Browsing by Subject "Chromosome Mapping"

Now showing 1 - 17 of 17

Open Access
A cross-species approach using an in vivo evaluation platform in mice demonstrates that sequence variation in human RABEP2 modulates ischemic stroke outcomes.
(American journal of human genetics, 2022-10) Lee, Han Kyu; Kwon, Do Hoon; Aylor, David L; Marchuk, Douglas A
Ischemic stroke, caused by vessel blockage, results in cerebral infarction, the death of brain tissue. Previously, quantitative trait locus (QTL) mapping of cerebral infarct volume and collateral vessel number identified a single, strong genetic locus regulating both phenotypes. Additional studies identified RAB GTPase-binding effector protein 2 (Rabep2) as the casual gene. However, there is yet no evidence that variation in the human ortholog of this gene plays any role in ischemic stroke outcomes. We established an in vivo evaluation platform in mice by using adeno-associated virus (AAV) gene replacement and verified that both mouse and human RABEP2 rescue the mouse Rabep2 knockout ischemic stroke volume and collateral vessel phenotypes. Importantly, this cross-species complementation enabled us to experimentally investigate the functional effects of coding sequence variation in human RABEP2. We chose four coding variants from the human population that are predicted by multiple in silico algorithms to be damaging to RABEP2 function. In vitro and in vivo analyses verify that all four led to decreased collateral vessel connections and increased infarct volume. Thus, there are naturally occurring loss-of-function alleles. This cross-species approach will expand the number of targets for therapeutics development for ischemic stroke.
Open Access
Beyond QTL cloning.
(PLoS Genet, 2010-11-11) Anderson, Jill T; Mitchell-Olds, Thomas
Open Access
Candidate genes on murine chromosome 8 are associated with susceptibility to Staphylococcus aureus infection in mice and are involved with Staphylococcus aureus septicemia in humans.
(PloS one, 2017-01) Yan, Qin; Ahn, Sun Hee; Medie, Felix Mba; Sharma-Kuinkel, Batu K; Park, Lawrence P; Scott, William K; Deshmukh, Hitesh; Tsalik, Ephraim L; Cyr, Derek D; Woods, Christopher W; Yu, Chen-Hsin Albert; Adams, Carlton; Qi, Robert; Hansen, Brenda; Fowler, Vance G
We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J) identified a locus 83180780-88103009 (GRCm38/mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~ 102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5β1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5β1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naïve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.
Open Access
cDNA for the human beta 2-adrenergic receptor: a protein with multiple membrane-spanning domains and encoded by a gene whose chromosomal location is shared with that of the receptor for platelet-derived growth factor.
(Proc Natl Acad Sci U S A, 1987-01) Kobilka, BK; Dixon, RA; Frielle, T; Dohlman, HG; Bolanowski, MA; Sigal, IS; Yang-Feng, TL; Francke, U; Caron, MG; Lefkowitz, RJ
We have isolated and sequenced a cDNA encoding the human beta 2-adrenergic receptor. The deduced amino acid sequence (413 residues) is that of a protein containing seven clusters of hydrophobic amino acids suggestive of membrane-spanning domains. While the protein is 87% identical overall with the previously cloned hamster beta 2-adrenergic receptor, the most highly conserved regions are the putative transmembrane helices (95% identical) and cytoplasmic loops (93% identical), suggesting that these regions of the molecule harbor important functional domains. Several of the transmembrane helices also share lesser degrees of identity with comparable regions of select members of the opsin family of visual pigments. We have localized the gene for the beta 2-adrenergic receptor to q31-q32 on chromosome 5. This is the same position recently determined for the gene encoding the receptor for platelet-derived growth factor and is adjacent to that for the FMS protooncogene, which encodes the receptor for the macrophage colony-stimulating factor.
Open Access
Chromosomal organization of adrenergic receptor genes.
