David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Spring Quarter 2006

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

Mon, Apr 03
The signature of recent directional selection in polymorphism data
Molly Przeworski, PhD, Assistant Professor, Department of Human Genetics, University of Chicago
Contact & Intro: Chiara Sabatti, PhD, ext 49567
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ABSTRACT: Genetic variation among extant individuals can be used to identify regions of the genome that underlie recent adaptations. This principle has motivated numerous efforts to map the genetic basis of adaptations by looking for the signature of positive selection in polymorphism data. To date, these searches have been guided by a simple model, in which a rare, co-dominant allele rapidly increases to fixation in a random-mating population of constant size. However, many of these assumptions are unrealistic, especially for humans. We have therefore characterized the signature of selection under more general models of selection. I will present the results of these studies, and discuss the implications for the interpretation of genome scans.

LITERATURE:
  1. The Signature of Positive Selection on Standing Genetic Variation. Przeworski M, Coop G, Wall JD. Evolution 59: 2312–2323 (2005).
  2. Absence of the TAP2 Human Recombination Hotspot in Chimpanzees. Ptak SE, Roeder AD, Stephens M, Gilad Y, Pääbo S, Przeworski M. PLoS Biology 2: 0849-0855 (2004).
Mon, Apr 10
DNA methylation in neural development and stem cell differentiation
Guoping Fan, PhD, Assistant Professor, Department of Human Genetics, UCLA
Contact & Intro: Chris Jamieson, PhD, ext 62597
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ABSTRACT: DNA methylation is a major epigenetic factor involved in gene regulation, genomic imprinting, and genome stability. Alterations in DNA methylation machinery are found to be associated with human diseases including cancer and mental retardation disorders such as Fragile-X, ICF, and Rett Syndromes. Our research work focuses on the role of DNA methylation in the development of the mammalian nervous system as well as in lineage-specification during in vitro differentiation of embryonic stem (ES) cells. In this seminar, I will discuss the important role for DNA methylation in neural stem cell differentiation, neuronal survival and maturation. Data will also be presented to show that dynamic methylation changes occur during in vitro ES cell differentiation, supporting the hypothesis that DNA methylation-related mechanisms play a key role in regulating stem cell differentiation.

LITERATURE:
  1. DNA methylation controls the timing of astrogliogenesis through regulation of JAK-STAT signaling. Fan G, Martinowich K, Chin M, He F, Fouse S, Hutnick L, Hattori D, Ge W, Shen Y, Wu H, ten Hoeve T, Shuai K, Sun Y. Development 132:3345-56 (2005).
  2. Dynamic expression of de novo DNA methyltransferases Dnmt3a and 3b in the central nervous system. Feng J, Chang H, Li E, Fan G. Journal of Neuroscience Research 79:734-746 (2005).
  3. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Martinowich K, Hatorri D, Wu H, Fouse S, He F, Hu Y, Fan G, Sun Y. Science 302:890-893 (2003).
Mon, Apr 17
Microarrays, mouse models, and mechanisms: dissecting lung disease
David Erle, MD, Professor, Pulmonary and Critical Care Unit, University of California, San Francisco
Contact & Intro: Chris Jamieson, PhD, ext 62597
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ABSTRACT: DNA microarrays are frequently used for investigating human disease. This approach is leading to the identification of novel disease-associated gene expression changes, but complementary approaches are required to address limitations of the approach. First, humans and human diseases are heterogeneous, which increases "noise" and makes it difficult to detect changes. Second, appropriate human tissues may not be available for analysis. Third, follow-on experiments necessary to establish cause and effect and test novel therapeutic targets generally cannot be performed in human subjects. As an alternative, we have used microarrays to study gene expression in many mouse models of human lung diseases, including asthma, chronic obstructive lung disease, and lung infections. This has resulted in the identification of relatively small sets of genes that are associated with specific pathological features and molecular mechanisms, and is clarifying the relationships between mouse models and human diseases.

