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  • International Mammalian Genome Society
    BHB 12 miles from downtown Bar Harbor http www bhbairport com Though this airport is the closest to downtown Bar Harbor there are fewer flights than BGR and all flights to BHB come from Boston Ground Transportation http www bhbairport com transportation html Other Airport Options Portland ME PWM http www portlandjetport org Manchester NH http www flymanchester com Car Bar Harbor is a five hour drive from Boston Google map destination is set to the Harborside Hotel and Marina http www theharborsidehotel com Enter the beginning location to get customized directions http goo gl maps YZAVD Local taxi service and local can mean between Bangor and Bar Harbor At Your Service Inc 207 288 9222 Bar Harbor Coastal Cab 207 288 1222 Hotel The registration fee does not include lodging Please make your own arrangements The conference hotel which is adjacent to the Bar Harbor Club where the sessions will take place is the Harborside Hotel and Marina 55 West Street Bar Harbor ME 04609 207 288 5033 The IMGS has arranged a special rate of 117 plus tax for a single or double room per night These rates will be honored from 10 22 through 11 1 14

    Original URL path: http://www.imgs.org/Archive/website/IMGS2014/Travel.html (2016-02-17)
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  • International Mammalian Genome Society
    Beutler Systems Genetics Workshop Site Bar Harbor Club Bar Harbor Club Bar Harbor Club Bar Harbor Club Location Pool House 2nd floor Board Rm Stotesbury Ballroom Stotesbury Ballroom Stotesbury Ballroom TUESDAY OCTOBER 28 Time 12 15 13 15 13 15 14 30 15 00 16 30 16 45 17 45 Event Nomenclature Lunch Mentor Lunch Systems Genetics Workshop MGI Workshop Keynote Lecture Jeanne Lawrence Site Bar Harbor Club Bar Harbor

    Original URL path: http://www.imgs.org/Archive/website/IMGS2014/Events.html (2016-02-17)
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  • International Mammalian Genome Society
    O 29 In mice with activated AKT constitutive reduction of MTOR reduces the expression of Cdk6 and delays the development of thymic lymphomas Joy Gary 1 Jinfei Xu 1 John Simmons 1 Shuling Zhang 2 Alexander Kovalchuk 1 Ke Zhang 1 Wendy DuBois 1 Joseph Testa 3 and Beverly Mock 1 1 NCI NIH Bethesda MD USA 2 Michigan State University East Lansing MI USA 3 Fox Chase Cancer Center Philadelphia PA USA The PI3K AKT MTOR signaling pathway is hyperactivated in a variety of solid tumors and hematologic malignancies This hyperactivation often results from overexpression or mutation loss in PI3K AKT or PTEN MTOR is a central downstream target of the pathway and is a critical modulator of cell cycle size proliferation and metabolism To examine the role of MTOR in the development of tumors induced by activated AKT Tg Lck Akt2 1Test Lck MyrAkt2 mice whose constitutively active AKT induces thymic lymphomas were crossed with Mtor tm1 1Lgm mice which constitutively express reduced levels of MTOR protein As expected Lck MyrAkt2 mice with wild type Mtor expression spontaneously developed thymic lymphomas at 10 20 weeks of age with an average age of 14 5 weeks for palpable tumors In the Lck MyrAkt2 mice with reduced Mtor expression tumor development was delayed with an average age of 26 weeks for palpable tumors and the mice lived longer with a median survival of 181 days which was three months longer than the mice with normal Mtor expression The frequency of t14 15 translocations was similar in both groups of lymphomas We performed gene expression profiling GEP of tumors arising from both groups of mice to uncover underlying mechanisms of reduced tumorigenicity seen in mice with low Mtor expression Molecular and functional enrichment analysis of the genes found to be differentially expressed between the two groups identified cell death and survival and DNA replication and repair as the most enriched networks Cdk6 expression was 10 fold lower in the tumors from the mice with low Mtor Cdk6 and Akt are frequently abnormally expressed in human T cell lymphoblastic lymphomas and may contribute to the pathogenesis of this malignancy We conclude that reduced levels of Mtor can inhibit tumor formation by activated AKT and that CDK6 may be a critical target of this inhibition O 30 A suppressor screen in mouse Mecp2 identifies cholesterol homeostasis as a therapeutic target in Rett Syndrome Christie M Buchovecky 1 Stephanie M Kyle 1 Stephen D Turley 2 David W Russell 2 Jay Shendure 3 and Monica J Justice 1 1 Department of Molecular and Human Genetics Baylor College of Medicine Houston TX 77030 2 Department of Internal Medicine and Department of Molecular Genetics The University of Texas Southwestern Medical School Dallas TX 75390 3 Department of Genome Sciences University of Washington Seattle WA 98105 Mutations in methyl CpG binding protein 2 MECP2 cause Rett Syndrome RTT the most severe autism spectrum disorder Mecp2 null mouse models recapitulate many of the symptoms of RTT and their study has provided insight into the physiological basis of disease Reactivating silent Mecp2 in symptomatic adult null mice reverses symptoms suggesting that therapeutic intervention may be possible in RTT patients Unfortunately as a widespread epigenetic factor MECP2 is extremely dosage sensitive making direct manipulation a poor treatment option MECP2 mutation impacts many biological pathways but it is unclear which are relevant to symptom onset and progression We used an unbiased forward genetic approach to identify dominant suppressors of phenotypes in Mecp2 null male mice dispensing with a priori beliefs about MECP2 function Five suppressor mutations which ameliorate symptoms of Mecp2 loss were identified using linkage mapping and whole exome sequencing One is a loss of function mutation in squalene epoxidase Sqle a rate limiting enzyme in committed cholesterol biosynthesis The underlying basis for the rescue is a previously undescribed metabolic syndrome that develops in Mecp2 mutant mice Although lipid metabolism has not been implicated in the pathogenesis of Rett Syndrome it is linked to many other neurological disorders Further MECP2 is required to link a repressor complex that regulates lipid homeostasis to DNA Accordingly