Mouse Genetics 2011: Meeting Report
Total Page：16
File Type：pdf, Size：1020Kb
Mamm Genome (2012) 23:225–231 DOI 10.1007/s00335-012-9390-6 MEETING REPORT Mouse genetics 2011: meeting report John K. Simmons • Jessica C. Amlin-Van Schaick • Thomas R. Geiger • Karlyne Reilly • Kent Hunter • Beverly A. Mock Received: 9 December 2011 / Accepted: 5 January 2012 / Published online: 23 February 2012 Ó Springer Science+Business Media, LLC (outside the USA) 2012 Introduction Overarching themes: highlights from the keynote address and Verne Chapman Lecture Mouse Genetics 2011 was organized by the Genetics Society of America in Washington, DC, as a joint meeting Francis Collins, director of the US National Institutes of of the 25th International Mammalian Genome Conference Health, delivered the keynote address entitled ‘‘Mickey, and the 10th Complex Traits Community Meeting.1 Mendel, and the Medical Magic of Mouse Genetics.’’ In his While celebrating the incredible progress made by the talk, Collins provided a brief overview of the current large field in the last 25 years, this year’s joint meeting illumi- NIH-sponsored efforts related to mouse models for nated the incredible possibility for the future. As genome- understanding human disease and biology, including the level studies have revolutionized the pace for discovering $47.2 million Knockout Mouse Project (KOMP, kom- the genetic underpinnings of human disease, an unprece- p.org), which had to date already generated 8,199 knockout dented opportunity exists for integrating those findings embryonic stem (ES) cells; the newly announced $110 with model organism genetics to achieve the common million phenotyping project designed to generate compre- goals of both understanding and improving human disease. hensive phenotypic data on knockout mice generated in The keynote address, Verne Chapman Lecture, plenary KOMP (called KOMP2); and the expansion of the Ency- presentations, and numerous platform talks all described clopedia of DNA Elements (ENCODE) project to include work highlighting advances where the interface of mouse the mouse genome using funds from the American models and human genetics has led to an extraordinary Recovery and Reinvestment Act (ARRA). The KOMP and understanding of the mechanisms of a disease or propelled KOMP2 projects join with European and Canadian efforts a discovery into clinical development. to make up the International Knockout Mouse Consortium. Collins then went on to discuss work from his own labo- ratory that is focused on three projects where mouse models are being employed to understand the genetics of human disease and develop medical interventions. In one J. K. Simmons Á T. R. Geiger Á K. Hunter Á B. A. Mock project, a knockout mouse for Igfbp2 had been created Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of using a conditional-ready construct from the EUCOMM Health, Bethesda, MD 20892, USA (European Conditional Mouse Mutagenesis Program) to explore the function of this gene, which had been previ- J. C. Amlin-Van Schaick Á K. Reilly ously identified by his lab and collaborators in a genome- Mammalian Genetics Cancer Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, USA 1 There were 375 participants from approximately 19 countries. The B. A. Mock (&) meeting was partially sponsored by the IMGS, the GSA, NHGRI and Laboratory of Cancer Biology and Genetics, Bldg. 37, Rm. 3146, NICHD of the NIH, The Ellison Medical Foundation, and Mouse News 37 Convent Drive, MSC 4258, Bethesda, MD 20892-4258, USA Letter, Ltd. The meeting program and abstracts are available online at e-mail: [email protected] http://www.imgs.org and http://www.mousegenetics2011.org/. 123 226 J. K. Simmons et al.: Mouse genetics 2011 meeting report wide association study (GWAS) of type II diabetes. He also Unraveling disease: genetics of physiology described work in his lab for identifying possible asthma and development susceptibility genes that has made use of the pre-Collabo- rative Cross Mouse strains. In his last example, Collins Many of the talks and posters at the meeting demonstrated detailed work toward understanding the rare accelerated- how mouse models were being used to give insight into aging disease Hutchinson-Gilford progeria, which has been congenital human diseases such as the neurodegenerative linked to a heterozygous mutation in the LMNA gene. This diseases Charcot-Marie-Tooth, Parkinson’s, and ALS; mutation leads to a shortened protein by introducing a congenital disorders such as Rett syndrome, autism, Down splice donor site. In this effort a transgenic mouse for the syndrome, hereditary hemorrhagic telangiectasia, and mutant Lmna gene was used to test potential drug treat- ophthalmo-acromelic syndrome; and normal and aberrant