LITERATURE:
  1. Airway inflammation and remodeling in asthma. Fahy JV, Corry DB, Boushey HA. Current Opinion in Pulmonary Medicine 6:15–20 (2000).
  2. Direct effects of interleukin-13 on epithelial cells cause airway hyperreactivity and mucus overproduction in asthma. Kuperman DA, Huang X, Koth LL, Chang GH, Dolganov GM, Zhu Z, Elias JA, Sheppard D, Erle DJ. Nature Medicine 8:885-889 (2002).
  3. Dissecting asthma using focused transgenic modeling and functional genomics. Kuperman D, Lewis C, Woodruff P, Rodriguez M, Yang Y, Dolganov G, Fahy J, Erle D. Journal of Allergy and Clinical Immunology 116:305-311 (2002).
Mon, Apr 24
Gene association studies in coronary artery disease and stroke
John P. Kane MD, PhD, Professor of Medicine, Professor of Biochemistry and Biophysics, University of California, San Francisco
Contact & Intro: Paivi Pajukanta, MD, PhD, ext 72011
Mon, May 01
Expression cloning of signaling molecules in immune cell activation pathways
Joel L. Pomerantz, PhD, Assistant Professor, Department of Biological Chemistry and Institute for Cell Engineering, Johns Hopkins University School of Medicine
Contact & Intro: Chris Jamieson, PhD, ext 62597
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ABSTRACT: Our laboratory studies the molecular machinery used by cells to interpret extracellular signals and transduce them to the nucleus to effect changes in gene expression. This process is of fundamental biological importance. The accurate response to extracellular signals results in a cell's decision to proliferate, differentiate, or die, and it is critical for normal development and physiology. The disregulation of this machinery underlies the unwarranted expansion or destruction of cell numbers that occurs in human diseases like cancer, autoimmunity, hyperinflammatory states, and neurodegenerative disease.

Currently, we study signaling pathways that are important in innate immunity, adaptive immunity, and in cancer, paying particular attention to pathways that regulate the activity of the pleiotropic transcription factor NF-kB.

LITERATURE:
  1. Pomerantz JL, Denny EM, Baltimore D. CARD11 mediates factor-specific activation of NF-kB by the T cell receptor complex. EMBO J. 21:5184-5194 (2002).
Wed, May 03
Special Guest Seminar, 9:30am - 10:30am
Identifying Novel Genetic Determinants of Hemostatic Balance
David Ginsburg, MD, James V. Neel Distinguished University Professor of Internal Medicine and Human Genetics, Howard Hughes Medical Institute, University of Michigan Medical School
Contact & Intro: Stephen Young, MD, ext 54934
Mon, May 08
Project management in pharmaceutical industry and an interdisciplinary research approach to Smith-Magenis Syndrome from a parent’s perspective
Charlene Liao, PhD, Product Portfolio Management, Genentech Inc, San Francisco
Contact & Intro: Chris Jamieson, PhD, ext 62597
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ABSTRACT: The Product Portfolio Management group is responsible for leading and managing drug development projects from research phase through product launch. A similar interdisciplinary approach can be taken to the Smith-Magenis Syndrome research. Smith-Magenis syndrome (SMS) is a rare genetic disorder with an estimated birth rate of 1:25,000. It is caused by an interstitial deletion of chromosome 17p11.2, resulting in characteristic and complex pattern of physical, developmental, and behavioral features. The SMS critical region (SMCR) spans about 1 Mb and contains ~ 20 genes, including the RAI 1 (Retinoic acid induced 1) gene whose frameshift and nonsense mutations were identified in five SMS patients. Various mouse models of SMS have been generated, carrying heterozygous deletions of the mouse region syntenic to the SMS critical region and, most recently, carrying the heterozygous knock-out of the RAI-1 gene. The understanding and management of SMS will benefit from interdisciplinary approach with basic research (molecular biology, molecular neurobiology, developmental biology, genetics and genomics), medical professions (pediatrics, human genetics, neurology, psychology, psychiatry, sleep experts, ophthalmology, endocrinology, dentistry etc.), other related professions (special education, speech and language pathology and therapy, occupational therapy, physical therapy and behavior management), parents and patients.