Mecp2 mutant mice were treated with cholesterol lowering statin drugs which alleviate motor symptoms and confer increased longevity in both males and females Cholesterol metabolism therefore represents a potential new therapeutic target for the treatment of RTT Our overarching goal is to identify a large number of suppressors through additional screening such that a list of potential therapeutic targets can be developed for RTT A similar systems biology approach could be exploited to identify targetable pathways involved in other untreatable diseases opening a new field for translational discovery O 31 Potent Modifiers of Intestinal Polyposis in Closely Related Inbred Mouse Strains Xiang Wang 1 2 Marco DeDominici 1 Yuhang Zhou 1 Fernando Pardo Manuel de Villena 3 Arthur M Buchberg 1 4 and Linda D Siracusa 1 1 Kimmel Cancer Center Department of Microbiology and Immunology Thomas Jefferson University Philadelphia PA 2 Department of Radiation Oncology Winship Cancer Institute of Emory University Atlanta GA 3 Department of Genetics Lineberger Comprehensive Cancer Center Carolina Center for Genome Sciences University of North Carolina at Chapel Hill Chapel Hill NC 4 American Association for Cancer Research Philadelphia PA The adenomatous polyposis coli APC tumor suppressor gene is mutated in Familial Adenomatous Polyposis FAP an inherited disorder that predisposes individuals to intestinal polyps and eventually leads to cancer In the Min mouse model the genetic background of mice carrying a mutation in the murine homolog of the APC gene Apc Min is essential to the development of tumors as inbred strains vary in their susceptibility to polyposis Although complex trait analyses have identified several loci that modify intestinal tumor number and size in Apc Min mice less than a handful of modifier genes have been identified to date Unlike traditional quantitative trait loci QTL studies that exploit the diversity among evolutionarily distant inbred strains we took advantage of genetic similarities between closely related inbred strains Here we report the identification of protective modifier loci in the C57L J L strain which is closely related to the C57BL 6J B6 strain The F1 Apc Min offspring from intercrosses between L and B6 mice exhibited significant differences in polyp phenotypes compared to their B6 parents Our QTL study revealed several autosomal regions that contain modifier genes Candidate genes in two of these loci were investigated and several polymorphisms were prioritized for further study We discuss the usefulness of this closely related strain approach in optimizing complex trait screens and speeding the process of causative gene identification Research supported in part by NCI grants to LDS O 32 CDCA7L is a male specific susceptibility locus and oncogene in glioma Min Hyung Lee 1 Sungjin Kim 2 Yanghong Liu 3 Rosy Luo 4 Joshua Rubin 4 Melissa Bondy 3 Karl Broman 2 and Karlyne Reilly 1 1 Mouse Cancer Genetics Program Center for Cancer Research National Cancer Institute Frederick MD USA 2 University of Wisconsin Madison WI USA 3 Baylor College of Medicine Houston TX USA 4 Washington University St Louis MO USA Astrocytoma and glioblastoma multiforme GBM are the most common primary brain tumors and are currently incurable Both astrocytoma and GBM show male predominance with a male to female ratio of 1 3 Previously our lab has demonstrated that astrocytoma GBM tumorigenesis in the Nf1 tm1Tyj Trp53 tm1Tyj NPcis mouse model shows gender bias in certain genetic contexts Using linkage analysis in the NPcis mouse we have identified a male specific genetic modifier locus on distal Chromosome 12 named Arlm1 for astrocytoma resistance locus in males 1 To identify candidate genes for the Arlm1 modifier of glioma risk we used combinational bioinformatics approaches and cross species comparisons identifying cell division cycle associated 7 like Cdca7l CDCA7L as a strong candidate for a male specific astrocytoma susceptibility gene among 503 candidate genes To investigate the role of CDCA7L in astrocytoma GBM we analyzed CDCA7L in both human GBM and mouse astrocytoma cell lines in both genders CDCA7L expression was upregulated in GBM and astrocytoma cells compared to normal brain with male predominance shRNA mediated Cdca7l CDCA7L silencing in male derived mouse astrocytoma cells and human GBM led to decrease of both cell growth and viability Further mechanistic study revealed that Cdca7l CDCA7L depletion in male derived mouse astrocytoma cells and human GBM cells was connected with the induction of caspase 3 activation and reduction of cyclin D1 expression suggesting the oncogenic role of CDCA7L in astrocytoma GBM On the other hand Cdca7l overexpression in female derived mouse astrocytoma cells showed less degree of cell proliferation and viability increases Strikingly CDCA7L depletion in human female derived GBM cell line U87MG caused increase of both cell growth and viability These data highlight the sex specificity of CDCA7L in astrocytoma GBM tumorigenesis and provide evidence for the first modifier of male specific susceptibility to brain tumors O 33 Rapid conversion of EUCOMM KOMP CSD alleles in mouse embryos using a cell permeable cre recombinase Ed Ryder Brendan Doe Diane Gleeson Richard Houghton Priya Dalvi Evelyn Grau Bishoy Habib Evelina Miklejewska Stuart Newman Debarati Sethi Sapna Vyas Hannah Wardle Jones Sanger Mouse Genetics Project Joanna Bottomley James Bussell Antonella Galli Jennifer Salisbury and Ramiro Ramirez Solis The Wellcome Trust Sanger Institute Hinxton Cambridgeshire CB10 1SA United Kingdom The goal of the International Mouse Phenotyping Consortium IMPC is to generate knockout strains for all protein coding genes in the mouse on a C57BL 6N genetic background and to elucidate gene function by use of a broad spectrum high throughput primary phenotyping screen These phenotypes can then be studied in more depth by the scientific community at large with specialized areas of interest To this end the IMPC makes use of the EUCOMM KOMP CSD embryonic knockout stem cell collection We describe the use of a cell permeable cre to efficiently convert the EUCOMM KOMP CSD knockout first conditional ready tm1a allele to the non conditional lacZ tagged null tm1b form in early mouse embryos