David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Spring Quarter 2008

Mondays, 11am - 12pm, Gonda Building First Floor Conference Room, 1357

Mon, Apr 07
Genetics of age-related maculopathy
Michael B. Gorin, MD, PhD, Harold and Pauline Price Professor of Ophthalmology, David Geffen School of Medicine and Chief, Retinal Disorders and Ophthalmic Genetics, University of California, Los Angeles
Contact & Intro: Paivi Pajukanta, ext 72011
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ABSTRACT: This presentation will review the 20 year path that has led to the identification of multiple genes and variants that contribute to ARM susceptibility. The roles of linkage analysis, candidate gene and genome-wide case control association studies will be presented. Implications of these findings and the need for additional research towards the understanding of the pathogenesis of ARM will be discussed in the context of the study of other complex genetic disorders.

LITERATURE:
  1. Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. Weeks DE, Conley YP, Tsai HJ, Mah TS, Schmidt S, Postel EA, Agarwal A, Haines JL, Pericak-Vance MA, Rosenfeld PJ, Paul TO, Eller AW, Morse LS, Dailey JP, Ferrell RE, Gorin MB. American Journal of Human Genetics 75:174-89 (2004).
  2. Susceptibility genes for age-related maculopathy on chromosome 10q26. Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB. American Journal of Human Genetics 77: 389-407 (2005).
  3. CFH, ELOVL4, PLEKHA1, and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. Conley YP, Jakobsdottir J, Mah, TS, Weeks, DE, Klein, R, Kuller L, Ferrell RE, Gorin MB. Human Molecular Genetics 15: 3206-18 (2006).
  4. A clinician’s view of the molecular genetics of age-related maculopathy. Gorin, MB. Archives of Ophthalmology 125: 21-9 (2007).
Mon, Apr 14
Mapping in non-human genomes - recent successes
Claire Wade, PhD, Senior Research Scientist, Center for Human Genetic Research, Massachusetts General Hospital
Contact & Intro: Eleazar Eskin
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ABSTRACT: Excellent gene mapping tools are available for mice and dogs and are in development for horses. What can these species teach us about the mechanisms of gene function? This talk will describe some wonderful tools that are available for analysis in non-human species and will discuss the outcomes from recent gene mapping work.

LITERATURE:
  1. A sequence-based variation map of 8.27 million SNPs in inbred mouse strains. Frazer KA, Eskin E, Kang HM, Bogue MA, Hinds DA, Beilharz EJ, Gupta RV, Montgomery J, Morenzoni MM, Nilsen GB, Pethiyagoda CL, Stuve LL, Johnson FM, Daly MJ, Wade CM, Cox DR. Nature 448: 1050-3 (2007). Epub Jul 29 (2007).
  2. Efficient mapping of mendelian traits in dogs through genome-wide association. Karlsson EK, Baranowska I, Wade CM, Salmon Hillbertz NH, Zody MC, Anderson N, Biagi TM, Patterson N, Pielberg GR, Kulbokas EJ 3rd, Comstock KE, Keller ET, Mesirov JP, von Euler H, Kämpe O, Hedhammar A, Lander ES, Andersson G, Andersson L, Lindblad-Toh K. Nature Genetics 39:1321-8 (2007). Epub Sep 30 (2007).
  3. Duplication of FGF3, FGF4, FGF19 and ORAOV1 causes hair ridge and predisposition to dermoid sinus in Ridgeback dogs. Salmon Hillbertz NH, Isaksson M, Karlsson EK, Hellmén E, Pielberg GR, Savolainen P, Wade CM, von Euler H, Gustafson U, Hedhammar A, Nilsson M, Lindblad-Toh K, Andersson L, Andersson G. Nature Genetics 39:1318-20 (2007). Epub Sep 30 (2007).
Mon, Apr 28
Searching for genetic determinants of common disease – a view from the outside looking in
Colin A. McKenzie, MBBS DPhil, Senior Lecturer, Tropical Metabolism Research Unit, University of the West Indies, Mona, Kingston, Jamaica
Contact & Intro: Chiara Sabatti, ext 49567
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ABSTRACT: The identification of genes responsible for simple Mendelian disorders appears, currently, to be a rather mundane task. A considerable amount of attention is now being focused on common, chronic non-communicable diseases. Among these diseases there are few that have as high a priority as hypertension, a disorder for which there is only a limited understanding of the underlying pathophysiology and for which there is a high lifetime risk and a significant association with morbidity and mortality. Rapid advances in technology and the success of large-scale public projects such as the HapMap have continued to fuel the belief that there will be reproducible identification of influential genetic variants in the near-term despite the complete absence of such results to date.