(Proc Natl Acad Sci U S A, 1990-02) Yang-Feng, TL; Xue, FY; Zhong, WW; Cotecchia, S; Frielle, T; Caron, MG; Lefkowitz, RJ; Francke, U
The adrenergic receptors (ARs) (subtypes alpha 1, alpha 2, beta 1, and beta 2) are a prototypic family of guanine nucleotide binding regulatory protein-coupled receptors that mediate the physiological effects of the hormone epinephrine and the neurotransmitter norepinephrine. We have previously assigned the genes for beta 2- and alpha 2-AR to human chromosomes 5 and 10, respectively. By Southern analysis of somatic cell hybrids and in situ chromosomal hybridization, we have now mapped the alpha 1-AR gene to chromosome 5q32----q34, the same position as beta 2-AR, and the beta 1-AR gene to chromosome 10q24----q26, the region where alpha 2-AR is located. In mouse, both alpha 2- and beta 1-AR genes were assigned to chromosome 19, and the alpha 1-AR locus was localized to chromosome 11. Pulsed field gel electrophoresis has shown that the alpha 1- and beta 2-AR genes in humans are within 300 kilobases (kb) and the distance between the alpha 2- and beta 1-AR genes is less than 225 kb. The proximity of these two pairs of AR genes and the sequence similarity that exists among all the ARs strongly suggest that they are evolutionarily related. Moreover, they likely arose from a common ancestral receptor gene and subsequently diverged through gene duplication and chromosomal duplication to perform their distinctive roles in mediating the physiological effects of catecholamines. The AR genes thus provide a paradigm for understanding the evolution of such structurally conserved yet functionally divergent families of receptor molecules.
Open Access
Complex evolutionary trajectories of sex chromosomes across bird taxa.
(Science, 2014-12-12) Zhou, Qi; Zhang, Jilin; Bachtrog, Doris; An, Na; Huang, Quanfei; Jarvis, Erich D; Gilbert, M Thomas P; Zhang, Guojie
Sex-specific chromosomes, like the W of most female birds and the Y of male mammals, usually have lost most genes owing to a lack of recombination. We analyze newly available genomes of 17 bird species representing the avian phylogenetic range, and find that more than half of them do not have as fully degenerated W chromosomes as that of chicken. We show that avian sex chromosomes harbor tremendous diversity among species in their composition of pseudoautosomal regions and degree of Z/W differentiation. Punctuated events of shared or lineage-specific recombination suppression have produced a gradient of "evolutionary strata" along the Z chromosome, which initiates from the putative avian sex-determining gene DMRT1 and ends at the pseudoautosomal region. W-linked genes are subject to ongoing functional decay after recombination was suppressed, and the tempo of degeneration slows down in older strata. Overall, we unveil a complex history of avian sex chromosome evolution.
Open Access
Detectable clonal mosaicism from birth to old age and its relationship to cancer.
(Nature genetics, 2012-05-06) Laurie, Cathy C; Laurie, Cecelia A; Rice, Kenneth; Doheny, Kimberly F; Zelnick, Leila R; McHugh, Caitlin P; Ling, Hua; Hetrick, Kurt N; Pugh, Elizabeth W; Amos, Chris; Wei, Qingyi; Wang, Li-e; Lee, Jeffrey E; Barnes, Kathleen C; Hansel, Nadia N; Mathias, Rasika; Daley, Denise; Beaty, Terri H; Scott, Alan F; Ruczinski, Ingo; Scharpf, Rob B; Bierut, Laura J; Hartz, Sarah M; Landi, Maria Teresa; Freedman, Neal D; Goldin, Lynn R; Ginsburg, David; Li, Jun; Desch, Karl C; Strom, Sara S; Blot, William J; Signorello, Lisa B; Ingles, Sue A; Chanock, Stephen J; Berndt, Sonja I; Le Marchand, Loic; Henderson, Brian E; Monroe, Kristine R; Heit, John A; de Andrade, Mariza; Armasu, Sebastian M; Regnier, Cynthia; Lowe, William L; Hayes, M Geoffrey; Marazita, Mary L; Feingold, Eleanor; Murray, Jeffrey C; Melbye, Mads; Feenstra, Bjarke; Kang, Jae H; Wiggs, Janey L; Jarvik, Gail P; McDavid, Andrew N; Seshan, Venkatraman E; Mirel, Daniel B; Crenshaw, Andrew; Sharopova, Nataliya; Wise, Anastasia; Shen, Jess; Crosslin, David R; Levine, David M; Zheng, Xiuwen; Udren, Jenna I; Bennett, Siiri; Nelson, Sarah C; Gogarten, Stephanie M; Conomos, Matthew P; Heagerty, Patrick; Manolio, Teri; Pasquale, Louis R; Haiman, Christopher A; Caporaso, Neil; Weir, Bruce S