in a high throughput manner consistent with the requirements of the IMPC affiliated NIH KOMP2 project This method results in rapid allele conversion and minimizes the use of experimental animals when compared to our CMV cre based transgenic mouse breeding resulting in a significant reduction in costs and time with increased welfare benefits O 34 Targeted chromosomal inactivation of the mouse Tyr insulators with engineered nucleases Davide Seruggia 1 2 Mario Hermann 3 Pawel Pelczar 3 and Lluis Montoliu 1 2 1 CNB CSIC Madrid Spain 2 CIBERER ISCIII Madrid Spain 3 Institute of Laboratory Animal Science University of Zurich Zurich Switzerland Chromatin boundaries or insulators are regulatory elements capable of dividing expression units into independent topological domains allowing its function in the proper tissue and in the proper developmental stage despite the epigenetic marks of the chromatin nearby We identified two of such elements in the mouse genome in the intergenic space in between of three differently expressed genes Nox4 Tyr and Grm5 When tested in plasmid based assays aimed to quantitate the insulator function in an artificial system these sequences showed values comparable to the most active known insulator the chicken HS4 insulator Nevertheless alike other regulatory elements such as enhancers insulators may fail to function when used ectopically For example in mouse transgenesis the efficacy of an insulator can vary dramatically according to the promoter used to drive the transgene This variability reflects the interdependence between the insulator and the genomic context the latter being the driving force for the first to appear and be conserved in the genome With this in mind we decided to study the mouse Tyr insulators in their full genomic context First with Chromosome Conformation Capture 3C we described the topological domain imposed by the Tyr insulators to the locus Second we designed engineered nucleases to produce the targeted inactivation of the Tyr insulators in transgenic mice Using the latest technology namely TALEN and CRISPRs Cas9 nucleases we succeeded in deleting these sequences in cultured cells We are currently applying our best performing nucleases for the generation of two transgenic mouse lines in order to observe the expression patterns of Nox4 Tyr and Grm5 in different tissues and developmental stages in the absence of the Tyr insulators O 35 Functional deciphering of genomic boundaries associated to cellular biological requirements Cristina Vicente Garcia 1 2 Davide Seruggia 1 2 Ana Fernandez Minan 3 Almudena Fernandez 1 2 Marta Cantero Gonzalez 1 2 Amalia Martinez Segura 1 Jose Luis Gomez Skarmeta 3 and Lluis Montoliu 1 2 1 CNB CSIC Madrid Spain 2 CIBERER ISCIII Madrid Spain 3 CABD UPO CSIC Sevilla Spain In mammalian genomes it is not uncommon to find a gene with a very restricted expression pattern right next to a ubiquitously expressed one This is possible thanks to the action of genomic boundaries or insulators which delimit expression domains and prevent undesirable crosstalk between the regulatory elements of adjacent domains Insulators can also be found partitioning the chromatin into active euchromatic and silenced heterochromatic regions as well as flanking and protecting clusters of co expressed genes In order to find boundaries in a genome wide fashion in the mouse genome we explored these scenarios where the presence of insulator elements is necessary for the correct functioning of the cell Several bioinformatic algorithms were developed and the resulting putative insulator sequences were functionally validated using various assays Their enhancer blocking properties were tested first in vitro in human cells in culture and then in vivo in zebrafish Additionally we analyzed the ability of the most powerful element to protect from chromosomal position effects in transgenic mice The description and characterization of new genomic boundaries would aid not only in the understanding of how genomes are organized but also in the improvement of the gene transfer technologies O 36 Examination of the effect of a DNA repair defect on the efficiency of ENU mutagenesis George A Carlson 1 Rose Pitstick 1 Janet Peters 1 Jabier Gallego 2 and David R Beier 1 2 1 McLaughlin Institute Great Falls MT 2 Seattle Childrens Research Institute Seattle WA ENU mutagenesis is a powerful method for generating novel lines of mice that are informative with respect to both fundamental biological processes and human disease Rapid developments in genomic technology have made the task of identifying causal mutations by positional cloning remarkably efficient One limitation of this approach remains the mutation frequency achievable using standard treatment protocols which currently generate approximately 1 sequence change per megabase when optimized In order to increase this efficiency we have initiated a study in which mice carrying a mutation in the DNA repair enzyme Msh6 are treated with ENU Of note heterozygous mice tolerate treatment well while homozygous mutant mice did not survive even at lower doses Mutation efficiency will be assessed by next generation sequence analysis of the G1 progeny exome sequencing will be done to sample the mutagenized genomes with high fidelity in an unbiased and cost effective manner As part of the same study and using the same method for genome sampling we will examine whether serial treatment of progeny of mutagenized mice can yield founders carrying large numbers of heterozygous mutations We presently have multiple independent lines both heterozygous for Msh6 and wild type which are on the third round of ENU treatment O 37 Suppression and quantitative control of meiotic recombination hotspot activity Pavlina M Petkova Christopher L Baker Michael Walker Petko M Petkov and Kenneth Paigen Center for Genome Dynamics The Jackson Laboratory Bar Harbor ME 04609 USA Meiotic recombination is a fundamental biological process that ensures production of haploid gametes and increases genetic diversity In mammals recombination occurs at specific sites known as hotspots whose positions are determined by Prdm9 While the role of Prdm9 in hotspot activation is well established the mechanisms regulating other aspects of hotspot activity including suppression