While the resources that are becoming available in the genome era appear to have the potential to accelerate the pace of gene discovery it is becoming clear that in order to achieve success for common disease, we will not only have to utilize the new technological resources, but we will also have to leverage talents available across the global knowledge network.

The approaches which have been used in the study of sickle cell disease may be instructive in this regard; considerable advances in our molecular and conceptual understanding of genetic determinants of disease have been achieved through work which has utilized this global knowledge base across the African Diaspora. It is possible that studies of hypertension conducted using this framework might ultimately yield similar successes.

In this seminar I will describe approaches that we are taking to identify determinants of hypertension risk in African-origin populations. The context within which this work is taking place will be illustrated by both a brief survey of projects being carried out at the TMRU and by work that we are conducting on genetic modifiers of sickle cell disease.

LITERATURE:
  1. The prevalence of hypertension in seven populations of west African origin. Cooper R, Rotimi C, Ataman S, McGee D, Osotimehin B, Kadiri S, Muna W, Kingue S, Fraser H, Forrester T, Bennett F, Wilks R. American Journal of Public Health 87:160-8 (1997).
  2. Classical sickle beta-globin haplotypes exhibit a high degree of long-range haplotype similarity in African and Afro-Caribbean populations. Hanchard N, Elzein A, Trafford C, Rockett K, Pinder M, Jallow M, Harding R, Kwiatkowski D, McKenzie C. BioMed Central Genetics 10:52 (2007).
  3. Angiotensin I-converting enzyme polymorphisms, ACE level and blood pressure among Nigerians, Jamaicans and African-Americans. Bouzekri N, Zhu X, Jiang Y, McKenzie CA, Luke A, Forrester T, Adeyemo A, Kan D, Farrall M, Anderson S, Cooper RS, Ward R. European Journal of Human Genetics 12:460-8 (2004).
Mon, May 05
Using mouse coat color mutants to explore the functions of Myosin V in melanocytes and neurons
John A. Hammer, PhD, Principal Investigator, Laboratory of Cell Biology, National Heart, Lung, and Blood Institute (NHLBI), Bethesda
Contact & Intro: Esteban Dell'Angelica, ext 63749
Mon, May 12
Insights into receptor-mediated endocytosis from disease
Linton M. Traub, PhD, Associate Professor, Department of Cell Biology and Physiology, University of Pittsburgh
Contact & Intro: Esteban Dell'Angelica, ext 63749
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ABSTRACT: A fundamental feature of receptor-mediated endocytosis is cargo selectivity. An array of structurally unrelated sorting signals are known that tag cell surface proteins for internalization. Recent work has dissected how these various signals are decoded by the endocytic machinery to account for cargo selectivity. In particular, the FXNPXY-type of sorting signal that is present in most, but not all, members of the low density lipoprotein (LDL) receptor superfamily is recognized by two endocytic proteins that can bind simultaneously to the receptor, clathrin, the AP-2 adaptor protein and to the plasma membrane-enriched lipid phosphatidylinositol 4,5-bisphosphate. Genetic analysis of patients with a rare autosomal recessive form of hypercholesterolemia has provided new insight into endocytic mechanisms, not only in humans but in invertebrates as well.