We detected clonal mosaicism for large chromosomal anomalies (duplications, deletions and uniparental disomy) using SNP microarray data from over 50,000 subjects recruited for genome-wide association studies. This detection method requires a relatively high frequency of cells with the same abnormal karyotype (>5-10%; presumably of clonal origin) in the presence of normal cells. The frequency of detectable clonal mosaicism in peripheral blood is low (<0.5%) from birth until 50 years of age, after which it rapidly rises to 2-3% in the elderly. Many of the mosaic anomalies are characteristic of those found in hematological cancers and identify common deleted regions with genes previously associated with these cancers. Although only 3% of subjects with detectable clonal mosaicism had any record of hematological cancer before DNA sampling, those without a previous diagnosis have an estimated tenfold higher risk of a subsequent hematological cancer (95% confidence interval = 6-18).
Open Access
Epistasis among Drosophila persimilis factors conferring hybrid male sterility with D. pseudoobscura bogotana.
(PLoS One, 2010-10-27) Chang, AS; Bennett, SM; Noor, MAF
The Bateson-Dobzhansky-Muller model posits that hybrid incompatibilities result from genetic changes that accumulate during population divergence. Indeed, much effort in recent years has been devoted to identifying genes associated with hybrid incompatibilities, often with limited success, suggesting that hybrid sterility and inviability are frequently caused by complex interactions between multiple loci and not by single or a small number of gene pairs. Our previous study showed that the nature of epistasis between sterility-conferring QTL in the Drosophila persimilis-D. pseudoobscura bogotana species pair is highly specific. Here, we further dissect one of the three QTL underlying hybrid male sterility between these species and provide evidence for multiple factors within this QTL. This result indicates that the number of loci thought to contribute to hybrid dysfunction may have been underestimated, and we discuss how linkage and complex epistasis may be characteristic of the genetics of hybrid incompatibilities. We further pinpoint the location of one locus that confers hybrid male sterility when homozygous, dubbed "mule-like", to roughly 250 kilobases.
Open Access
Generalized admixture mapping for complex traits.
(G3 (Bethesda), 2013-07-08) Zhu, Bin; Ashley-Koch, Allison E; Dunson, David B
Admixture mapping is a popular tool to identify regions of the genome associated with traits in a recently admixed population. Existing methods have been developed primarily for identification of a single locus influencing a dichotomous trait within a case-control study design. We propose a generalized admixture mapping (GLEAM) approach, a flexible and powerful regression method for both quantitative and qualitative traits, which is able to test for association between the trait and local ancestries in multiple loci simultaneously and adjust for covariates. The new method is based on the generalized linear model and uses a quadratic normal moment prior to incorporate admixture prior information. Through simulation, we demonstrate that GLEAM achieves lower type I error rate and higher power than ANCESTRYMAP both for qualitative traits and more significantly for quantitative traits. We applied GLEAM to genome-wide SNP data from the Illumina African American panel derived from a cohort of black women participating in the Healthy Pregnancy, Healthy Baby study and identified a locus on chromosome 2 associated with the averaged maternal mean arterial pressure during 24 to 28 weeks of pregnancy.
Open Access
Genome-wide linkage analysis for human longevity: Genetics of Healthy Aging Study.