and quantitative regulation have remained unclear Here we show that Prdm9 regulates these phenomena as well The recombination hotspot Ush2a is suppressed in F1 of CAST EiJ x C57BL 6J mice and active only on a pure C57BL 6J background To identify the suppressing factor we measured Ush2a hotspotactivity in mice containing various combinations of Prdm9 alleles when the rest of the genetic background was either homozygous B6 B6 or heterozygous B6 CAST In all crosses the presence of the Prdm9 CAST allele was necessary and sufficient to suppress Ush2a hotspot activity To genetically map quantitative regulators we followed the behavior of two hotspots whose activity is either increased Esrrg2 hotspot or decreased Pbx1 hotspot in the presence of distant CAST EiJ alleles in a segregating F2 cross between C57BL 6J and CAST EiJ We quantitated hotspot activity using a new high throughput sequencing method A single QTL on Chr 17 overlapping with Prdm9 was responsible for the change in activity at the Pbx1 hotspot In addition ChIP Seq analysis of H3K4me3 the chromatin modification catalyzed by PRDM9 shows that the quantitative control at the Essrg2 hotspot is likely due to two closely spaced hotspots activated by the B6 and CAST alleles of PRDM9 Taken together these results suggest that Prdm9 is the primary determinant of the quantitative differences at recombination hotspots and that suppression is an extreme case of quantitative control O 38 Prdm9 variability and its effect on genetic recombination in a Robertsonian house mouse natural population Laia Capilla 1 2 Nuria Medarde 2 Alexandra Alemany Scmidt 3 Maria Oliver Bonet 3 Jacint Ventura 2 and Aurora Ruiz Herrera 1 4 1 Institut de Biotecnologia i Biomedicina Universitat Autonoma de Barcelona Spain 2 Departament de Biologia Animal Biologia Vegetal i Ecologia Universitat Autonoma de Barcelona Spain 3 Unitat Investigacio Hospital Universitari Son Espases Palma Spain 4 Departament de Biologia Cellular Fisiologia i Immunologia Universitat Autonoma de Barcelona Spain Understanding the mechanisms underlying speciation has been of special interest in biology Although chromosomal rearrangements have been shown to play an important role in the process more recently different studies have suggested that Prdm9 might be involved in the speciation process as its highly mutable sequence determines the position number and strength of recombination events In this context the main aim of this study is to shed light in the impact if any of chromosomal rearrangements and Prdm9 genetic variability in recombination In order to do so we have analyzed meiotic recombination jointly with Prdm9 sequence variability across the Barcelona Robertsonian Rb polymorphism zone a wild house mouse population with a wide range of diploid numbers from 2n 22 to 2n 40 Our analysis revealed the presence of new Prdm9 allelic variants in the Barcelona population that show differences in both sequence and number of zinc finger repeats compared to previous studies Our results also revealed a significant decrease in the number of crossovers per cell in Rb specimens especially so in specimens with low zinc finger repeats Based on these observations we postulate that the presence of chromosomal rearrangements and the reduction in the number of Prdm9 zinc finger repeats would influence the overall recombination rates that characterize Rb specimens Financial support from Ministerio de Economia y Competitividad project ref CGL2010 15243 and CGL 2010 20170 is gratefully acknowledged Laia Capilla is supported by a FPI PhD fellowship BES 2011 047722 O 39 PRDM9 dependent modification organizes hotspot chromatin structure Christopher L Baker Michael Walker Shimpei Kajita Petko M Petkov and Kenneth Paigen Center for Genome Dynamics The Jackson Laboratory Bar Harbor ME 04609 USA Meiotic recombination is restricted to 1 2 kb regions termed hotspots In mouse and human recombination at hotspots is initiated when the zinc finger protein PRDM9 binds to DNA and locally activates chromatin This subsequently leads to introduction of DNA double stranded breaks which are repaired using a non homologous chromatid as a template Previous genome wide analysis of hotspots in mouse has focused on determining the position of meiotic double strand breaks and found that most breaks overlap with PRDM9 modified chromatin We now add to this understanding by providing a detailed picture of hotspot chromatin organization confirmation that PRDM9 physically binds the identified motifs and insight into downstream consequences of PRDM9 dependent modification on meiotic recombination We combine genome wide analyses of PRDM9 modification with fine scale analysis of hotspots using chromatin immunoprecipitation with H3K4me3 antibody followed by high throughput sequencing To facilitate the identification of PRDM9 dependent chromatin modifications we have compared the H3K4me3 pattern of C57BL 6J containing Prdm9 b allele with that of a B6 knockin mouse strain containing the Prdm9 wm7 allele We find that PRDM9 trimethylated nucleosomes are symmetrically organized around a central nucleosome depleted region The latter extends for about 165 bp much longer than the typical 35 bp spacer region between nucleosomes and contains the predicted PRDM9 binding motif We demonstrate that PRDM9 expressed in E coli does indeed bind the hotspot DNA sequence in vitro within this spacer region at the predicted motif Importantly this chromatin organization is a product of PRDM9 presence as it only occurs at hotspots when the corresponding Prdm9 allele is present We find that meiotic crossing over is constrained within the trimethylated nucleosomes suggesting that the new chromatin environment generated by PRDM9 is required for Holliday junction migration These findings show that PRDM9 significantly alters the hotspot chromatin environment potentially creating a permissible landscape for downstream meiotic recombination machinery O 40 Defects in Nek8 result in abnormal specification of developmental patterning polycystic kidney disease and impaired response to replication stress Danielle K Manning 1 Mikhail Sergeev 2 3 Scott Houghtaling 4 Hyo Jei Claudia Choi 5 Karlene A Cimprich 5 Jagesh V Shah 2 3 and David R Beier 1 4 1 Brigham and Womens Hospital Division