LITERATURE:
  1. Adaptor protein Disabled-2 modulates low density lipoprotein receptor synthesis in fibroblasts from patients with autosomal recessive hypercholesterolaemia. Eden ER, Sun X-M, Patel DD, Soutar AK. Human Molecular Genetics 16:2751–2759 (2007).
  2. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein. Garcia CK, Wilund K, Arca M, Zuliani G, Fellin R, Maioli M, Calandra S, Bertolini S, Cossu F, Grishin N, Barnes R, Cohen JC, Hobbs HH. Science 292:1394-1398 (2001).
Fri, May 16
Special Talk: Friday, May 16, 1-2pm, Neuroscience Research Building Auditorium
Zebrafish model system for immune dysfunction and drug treatment
Nikolaus Trede, MD, PhD, Assistant Professor of Pediatrics, Investigator, The Huntsman Cancer Institute, University of Utah
Contact & Intro: Talal Chatila, MD, ext 56481
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ABSTRACT: The focus of our lab is centered on modeling human diseases of the immune system in zebrafish. To accomplish this task we exploit the advantages zebrafish offer (small size, optical transparency, favorable genetics) and employ a variety of tools, including genetic screens using transgenic lines of zebrafish. We are trying to understand increased susceptibility to infection, frequently encountered in pediatric practice, by dissecting signaling pathways involved in the primary and anticipatory defense against microbes, innate and adaptive immunity. Genes of pivotal importance for T cell development, whose absence can lead to severe immunodeficiencies, are identified in the first week of development through visual inspection of mutagenized zebrafish for lack of T cells that carry the transgenic fluorochrome GFP. We also monitor mutagenized transgenic zebrafish for T cell infiltration into target tissues (such as the pancreas), as a surrogate marker for T cell mediated autoimmunity -– pancreatic T cell infiltration is characteristic for autoimmune-mediated type I diabetes. Finally, T cell expansion in the thymus is a hallmark for T cell acute lymphatic leukemia (T-ALL), and can be easily monitored through in-vivo fluorescent microscopy of mutagenized zebrafish. Positional cloning of genes responsible for mutant phenotypes will identify actors involved in immune pathology. We have identified and phenotypically verified mutants with leukemic phenotypes, and characterized and genetically mapped a number of immunodeficient mutants.

We have also initiated a screen of a large chemical library for compounds with anti-T cell activity that is easy to read out using our transgenic zebrafish line where all T cells are GFP positive. If a small molecule causes absence of fluorescent T cells, it has potential to be an active compound in the treatment of T-ALL and/or T cell-mediated autoimmunity. We have identified several compounds with this characteristic, and one of these molecules kills human T leukemia cells, but not B cell leukemia or kidney cells. Testing in mice is ongoing to develop this compound into a clinically useful drug.

This effort will establish lower vertebrate models for human disease and will represent a platform for screens tailored to identify modifying genes and drugs that alter disease outcome.