LITERATURE:
  1. Smith-Magenis syndrome (Book chapter). Smith ACM and Gropman A. In “Management of Genetic Syndromes” (2nd edition) ed. Cassidy SB and Allanson JB (2005). Publisher: Wiley-Liss Inc. (ISBN 0-471-30870-6)
  2. Diagnostic FISH probes for del(17)(p11.2p11.2) associated with Smith-Magenis syndrome should contain the RAI1 gene. Vlangos CN, Wilson M, Blancato J, Smith AC, Elsea SH. Am J Med Genet A. 132:278-82 (2005).
  3. Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome. Bi W, Ohyama T, Nakamura H, Yan J, Visvanathan J, Justice MJ, Lupski JR. Hum Mol Genet. 14:983-95 (2005).
  4. Mutations in RAI1 associated with Smith-Magenis syndrome. Slager RE, Newton TL, Vlangos CN, Finucane B, Elsea SH. Nat Genet. 33:466-8 (2003).
Mon, May 15
Exploring the link between interstitial lung disease and mutations in the SFTPC gene
Timothy E. Weaver, MS, PhD, Professor of Pediatrics and Co-Director, Division of Pulmonary Biology, Cincinnati Children's Research Foundation, Cincinnati Children's Hospital Medical Center
Contact & Intro: Esteban dell ‘Angelica, PhD, ext 63749
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ABSTRACT: ERAD (endoplasmic reticulum associated degradation) is a cytoprotective pathway that surveys newly synthesized proteins in the endoplasmic reticulum (quality control) and selects terminally misfolded proteins for degradation by the proteasome. When the ERAD pathway is overwhelmed, misfolded protein accumulates leading to cell injury or death. Many diseases have been linked to genetic mutations that cause misfolding and accumulation of cytotoxic proteins within the cell.

Surfactant protein C (SP-C), a protein that is synthesized and secreted by alveolar epithelial cells, plays an important role in maintaining alveolar structure and the integrity of the air-blood barrier. Mutations in the gene encoding SP-C (SFTPC) were recently linked to the development of interstitial lung disease (ILD) in human patients.

The overall goal of research in the Weaver lab at Cincinnati Children’s Hospital Medical Center is to identify molecular pathways that link protein misfolding to ILD and to develop novel treatment strategies for this fatal disease.

LITERATURE:
  1. Expression of a Human Surfactant Protein C Mutation Associated with Interstitial Lung Disease Disrupts Lung Development in Transgenic Mice. Bridges JP, Wert SE, Nogee LM, Weaver TE. The Journal of Biological Chemistry 278:52739–52746 (2003).
  2. Adaptation and increased susceptibility to infection associated with constitutive expression of misfolded SP-C. Bridges JP, Xu Y, Na CL, Wong HR, Weaver TE. The Journal of Cell Biology 172:393-407 (2006).
  3. Hydrophobic Surfacant Proteins in Lung Function and Disease. Whitsett JA, Weaver TE. New England Journal of Medicine 347: 2141-2148 (2002).
Mon, May 22
Modeling the structure and dynamics of gene regulatory networks
Reka Albert, PhD, Assistant Professor, Department of Physics, Pennsylvania State University
Contact & Intro: Chiara Sabatti, PhD, ext 49567
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ABSTRACT: Interaction between genes and gene products forms the basis of essential biological processes like signal transduction, cell metabolism or embryonic development. Recent experimental advances helped uncover the structure of many gene control networks, creating a surge of interest in the dynamical description of gene regulation. Traditionally genetic and protein interactions are modeled by differential equations based on reaction kinetics, but these studies are greatly hampered by the sparsity of known kinetic detail. As an alternative, qualitative models assuming a small set of discrete states for gene products, or employing combinations of discrete and continuous dynamics, are gaining acceptance. Many results also suggest that the interaction topology plays a determining role in the dynamics of regulatory networks and there is significant robustness to changes in kinetic parameters. This presentation will explore three models of the gene regulatory network governing the segmentation of fruit fly embryos. Each model is able to give predictions and insights into this biological process, and taken together, they illuminate the emergent (network-level) functional robustness of gene regulatory networks.