of Genetics Boston MA 2 Harvard Medical School Systems Biology Boston MA 3 Brigham and Womens Hospital Renal Division Boston MA 4 Center for Developmental Biology and Regenerative Medicine Seattle Children s Research Institute Seattle WA 5 Stanford University School of Medicine Department of Chemical and Systems Biology Stanford CA The kinase Nek8 is emerging as a multifunctional protein with roles in disparate cellular functions We discovered Nek8 in an analysis of the juvenile cystic kidneys jck model of PKD affected mice carry a missense mutation in the presumptive regulatory domain Missense mutations in this domain of Nek8 have also been identified in patients with the renal cystic disease nephronophthisis NPHP9 and in the Lewis polycystic kidney rat We generated a Nek8 null allele Nek8 tm1Bei homozygous mice die at birth and exhibit randomization of left right asymmetry Ciliogenesis is intact in Nek8 deficient embryos and cells but nodal ciliary signaling is perturbed as embryonic left sided marker genes are misexpressed We generated Nek8 jck Nek8 tm1Bei compound heterozygotes these mutants develop less severe cystic disease than jck homozygotes suggesting that the jck missense allele encodes a gain of function protein Notably Nek8 and Pkd2 embryonic phenotypes are strikingly similar PKD2 PC2 is expressed properly in Nek8 deficient embryos and cells however similar to cells lacking PKD2 Nek8 depleted IMCD cells exhibit diminished flow dependent calcium influx which suggests Nek8 mediates PKD2 dependent signaling More recently Nek8 has been identified as an effector of the ATR ataxia telangiectasia and Rad3 related replication stress response Cells lacking Nek8 form DNA double strand breaks and NEK8 protein physically interacts with ATR and travels with the replication fork Notably elevated DNA damage signaling is evident in jck homozygous kidneys at 3 weeks of age well prior to the point that they exhibit extensive cystic disease Thus in addition to the well established specific localization of NEK8 to the inversin compartment of the ciliary axoneme it is also present in the nucleus and binds to chromatin Functionally it plays a role in mediating embryonic nodal signaling maintenance of renal tubular integrity and DNA damage response It will be of interest to assess whether these activities reflect multiple independent Nek8 activities or are mechanistically related O 41 The ENU induced mutation germ cell depletion 2 gcd2 is a missense mutation in Kif18a that causes cell type specific mitotic defects Candice Byers 1 Anne Czechanski 1 Ian Greenstein 1 Haein Kim 2 Jason Stumpff 2 and Laura Reinholdt 1 1 Genetic Resource Science The Jackson Laboratory Bar Harbor ME 04609 2 Department of Molecular Physiology and Biophysics University of Vermont Burlington VT 05405 Using high throughput sequencing we ve discovered that the ENU induced germ cell depletion 2 gcd2 mutation is a missense mutation in Kif18a KIF18A is a microtubule motor protein that is uniquely capable of controlling the plus end spindle microtubule dynamics that are essential for mitotic chromosome congression and alignment during metaphase In HeLa cells loss of KIF18A causes mis alignment of metaphase chromosomes elongated spindles and activation of the spindle assembly checkpoint The gcd2 mutation leads to a conservative amino acid change R308K in a highly conserved arginine within the motor domain of Kif18a To test the impact of this conservative amino acid change we expressed a GFP tagged version of the orthologous human mutant protein in HeLa cells and using live cell imaging found the phenotype to be identical to that of functional null alleles when compared to that of similarly GFP tagged wild type KIF18A Specifically mutant KIF18A was unable to accumulate at the plus end of kinetochore microtubules which resulted in increased chromosome oscillations at metaphase and ultimately mitotic arrest Therefore we conclude that the Kif18a gcd2 allele is a functional null To examine the impact of this mutation in primary cells we derived embryonic fibroblasts from mutant and control embryos Cell cycle and growth curve analyses revealed severe proliferation defects in the absence of cell cycle arrest Moreover mutant MEFs fetal germ cells and spermatogonia accumulated in M phase and exhibited defects in chromosome alignment While Kif18a is broadly expressed and has an essential function in mitosis we have yet to discover a phenotype outside of the developing germ line Therefore Kif18a appears to be one of a growing number of genes with generalized roles in genome dynamics that are uniquely required for germ cell development O 42 Rat Resource and Research Center Elizabeth Bryda Craig Franklin Yuksel Agca James Amos Landgraf and Aaron Ericsson Department of Veterinary Pathobiology College of Veterinary Medicine University of Missouri Columbia MO USA The Rat Resource and Research Center RRRC was established in 2001 with funding from the National Institutes of Health The goals of the RRRC are to 1 provide the biomedical community with a repository for valuable rat strains and 2 shift the burden for maintaining and distributing rat models from individual investigators to a centralized repository Currently the RRRC has approximately 350 rat lines received through active recruitment of valuable rat models and donations from investigators Upon importation of rat strains stocks into the RRRC gametes and embryos are cryopreserved to ensure against future loss of the model Quality control measures include extensive genetic validation and pathogen testing Models in the RRRC are distributed as live animals and cryopreserved gametes and embryos Additionally rat embryonic stem cell lines are available Research efforts by the RRRC have advanced cryobiology and assisted reproductive technologies for the rat Due to high success rates with intra cytoplasmic sperm injection the RRRC uses sperm cryopreservation as a cost effective method for banking large collections of single gene mutations and ensuring reliable recovery when models are requested The RRRC has expertise in rat reproductive biology colony management health monitoring genetic assay development optimization and the isolation of germline competent ES cell lines from transgenic rats our staff