(Aging Cell, 2013-04) Beekman, Marian; Blanché, Hélène; Perola, Markus; Hervonen, Anti; Bezrukov, Vladyslav; Sikora, Ewa; Flachsbart, Friederike; Christiansen, Lene; De Craen, Anton JM; Kirkwood, Tom BL; Rea, Irene Maeve; Poulain, Michel; Robine, Jean-Marie; Valensin, Silvana; Stazi, Maria Antonietta; Passarino, Giuseppe; Deiana, Luca; Gonos, Efstathios S; Paternoster, Lavinia; Sørensen, Thorkild IA; Tan, Qihua; Helmer, Quinta; van den Akker, Erik B; Deelen, Joris; Martella, Francesca; Cordell, Heather J; Ayers, Kristin L; Vaupel, James W; Törnwall, Outi; Johnson, Thomas E; Schreiber, Stefan; Lathrop, Mark; Skytthe, Axel; Westendorp, Rudi GJ; Christensen, Kaare; Gampe, Jutta; Nebel, Almut; Houwing-Duistermaat, Jeanine J; Slagboom, Pieternella Eline; Franceschi, Claudio; GEHA consortium
Clear evidence exists for heritability of human longevity, and much interest is focused on identifying genes associated with longer lives. To identify such longevity alleles, we performed the largest genome-wide linkage scan thus far reported. Linkage analyses included 2118 nonagenarian Caucasian sibling pairs that have been enrolled in 15 study centers of 11 European countries as part of the Genetics of Healthy Aging (GEHA) project. In the joint linkage analyses, we observed four regions that show linkage with longevity; chromosome 14q11.2 (LOD = 3.47), chromosome 17q12-q22 (LOD = 2.95), chromosome 19p13.3-p13.11 (LOD = 3.76), and chromosome 19q13.11-q13.32 (LOD = 3.57). To fine map these regions linked to longevity, we performed association analysis using GWAS data in a subgroup of 1228 unrelated nonagenarian and 1907 geographically matched controls. Using a fixed-effect meta-analysis approach, rs4420638 at the TOMM40/APOE/APOC1 gene locus showed significant association with longevity (P-value = 9.6 × 10(-8) ). By combined modeling of linkage and association, we showed that association of longevity with APOEε4 and APOEε2 alleles explain the linkage at 19q13.11-q13.32 with P-value = 0.02 and P-value = 1.0 × 10(-5) , respectively. In the largest linkage scan thus far performed for human familial longevity, we confirm that the APOE locus is a longevity gene and that additional longevity loci may be identified at 14q11.2, 17q12-q22, and 19p13.3-p13.11. As the latter linkage results are not explained by common variants, we suggest that rare variants play an important role in human familial longevity.
Open Access
Identification and utilization of arbitrary correlations in models of recombination signal sequences.
(Genome Biol, 2002) Cowell, Lindsay G; Davila, Marco; Kepler, Thomas B; Kelsoe, Garnett
BACKGROUND: A significant challenge in bioinformatics is to develop methods for detecting and modeling patterns in variable DNA sequence sites, such as protein-binding sites in regulatory DNA. Current approaches sometimes perform poorly when positions in the site do not independently affect protein binding. We developed a statistical technique for modeling the correlation structure in variable DNA sequence sites. The method places no restrictions on the number of correlated positions or on their spatial relationship within the site. No prior empirical evidence for the correlation structure is necessary. RESULTS: We applied our method to the recombination signal sequences (RSS) that direct assembly of B-cell and T-cell antigen-receptor genes via V(D)J recombination. The technique is based on model selection by cross-validation and produces models that allow computation of an information score for any signal-length sequence. We also modeled RSS using order zero and order one Markov chains. The scores from all models are highly correlated with measured recombination efficiencies, but the models arising from our technique are better than the Markov models at discriminating RSS from non-RSS. CONCLUSIONS: Our model-development procedure produces models that estimate well the recombinogenic potential of RSS and are better at RSS recognition than the order zero and order one Markov models. Our models are, therefore, valuable for studying the regulation of both physiologic and aberrant V(D)J recombination. The approach could be equally powerful for the study of promoter and enhancer elements, splice sites, and other DNA regulatory sites that are highly variable at the level of individual nucleotide positions.