LITERATURE:
  1. In vivo tracking of T cell development, ablation, and engraftment in transgenic zebrafish. Langenau DM, Ferrando AA, Traver D, Kutok JL, Hezel JP, Kanki JP, Zon LI, Look AT, Trede NS. Proceedings of the National Academy of Sciences 101:7369-74 (2004).
  2. Network of coregulated spliceosome components revealed by zebrafish mutant in recycling factor p110. Trede NS, Medenbach J, Damianov A, Hung LH, Weber GJ, Paw BH, Zhou Y, Hersey C, Zapata A, Keefe M, Barut BA, Stuart AB, Katz T, Amemiya CT, Zon LI, Bindereif A. Proceedings of the National Academy of Sciences 104:6608-13 (2007).
  3. Immunology and Zebrafish: Spawning New Models of Human Disease. Meeker, ND, Trede, NS. Developmental & Comparative Immunology 32:745-57 (2008).
Mon, May 19
A chemical approach to pluripotency and reprogramming
Sheng Ding, PhD, Associate Professor, Departments of Chemistry and Cell Biology, Scripps Research Institute, La Jolla
Contact & Intro: Guoping Fan, ext 70439
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ABSTRACT: Recent advances in stem cell biology may make possible new approaches for the treatment of a number of diseases. A better understanding of the molecular mechanisms that control stem cell fates as well as an improved ability to manipulate them are required. Toward these goals, we have developed and implemented chemical and functional genomic tools, including high throughput cell-based phenotypic screens of arrayed chemical, cDNA and RNAi libraries, genomic and proteomic profiling of homogenous undifferentiated/self-renewing or selectively differentiated cell populations under chemically defined conditions, and in-depth biochemical and functional assays in vitro and in vivo, to identify and further characterize small molecules and genes that can control stem cell fate in various systems. This talk will provide specific examples of stem cell discovery efforts in my lab that have advanced our ability and understanding toward controlling embryonic stem cell fate and reprogramming to pluripotency.

LITERATURE:
  1. A small molecule that sustains self-renewal of embryonic stem cells. Chen S, Zhang Q, Do J-T, Yao S, Yan F, Peters EC, Schöler HR, Schultz PG, Ding S. Proceedings of the National Academy of Sciences 103:17266-17271 (2006).
  2. A small molecule synergist of the Wnt signaling pathway. Zhang Q, Major B, Takanashi S, Camp ND, Nishiya N, Ginsberg M, Schultz PG, Moon RT, Ding S. Proceedings of the National Academy of Sciences 104:7444 (2007).
Mon, Jun 02
Family-based tests for association on the X chromosome
Eden Martin, PhD, Professor of Medicine and Director, Center for Genetic Epidemiology and Statistical Genetics, Miami Institute for Human Genomics, University of Miami Miller School of Medicine
Contact & Intro: Chiara Sabatti, ext 49567
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ABSTRACT: Family-based tests of association provide alternative approaches to case-control tests which use unrelated individuals. While family-based tests of association are widely used, their primary development has focused on analysis of autosomal markers. We have developed three novel tests for association for the X-chromosome based on existing tests: X-APL, X-LRT and X-QTL. X-APL and X-LRT are designed for analysis of binary traits in nuclear families, while X-QTL is designed for analysis of continuous traits. We describe these tests, and show results from simulations to evaluate power and type I error. We further demonstrate their utility and compare the methods to analysis stratifying by sex in a Parkinson disease family dataset. These results demonstrate that these are viable approaches to analysis of association of X-chromosome markers in family data.

LITERATURE:
  1. X-APL: An improved family-based test of association for the X chromosome. Chung RH, Morris RW, Li Z, Li Y-J, Martin ER. American Journal of Human Genetics 80:59-68 (2007).
  2. Response to Ding and Lin. Letters to the Editor. Chung RH, Morris RW, Martin ER. American Journal of Human Genetics 82:530-531 (2008).
  3. X-LRT: A likelihood approach to estimate genetic risks and test association with x-linked markers using a case-parents design. Zhang L, Li Y-J, Chung RH, Martin ER, Morris R. Genetic Epidemiology 32:370-380 (2008).
Fri, Jun 27
David L. Rimoin Lectureship in Medical Genetics Education: 11am - 12pm, Neuroscience Research Building Auditorium
The developmental genome anatomy project (DGAP): a cytogenetic approach to gene discovery in the genome era
Cynthia Morton, PhD, William Lambert Richardson Professor, Department of Obstetrics, Gynecology and Reproductive Biology, Harvard Medical School Director, Cytogenetics, Brigham and Women's Hospital, Program Director, Developmental Genome Anatomy Project, Research Director of the Center for Uterine Fibroids
Contact & Intro: David Rimoin, 323-423-4461

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