and researchers are readily available for consultation The RRRC has a number of fee for service capabilities such as a wide variety of genetic analyses cytogenetic characterization including spectral karyotype analysis strain rederivation and spermatozoa cryopreservation Our website www rrrc us allows user friendly navigation and provides information about all strains cell lines model donation procedures on line ordering lists of services publications and protocols The RRRC is a valuable resource for rat users as it continues to expand the number of accessible rat models and services available to the global biomedical community O 43 Status of The Diversity Outbred Population Gary A Churchill Elissa J Chesler Karen L Svenson Marge Strobel and Daniel M Gatti The Jackson Laboratory Bar Harbor ME 04609 The Diversity Outbred DO population is a heterogeneous stock derived from the same eight founder strains as the Collaborative Cross inbred strains This talk will summarize the status of DO colony which is in the 14 th generation of outbreeding as of May 2013 Several large projects are underway using DO mice to investigate genetics of complex traits New genotyping resources and analytical tools have been developed to support these studies Accumulation of recombination events in the DO is tracking predicted rate However there was a major distortion in the founder allele frequencies driven by a selective sweep of WSB EiJ allele on Chromosome 2 Corrective action was taken to restore allelic balance in this region We will present empirical results and simulations to support sample size and other study design decisions The DO is thriving and ready for widespread adoption by this community O 44 The Mouse Genomes Project From sequence variation to complete genomes K Wong 1 Richard Mott 2 Jonathan Flint 2 David J Adams 1 and TM Keane 1 1 Wellcome Trust Sanger Institute Hinxton Cambridge UK 2 Wellcome Trust Centre for Human Genetics University of Oxford Oxford UK The Mouse Genomes Project is an ongoing effort to sequence the genomes of the common laboratory mouse strains cataloguing all forms of molecular variation and to produce genome sequences of each strain Phase 1 of the project involved deep sequencing of the strains and creating comprehensive catalogs of molecular variation ranging from single base changes up to large structural differences of multiple kilobases We are now in phase 2 of the project with the focus being the production of accurate genome sequences and gene annotation for each of the strains Therefore in 2012 we resequenced each of the strains to between 40 80x coverage on the HiSeq platform and have been finalising the sequencing of large fragment libraries of varying sizes and generating long range optical maps for a subset of the wild derived strains Our initial assessments of the genome sequences show that they contain 98 99 of the protein coding exons with 60 72 of genes currently contained in single scaffolds We have examined the representation of 742 validated structural variants in the assemblies and find that the majority are represented correctly Perhaps the most interesting aspect of having genome sequences for the strains is the proportion of sequence not found in the C57BL 6J reference genome We estimate that there is up to 4 5Mbp of new sequence in the strains and are currently examining this for coding sequences Finally we find that there is varying representation of the known forms of repeat elements SINE LINE and ERVs O 45 The Next Gen Mouse and the Missense Mutation Library delivering new resources for understanding human disease Michael S Dobbie The Australian Phenomics Facility The Australian Phenomics Network The Australian National University Canberra Australia The Australian Phenomics Network APN and Australian Phenomic Facility APF have capitalised on expertise in genome wide mutagenesis and advances in DNA sequencing efficiency to create a new library of missense and nonsense alleles in the mouse http databases apf edu au mutations Treatment of mice with the chemical mutagen N ethyl N nitrosourea ENU efficiently generates random single base mutations in the germline DNA ENU induced mutations are subtle hypomorphic dominant negative gain of function and model human single nucleotide variants SNVs the most common kind of disease causing mutation ENU mutagenesis is the most powerful forward genetic strategy in the mouse However the dramatic fall in the cost of DNA sequencing renders ENU mutagenesis an attractive reverse genetic strategy without the need for ES cells Exome sequencing of each first generation offspring of an ENU treated male C57BL 6 mouse identifies on average 25 protein changing de novo mutations in a heterozygous state By mid 2013 the library contained over 16 000 SNVs including 650 nonsense mutations 2 200 predicted to disrupt splicing and 5 000 that are probably damaging as predicted by PolyPhen 2 Bioinformatic analysis of the SNVs against human Multiz alignments to UCSC liftOver mutations into human coordinates identified five SNVs mapped to human genes from ClinVar Additionally over 2 100 SNVs correlate with Orphanet rare human disease associated genes Importantly many of these alleles are live and can be rapidly accessed for specific phenotyping based on known disease associations Researchers who maintain a secure Gene Watch account are alerted when alleles are found in their specific genes of interest and can respond while the Next Gen Mouse is live The Missense Mutation Library continues to grow and is expected to offer alleles in over 50 of genes by the end of 2013 More information about these and other resources at apf anu edu au and www australianphenomics org au Supported by Australian Federal and State Government research infrastructure funding and by the APN partners O 46 Informatics for the International Mouse Phenotyping Consortium Hugh Morgan 1 Julian Atienza Herrero 1 Andrew Blake 1 Chao Kung Chen 2 Armida Di Fenza 1 Richard Easty 3 Tanja Fiegel 1 Alan Horne 3 Vivek Iyer 3 Natasha Karp 3 Gautier Koscielny 2 Jeremy Mason 2 Terrence Meehan 2 David Melvin 3 Ahmad Retha 1 Luis Santos 1 Duncan Sneddon 1 Jonathan Warren 2 Henrik Westerberg 1 Robert Wilson 3 Gagarine Yaikhom 1 Steve Brown 1 Paul Flicek 2 Helen Parkinson 2 William