Open Access
Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy.
(J Clin Invest, 2010-03) O'Toole, JF; Liu, Y; Davis, EE; Westlake, CJ; Attanasio, M; Otto, EA; Seelow, D; Nurnberg, G; Becker, C; Nuutinen, M; Kärppä, M; Ignatius, J; Uusimaa, J; Pakanen, S; Jaakkola, E; van den Heuvel, LP; Fehrenbach, H; Wiggins, R; Goyal, M; Zhou, W; Wolf, MT; Wise, E; Helou, J; Allen, SJ; Murga Zamalloa, CA; Ashraf, S; Chaki, M; Heeringa, S; Chernin, G; Hoskins, BE; Chaib, H; Gleeson, J; Kusakabe, T; Suzuki, T; Isaac, RE; Quarmby, LM; Tennant, B; Fujioka, H; Tuominen, H; Hassinen, I; Lohi, H; van Houten, JL; Rotig, A; Sayer, JA; Rolinski, B; Freisinger, P; Madhavan, SM; Herzer, M; Madignier, F; Prokisch, H; Nurnberg, P; Jackson, PK; Jackson, P; Khanna, H; Katsanis, N; Hildebrandt, F
The autosomal recessive kidney disease nephronophthisis (NPHP) constitutes the most frequent genetic cause of terminal renal failure in the first 3 decades of life. Ten causative genes (NPHP1-NPHP9 and NPHP11), whose products localize to the primary cilia-centrosome complex, support the unifying concept that cystic kidney diseases are "ciliopathies". Using genome-wide homozygosity mapping, we report here what we believe to be a new locus (NPHP-like 1 [NPHPL1]) for an NPHP-like nephropathy. In 2 families with an NPHP-like phenotype, we detected homozygous frameshift and splice-site mutations, respectively, in the X-prolyl aminopeptidase 3 (XPNPEP3) gene. In contrast to all known NPHP proteins, XPNPEP3 localizes to mitochondria of renal cells. However, in vivo analyses also revealed a likely cilia-related function; suppression of zebrafish xpnpep3 phenocopied the developmental phenotypes of ciliopathy morphants, and this effect was rescued by human XPNPEP3 that was devoid of a mitochondrial localization signal. Consistent with a role for XPNPEP3 in ciliary function, several ciliary cystogenic proteins were found to be XPNPEP3 substrates, for which resistance to N-terminal proline cleavage resulted in attenuated protein function in vivo in zebrafish. Our data highlight an emerging link between mitochondria and ciliary dysfunction, and suggest that further understanding the enzymatic activity and substrates of XPNPEP3 will illuminate novel cystogenic pathways.
Open Access
Inefficient dystrophin expression after cord blood transplantation in Duchenne muscular dystrophy.
(Muscle & nerve, 2010-06) Kang, Peter B; Lidov, Hart GW; White, Alexander J; Mitchell, Matthew; Balasubramanian, Anuradha; Estrella, Elicia; Bennett, Richard R; Darras, Basil T; Shapiro, Frederic D; Bambach, Barbara J; Kurtzberg, Joanne; Gussoni, Emanuela; Kunkel, Louis M
We report a boy who received two allogeneic stem cell transplantations from umbilical cord donors to treat chronic granulomatous disease (CGD). The CGD was cured after the second transplantation, but 2.5 years later he was diagnosed with Duchenne muscular dystrophy (DMD). Examinations of his DNA, muscle tissue, and myoblast cultures derived from muscle tissue were performed to determine whether any donor dystrophin was being expressed. The boy was found to have a large-scale deletion on the X chromosome that spanned the loci for CYBB and DMD. The absence of dystrophin led to muscle histology characteristic of DMD. Analysis of myofibers demonstrated no definite donor cell engraftment. This case suggests that umbilical cord-derived hematopoietic stem cell transplantation will not be efficacious in the therapy of DMD without additional interventions that induce engraftment of donor cells in skeletal muscle.
