00
abstract::RNAs are localized by microtubule-based pathways to both the anterior and posterior poles of the developing Drosophila oocyte. We describe a new gene, wispy, required for localization of mRNAs to both poles of the egg. Embryos from wispy mothers arrest development after abnormal oocyte meiosis and failure of pronuclei...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:2000-04-01 00:00:00
abstract::For multiallelic loci, standard measures of linkage disequilibrium provide an incomplete description of the correlation of variation at two loci, especially when there are different numbers of alleles at the two loci. We have developed a complementary pair of conditional asymmetric linkage disequilibrium (ALD) measure...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.114.165266
更新日期:2014-09-01 00:00:00
abstract::The DC2 gene was isolated previously on the basis of sequence similarity to DC0, the major Drosophila protein kinase A (PKA) catalytic subunit gene. We show here that the 67-kD Drosophila DC2 protein behaves as a PKA catalytic subunit in vitro. DC2 is transcribed in mesodermal anlagen of early embryos. This expression...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1995-12-01 00:00:00
abstract::We developed a screening approach that utilizes an inverse polymerase chain reaction (PCR) to detect P element insertions in or near previously cloned genes in Drosophila melanogaster. We used this approach in a large scale genetic screen in which P elements were mobilized from sites on the X chromosome to new autosom...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1995-02-01 00:00:00
abstract::Type III galactosemia is a metabolic disorder caused by reduced activity of UDP-galactose-4-epimerase, which participates in galactose metabolism and the generation of various UDP-sugar species. We characterized gale-1 in Caenorhabditis elegans and found that a complete loss-of-function mutation is lethal, as has been...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.114.170084
更新日期:2014-12-01 00:00:00
abstract::X chromosome duplications have been used previously to vary the dose of specific regions of the X chromosome to study dosage compensation and sex determination in Caenorhabditis elegans. We show here that duplications suppress and X-linked hypomorphic mutation and elevate the level of activity of an X-linked enzyme, a...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1988-06-01 00:00:00
abstract::The DNMT1 cytosine methyltransferase enzyme contains a large ∼300-aa intrinsically disordered domain (IDD) that we previously showed regulated DNA methylation patterns in mouse ES cells. Here we generated seven mouse lines with different mutations in the IDD. Homozygous mutant mice of five lines developed normally, wi...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.114.173609
更新日期:2015-02-01 00:00:00
abstract::A study of DNA polymorphism and divergence was conducted for the cytosolic phosphoglucose isomerase (PGI:E.C.5.3.1.9) gene of five species of the mustard genus Leavenworthia: Leavenworthia stylosa, L. alabamica, L. crassa, L. uniflora, and L. torulosa. Sequences of an internal 2.3-kb PgiC gene region spanning exons 6-...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1999-11-01 00:00:00
abstract::Mutations in the Saccharomyces cerevisiae SPT8 gene were previously isolated as suppressors of retrotransposon insertion mutations in the 5' regions of the HIS4 and LYS2 genes. Mutations in SPT8 confer phenotypes similar to those caused by particular mutations in SPT15, which encodes the TATA-binding protein (TBP). Th...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1994-07-01 00:00:00
abstract::Mutator and antimutator alleles often arise and spread in both natural microbial populations and laboratory evolution experiments. The evolutionary dynamics of these mutation rate modifiers are determined by indirect selection on linked beneficial and deleterious mutations. These indirect selection pressures have been...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.116.193565
更新日期:2016-11-01 00:00:00
abstract::We examine the influence of nonrandom mating and immigration on the evolutionary dynamics of cytonuclear associations in hybrid zones. Recursion equations for allelic and genotypic cytonuclear disequilibria were generated under models of (1) migration alone, assuming hybrid zone matings are random with respect to cyto...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1989-08-01 00:00:00
abstract::Two Podospora mutants carrying mutations modE and modF were persumed to be quiescent defective, because, when grown under glucose limitation, they differed from the wild-type strain in an excess of dry weight production and a reduction of cell survival. New insight on the action of modE and modF mutations was provided...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1985-01-01 00:00:00
abstract::The maize ligule is an adaxial membranous structure on the leaf that develops at the boundary of the sheath and blade. The ligule and the associated auricle are dispensable structures, amenable to genetic manipulation. We present here a genetic analysis of liguleless1 (lg1) and liguleless2 (lg2), the two genes known t...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1996-12-01 00:00:00
abstract::We develop the theory for computing the joint frequency spectra of alleles in two closely related species. We allow for arbitrary population growth in both species after they had a common ancestor. We focus on the case in which a single chromosome is sequenced from one of the species. We use classical diffusion theory...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.107.070730
更新日期:2007-09-01 00:00:00
abstract::Lethal and sterility mutations were accumulated in a cage population which was initiated with lethal- and sterility-free second chromosomes of D. melanogaster. It took about 2,000 days for the frequencies of these genes to reach equilibrium levels, i.e., 18% lethal and 9% male-sterile chromosomes. Two other cage popul...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1977-07-01 00:00:00
abstract::Actin is a major component of the cytoskeleton and one of the most abundant proteins found in eukaryotic cells. Comparative sequence analysis shows that this essential gene has been highly conserved throughout eukaryotic evolution making it useful for phylogenetic analysis. Complete cDNA clones for the actin-encoding ...
journal_title:Genetics
pub_type: 杂志文章
doi:
更新日期:1994-07-01 00:00:00
abstract::Genome-wide association studies have identified thousands of variants implicated in dozens of complex diseases. Most studies collect individuals with and without disease and search for variants with different frequencies between the groups. For many of these studies, additional disease traits are also collected. Joint...
journal_title:Genetics
pub_type: 杂志文章
doi:10.1534/genetics.116.198473
更新日期:2017-03-01 00:00:00