Skarnes 3 and Ann Marie Mallon 1 1 MRC Mammalian Genetics Unit MRC Harwell Harwell Science and Innovation Campus Harwell OX11 0RD UK 2 European Molecular Biology Laboratory European Bioinformatics Institute Wellcome Trust Genome Campus Hinxton Cambridge CB10 1SD UK 3 Wellcome Trust Sanger Institute Morgan Building Wellcome Trust Genome Campus Hinxton Cambridge CB10 1SA UK The International Mouse Phenotyping Consortium IMPC is generating and characterizing a knockout mouse strain for almost every protein coding gene in the mouse genome Data from a standardized broad based phenotyping pipeline is being centralized analysed and integrated by the MPI2 consortium in the IMPC Data coordinating center Dedicated data wranglers are working with the production centers to ensure proper transfer and quality control of data occurs An automated statistical analysis pipeline is identifying knockout strains whose phenotype parameters have values that lie outside the normal range Annotation with biomedical ontologies is allowing biologists and clinicians to easily find mouse strains with phenotypic traits relevant to their research Data integration with other resources will provide insights into mammalian gene function and human disease Users can now search the database to find new phenotype data from IMPC strains characterized at international centers and find the production status of a knockout strain for any gene The community is invited to explore and provide feedback as we build the first comprehensive mammalian functional genomic catalog at www mousephenotype org O 47 Quantitative Trait Locus Mapping in Diversity Outbred Mice Daniel M Gatti 1 Karen L Svenson 1 Riyan Cheng 2 Andrey Shabalin 3 Daniel Pomp 4 Neal Goodwin 1 Abraham Palmer 2 Karl Broman 5 and Gary A Churchill 1 1 The Jackson Laboratory Bar Harbor ME USA 2 Dept of Human Genetics Univ of Chicago Chicago IL USA 3 Medical College of Virginia of Virginia Commonwealth University Richmond VA USA 4 Dept of Genetics University of North Carolina Chapel Hill NC USA 5 Dept of Biostatistics and Medical Informatics University of Wisconsin Madison WI USA The search for genes underlying complex phenotypes has been greatly aided by genetic mapping in the mouse Traditionally mapping has been carried out in two parent intercrosses with limited mapping resolution Relatively few of these studies have led directly to the discovery of a gene that regulates the phenotype of interest In order to improve mapping resolution advanced intercrosses and multi founder crosses have been developed Diversity Outbred DO mice

    Original URL path: http://www.imgs.org/Archive/website/IMGS2013/program.html (2016-02-17)
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  • International Mammalian Genome Society
    such as IKMC international mouse knock out consortium GRC genome reference consortium and CCDS consensus CDS If delegates have any particular annotation queries about their genes of interest we are happy to discuss these This will be held in the Colegio Fonseca and each participant should bring a laptop if they wish to see examples during the workshop Places must be pre booked for this meeting at the extra cost of 60 please specify if you wish to register for this meeting in section 3 of the registration process Student Satellite Symposium There will be a satellite meeting on Sunday from 2 30pm 7 30pm specifically for students to present oral presentations to an audience consisting mainly of other students and post docs A selection of these presentations will be asked to present to the main conference and all other student presentations will be presented as posters at the main conference For scholarship recipients all the costs of this satellite meeting will be covered in the scholarship awards please see below for further information other delegates are also encouraged to attend Cost 60 When submitting your abstract within the submission system please select if you wish it to be considered for the Student Conference in addition to the Main Conference you will find a tick box within the submission system Systems Genetics Workshop The Systems Genetics workshop will be held on Monday the 16 th from 5 30 until 8 30 pm in the Sala Menor The aim of this workshop is to familiarize current and potential users with two systems genetics platforms and their associated tools The two reference populations GRPs are the Collaborative Cross and Diversity Outbred populations The course will introduce and facilitate utilization of GRPs to address complex biological questions Syllabus items include Introduction to GRPs

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  • International Mammalian Genome Society
    system In addition please register on this site and choose Direct bill in the payment section and you will not need to pay when you register Finances can be sorted out after the scholarship awards are given You should ALSO submit your abstract on line by the deadline As in previous years you must be an International Mammalian Genome Society member to receive financial aid The membership rate for students and post docs with paper copy of the journal Mammalian Genome is US 49 per calendar year and US 30 for students and post docs who do not wish to receive the journal To become a member you can apply at http www imgs org Applications for membership and aid can be processed simultaneously IMGS Student Scholarship Sponsors Funding for student scholarships was made possible by 2R13HG002394 from NHGRI and NICHD at NIH and from Mouse News Letter Ltd Scholarship Awards through the COST Action SYSGENET The COST Action SYSGENET BM 0901 will support the attendance of young scientists from COST countries http www cost eu about cost cost countries Interested applicants are invited to submit their application with the following required documents until July 27 2013 by email to

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  • International Mammalian Genome Society