Open Access
Natural allelic variation of the IL-21 receptor modulates ischemic stroke infarct volume.
(The Journal of clinical investigation, 2016-08) Lee, Han Kyu; Keum, Sehoon; Sheng, Huaxin; Warner, David S; Lo, Donald C; Marchuk, Douglas A
Risk for ischemic stroke has a strong genetic basis, but heritable factors also contribute to the extent of damage after a stroke has occurred. We previously identified a locus on distal mouse chromosome 7 that contributes over 50% of the variation in postischemic cerebral infarct volume observed between inbred strains. Here, we used ancestral haplotype analysis to fine-map this locus to 12 candidate genes. The gene encoding the IL-21 receptor (Il21r) showed a marked difference in strain-specific transcription levels and coding variants in neonatal and adult cortical tissue. Collateral vessel connections were moderately reduced in Il21r-deficient mice, and cerebral infarct volume increased 2.3-fold, suggesting that Il21r modulates both collateral vessel anatomy and innate neuroprotection. In brain slice explants, oxygen deprivation (OD) activated apoptotic pathways and increased neuronal cell death in IL-21 receptor-deficient (IL-21R-deficient) mice compared with control animals. We determined that the neuroprotective effects of IL-21R arose from signaling through JAK/STAT pathways and upregulation of caspase 3. Thus, natural genetic variation in murine Il21r influences neuronal cell viability after ischemia by modulating receptor function and downstream signal transduction. The identification of neuroprotective genes based on naturally occurring allelic variations has the potential to inform the development of drug targets for ischemic stroke treatment.
Open Access
The evolutionary forest algorithm.
(Bioinformatics (Oxford, England), 2007-08) Leman, Scotland C; Uyenoyama, Marcy K; Lavine, Michael; Chen, Yuguo
Motivation
Gene genealogies offer a powerful context for inferences about the evolutionary process based on presently segregating DNA variation. In many cases, it is the distribution of population parameters, marginalized over the effectively infinite-dimensional tree space, that is of interest. Our evolutionary forest (EF) algorithm uses Monte Carlo methods to generate posterior distributions of population parameters. A novel feature is the updating of parameter values based on a probability measure defined on an ensemble of histories (a forest of genealogies), rather than a single tree.
Results
The EF algorithm generates samples from the correct marginal distribution of population parameters. Applied to actual data from closely related fruit fly species, it rapidly converged to posterior distributions that closely approximated the exact posteriors generated through massive computational effort. Applied to simulated data, it generated credible intervals that covered the actual parameter values in accordance with the nominal probabilities.
Availability
A C++ implementation of this method is freely accessible at http://www.isds.duke.edu/~scl13
Open Access
The PsychENCODE project.