ments for children with this disease. Collins happily immune system function, including the autoimmune dis- reported that farnesyl transferase inhibitors, which had order lupus. been shown to be effective in his mouse model, had been Two plenary talks from human geneticists Han Brunner brought into the clinic, and a phase II clinical trial was now and David Valle provided context for how new genome into its second year with 40 children enrolled. The work and exome sequencing platforms are dramatically reshap- presented in this keynote exemplified the usefulness of the ing the identification of candidate gene polymorphisms in mouse as a model of human disease not only for increasing rare hereditary developmental and intellectual disorders. our understanding but also for translating molecular dis- Both speakers underscored that while genomic technolo- coveries into useful therapeutics. gies may be rapidly accelerating the identification of gene William Dove of the University of Wisconsin gave the polymorphisms of these diseases, the furthering of the Verne Chapman Lecture. As the concluding talk of the biological understanding for these candidate genes will be conference, Dove provided a unique perspective on the accomplished almost exclusively with mouse models. advances made in molecular biology, enabled by model The application of a systems biology approach to organism genetics, and detailed some of the remarkable understanding the complex signaling cascades of the opportunities for future work to answer previously intrac- immune system was presented during a plenary talk by table questions of biomedical research. Aviv Regev. The experimental paradigm of ‘‘observe ? Beginning with a quote by the famed naturalist John model ? perturb’’ was demonstrated in work aimed at Muir, ‘‘When we try to pick out anything by itself, we find understanding the gene regulatory circuitry of toll-like it hitched to everything else in the Universe,’’ Dove receptors (TLR) in primary mouse dendritic cells. Regev described how the recent emergence of systems biology explained that her findings show many transcriptional approaches is reflective of the long-standing principle of regulators downstream of an individual TLR, and the holism in biology. Dove enumerated seven themes for activation of these regulators can vary dramatically and moving biomedical research forward with mouse models: yield quite different transcriptional changes based upon the reductionism to holism, dissecting the genetic system, type of immune stimulation. In a particular example, two phenotyping and rephenotyping, genome-wide mutational cell cycle genes (Plk2 and Plk4) had been co-opted in the analysis, somatic mutations meet epigenetics, and diversity nondividing dendritic cells to modulate the overall antiviral drives genetics. Reflecting on work in his own lab, Dove transcriptional response. described how one of the most widely used mouse models The plenary talk by Miriam Meisler focused on the of cancer, the ApcMin mouse, was identified by careful mechanism of neurodegeneration in the pale tremor mutant observation of offspring from the mutagenesis screen as mouse, which was found to have a mutation in the Fig4 having pale feet, which was later found to be a result of gene. Fig4 is involved in the PI3K pathway, and its blood loss from cancerous intestines. Dove also detailed mutation leads to spongiform degeneration in the central on-going work in his lab, including a rat mutagenesis and peripheral nervous systems of mutant mice. The phe- screen that identified a Pirc mutation that leads to tumors notype of the Fig4 mutant mouse was similar to that of of the colon, in contrast with the small-intestine tumors patients with Charcot-Marie-Tooth (CMT) syndrome, and seen in the ApcMin mouse. Work focusing on epigenetic sequencing of this gene in patient samples found several changes in carcinogenesis was also discussed. Advocating Fig4 mutations. In the severely neurodegenerative CMT4F for the sharing of discoveries openly with the greater sci- disease variant, all 16 patients sequenced had FIG4 entific community, Dove pointed to the 1,100 ? publica- mutations, with 14 having mutations leading to the same tions from researchers around the world using the ApcMin I41T substitution. Neurodegenerative diseases were the model, which has been openly distributed via The Jackson focus of a number of posters as well, including a-synuclein Laboratory for many years. function in Parkinson’s disease (123C Cabin and 125B 123 J. K. Simmons et al.: Mouse genetics 2011 meeting report 227 Casey), loss of Tsg101, as a model for neurodegenerative Cerebellar dysmorphology seen in this model demonstrated pathology due to endo/lysosomal sorting dysfunction that a single