    consistency a member of The International Committee on Standardized Genetic Nomenclature for Mice will be editing all submitted abstracts for the proper use of gene and protein nomenclature No changes other than nomenclature usage will be made Corrected abstracts will be sent back to authors for review Please refer to the Mouse Genome Informatics MGI website for official mouse nomenclature and the MGI Nomenclature Homepage under Additional Resources for links to the HUGO Gene Nomenclature and the Rat Genome Database websites Nomenclature for other species can be found at NCBI Entrez Gene Student posters will once again be judged for nomenclature and a prize awarded for Nomenclature Excellence Presentation Guidelines Oral Presentations Checking in your Presentation Each presenter should check in his her presentation at least four hours before he she is due to present It is recommended that you bring your presentation on a USB memory stick Presenters do not need to bring a laptop as presentations will be loaded onto a main computer Only computer presentations can be accepted There will be no facilities for 35mm slide projection or overhead projection NB If there are movie clips included in your presentation you must bring the original movie files as well as the PowerPoint file otherwise your movie clips will not run Presentation Timing Please make your way to the room in which you are presenting a minimum of ten minutes prior to the start of the session This will allow you to meet with the Chair of your session Keeping to Time The program is very tight and it is imperative that the sessions run on time Poster Presentations Authors are reminded that the dimensions of the displays are 90 cm wide x 120 cm tall Please note that a supply of Velcro will be available at the

    Original URL path: http://www.imgs.org/Archive/website/IMGS2013/abstracts.html (2016-02-17)
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  • International Mammalian Genome Society
    services are available from the Conference Organizer Darla Miller A free 50 word entry into the Final Program and your company logo and website link will be carried on the conference website on the sponsors page PLENARY SPEAKERS 1 500 As a sponsor of the organizing committee s selection of a speaker your support will be acknowledged by the Chairperson at the start of the session and your logo will be displayed on the opening slide and in the final program POSTER BOARDS 650 Your logo will appear on each poster board beside the poster number and the IMGC logo SOCIAL PROGRAM Support of all or parts of the evening social program is sought Options include Welcome Reception on Sunday 1 250 Poster Session 1 000 Conference dinner 2 500 CONFERENCE BAGS 1 800 The meeting has a tradition of supplying quality conference bags to delegates You can either supply the bags with the organizer s approval or we can source them for you and your organization will pay for them Your logo one color will be carried alongside the meeting logo NOTEPADS PENS INSERTS IN BAGS Your own pens notepads or one piece of lightweight literature can be inserted into each delegate bag at the following costs per item Notepads only 200 Pens only 200 Notepads and Pens 350 Inserts in Bags 400 BADGE LANYARDS 950 Your company logo will be printed on the badge lanyards ribbons which will be given to all delegates as they arrive at the registration desk ADVERTISING Advertising opportunities will be available in the Final Program and Book of Abstracts which will be given to every delegate who attends the conference This advert must arrive with the Conference Organizers by August 15 2013 Full Color Page Outside Back 1 500 Inside Front 1 300

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  • International Mammalian Genome Society
    Chamartin Train Station be careful because there are two train stations in Madrid and the only one that has trains to Salamanca is the Chamartin station The taxi ride will take a half an hour and should be between 25 and 30 depending on your luggage Then take the train to Salamanca There are 6 departures from Madrid Chamartin to Salamanca daily and the train ride will take two and a half hours The train departure times are as follows Madrid Salamanca Salamanca Madrid 08 45 hours 11 00 hours 13 45 hours 15 45 hours 19 45 hours 21 30 hours 6 00 hours 7 45 hours 12 45 hours 15 50 hours 18 10 hours 19 53 hours Orientative prices One Way ticket 14 15 Euros Return ticket 25 50 Euros Alternatively you could take the metro from the airport to Chamartin train station It costs 1 Euro and takes about 30 minutes You will have to change lines at Nuevos Ministerios 2 BY BUS After you arrive at the Barajas Airport take a taxi from the airport to Sur Mendez Alvaro Bus Station or the Auto res Bus Station The taxi ride will last approximately a half an hour and should be between 25 and 30 depending on how much luggage you have At the bus station take an express bus to Salamanca you have one every hour From 07 00 to 22 00 hours Monday to Satudary From 08 00 to 23 00 hours Sunday Orientative prices One Way ticket 16 Return ticket 26 Alternatively you could take the metro from the airport to the metro stop Plaza Sur Mendez Alvaro The metro costs 1 Euro and it will take you about 40 minutes You will have to change lines at the metro stop Nuevos Ministerios 3 BY CAR If you prefer to come to Salamanca by car from Madrid you need to get the AP6 motorway leave AP6 at exit 81 and take AP51 to Salamanca Although Salamanca has a small airport at present it is only connected with Barcelona airport with 1 flight day on Iberia Airlines arriving at Salamanca late evening departing from Salamanca early morning Besides Salamanca the two closest airports to this city are Valladolid and Madrid Valladolid airport is the closest one 115 km from Salamanca but it does not have easy direct ground connection with Salamanca So unless you have someone to pick you up or takes you there flying to Valladolid is not a good choice Valladolid airport is flight connected with Barcelona and Valencia Iberia and with London Stansted Ryanair However the Barcelona Valladolid flights are quite expensive and Valladolid London Stansted while cheap are not very convenient times The Venue of the Symposium is the Hospedería del Colegio Fonseca Calle Fonseca 2 37002 Salamanca SALAMANCA AIRPORT You can fly directly to Salamanca Airport but it is a very small airport with very limited flights VALLADOLID SALAMANCA Salamanca is 115 Km southeast of Valladolid and there is

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