(Nat Neurosci, 2015-12) PsychENCODE Consortium; Akbarian, Schahram; Liu, Chunyu; Knowles, James A; Vaccarino, Flora M; Farnham, Peggy J; Crawford, Gregory E; Jaffe, Andrew E; Pinto, Dalila; Dracheva, Stella; Geschwind, Daniel H; Mill, Jonathan; Nairn, Angus C; Abyzov, Alexej; Pochareddy, Sirisha; Prabhakar, Shyam; Weissman, Sherman; Sullivan, Patrick F; State, Matthew W; Weng, Zhiping; Peters, Mette A; White, Kevin P; Gerstein, Mark B; Amiri, Anahita; Armoskus, Chris; Ashley-Koch, Allison E; Bae, Taejeong; Beckel-Mitchener, Andrea; Berman, Benjamin P; Coetzee, Gerhard A; Coppola, Gianfilippo; Francoeur, Nancy; Fromer, Menachem; Gao, Robert; Grennan, Kay; Herstein, Jennifer; Kavanagh, David H; Ivanov, Nikolay A; Jiang, Yan; Kitchen, Robert R; Kozlenkov, Alexey; Kundakovic, Marija; Li, Mingfeng; Li, Zhen; Liu, Shuang; Mangravite, Lara M; Mangravite, Lara M; Mattei, Eugenio; Markenscoff-Papadimitriou, Eirene; Navarro, Fábio CP; North, Nicole; Omberg, Larsson; Panchision, David; Parikshak, Neelroop; Poschmann, Jeremie; Price, Amanda J; Purcaro, Michael; Reddy, Timothy E; Roussos, Panos; Schreiner, Shannon; Scuderi, Soraya; Sebra, Robert; Shibata, Mikihito; Shieh, Annie W; Skarica, Mario; Sun, Wenjie; Swarup, Vivek; Thomas, Amber; Tsuji, Junko; van Bakel, Harm; Wang, Daifeng; Wang, Yongjun; Wang, Kai; Werling, Donna M; Willsey, A Jeremy; Witt, Heather; Won, Hyejung; Wong, Chloe CY; Wray, Gregory A; Wu, Emily Y; Xu, Xuming; Yao, Lijing; Senthil, Geetha; Lehner, Thomas; Sklar, Pamela; Sestan, Nenad
Restricted
Two genes on A/J chromosome 18 are associated with susceptibility to Staphylococcus aureus infection by combined microarray and QTL analyses.
(PLoS Pathog, 2010-09-02) Ahn, SH; Deshmukh, H; Johnson, N; Cowell, LG; Rude, TH; Scott, WK; Nelson, CL; Zaas, AK; Marchuk, DA; Keum, S; Lamlertthon, S; Sharma Kuinkel, BK; Sempowski, GD; Fowler Jr, VG
Although it has recently been shown that A/J mice are highly susceptible to Staphylococcus aureus sepsis as compared to C57BL/6J, the specific genes responsible for this differential phenotype are unknown. Using chromosome substitution strains (CSS), we found that loci on chromosomes 8, 11, and 18 influence susceptibility to S. aureus sepsis in A/J mice. We then used two candidate gene selection strategies to identify genes on these three chromosomes associated with S. aureus susceptibility, and targeted genes identified by both gene selection strategies. First, we used whole genome transcription profiling to identify 191 (56 on chr. 8, 100 on chr. 11, and 35 on chr. 18) genes on our three chromosomes of interest that are differentially expressed between S. aureus-infected A/J and C57BL/6J. Second, we identified two significant quantitative trait loci (QTL) for survival post-infection on chr. 18 using N(2) backcross mice (F(1) [C18A]xC57BL/6J). Ten genes on chr. 18 (March3, Cep120, Chmp1b, Dcp2, Dtwd2, Isoc1, Lman1, Spire1, Tnfaip8, and Seh1l) mapped to the two significant QTL regions and were also identified by the expression array selection strategy. Using real-time PCR, 6 of these 10 genes (Chmp1b, Dtwd2, Isoc1, Lman1, Tnfaip8, and Seh1l) showed significantly different expression levels between S. aureus-infected A/J and C57BL/6J. For two (Tnfaip8 and Seh1l) of these 6 genes, siRNA-mediated knockdown of gene expression in S. aureus-challenged RAW264.7 macrophages induced significant changes in the cytokine response (IL-1 beta and GM-CSF) compared to negative controls. These cytokine response changes were consistent with those seen in S. aureus-challenged peritoneal macrophages from CSS 18 mice (which contain A/J chromosome 18 but are otherwise C57BL/6J), but not C57BL/6J mice. These findings suggest that two genes, Tnfaip8 and Seh1l, may contribute to susceptibility to S. aureus in A/J mice, and represent promising candidates for human genetic susceptibility studies.

Browsing by Subject "Chromosome Mapping"

Motivation

Results

Availability