LITERATURE:
  1. Scale-free networks in cell biology. Albert R. Journal of Cell Science 118:4947-4957 (2005).
  2. Boolean modeling of genetic regulatory networks. Albert R. In: Complex Networks. Ben-Naim E, Frauenfelder H, Toroczkai Z (eds). Springer Verlag (2004).
Tue, May 23
Special Guest Seminar, 11:30am - 12:30pm
Genomic Approaches to Understanding the Genetic Basis of Human Disease
Eleazar Eskin, PhD, Assistant Professor in Residence, Department of Computer Science and Engineering, University of California, San Diego
Contact & Intro: Kenneth Lange, ext 68076
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ABSTRACT: Variation in human DNA sequences account for a significant amount of the genetic risk factors for common disease such as hypertension, diabetes, Alzheimer's disease, and cancer. Identifying the common variation that influences susceptibility to disease will usher in a new era of personalized medicine where treatment decisions are based not only on clinical observations, but also take into account an individual's genetic makeup. Recent technological advances in high-throughput genotyping technology allow us for the first time to collect human variation information on a large enough scale to identify the variation involved in disease. This talk focuses on two challenges associated with the analysis of high-throughput genotype data. Since the new cost effective technologies obtain human variation information from both pairs of human chromosomes simultaneously, the first step in analysis of these datasets is computational prediction of the human variation on each chromosome or the haplotype phasing problem. We discuss the results of our collaboration with Perlegen Sciences on the phasing of whole genome human haplotypes. A second challenge is the association of whole genome variation data to phenotypic data or clinical traits. Using the inbred mouse as a model organism, we demonstrate how our methods are able to discover many regions in the mouse genome associated with phenotypes and how many of our predictions are consistent with genes known to influence specific traits.

Fri, Jun 02
David L. Rimoin Lecture in Genetics Education, 11:30am - 12:30pm, Louis Jolyon West Auditorium, NPI Building, C8-183, 720 Westwood Plaza
The Genome Revolution in Human Genetics and Genomic Medicine
Huntington F. Willard, PhD, Director, Institute for Genome Sciences & Policy, Vice Chancellor for Genome Sciences, Nanaline H. Duke Professor of Genome Sciences, Duke University
Contact & Intro: David Rimoin, MD, 310-423-4461
Mon, Jun 05
Special Guest Seminar, 11am - 12pm
Sprouty-ing new teeth: FGF signaling in dental and craniofacial development
Ophir Klein, MD, PhD, FAAP, Clinical Fellow in Genetics, University of California, San Francisco
Contact & Intro: Eric Vilain, MD, PhD, ext 72455
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ABSTRACT: The Fibroblast Growth Factor (FGF) family is comprised of greater than 20 signaling molecules, many of which are critical regulators of embryonic development. Mutations in genes encoding FGFs and their effector molecules cause developmental anomalies in humans, including a variety of craniosynostosis syndromes and other craniofacial disorders. Sprouty (Spry) is an intracellular inhibitor of FGF function, and my research focuses on the role of FGF signaling and Sprouty genes in mouse tooth and craniofacial development. We have found that two Sprouty family members, Spry2 and Spry4, are essential in mice for the formation of the normal number of teeth in both the molar and incisor regions. We have also found that loss of Sprouty function leads to the presence of stem cells in a region of the tooth where they are not normally found, and we are currently trying to determine the mechanisms that lead to this aberration. Additionally, the role of FGF signaling in development of the facial primordia will be addressed.

Mon, Jun 19
Special Guest Seminar, 11:30am - 12:30pm
Molecular Determinants of Drosophila Hematopoietic Precursors in Lymph Gland Development
Julian A. Martinez-Agosto, MD, PhD, FACMG, FAAP, Clinical Instructor, Division of Medical Genetics, Department of Pediatrics, UCLA
Contact & Intro: Eric Vilain, ext 72455
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ABSTRACT: The Drosophila larva hematopoietic organ, the lymph gland, is composed of two primary lobes and several secondary lobes in association with the dorsal vessel. Histochemical analysis of lymph glands in late third instar larvae has revealed the presence of two distinct zones within the primary lymph gland lobes. The first zone is composed of a peripheral layer of cells that express hemocyte maturation markers named the cortical zone. We have identified an additional region in the lymph gland, the medullary zone (MZ), which contains quiescent cells that do not express any differentiation markers. These cells are defined by their location and expression of a GAL4 reporter line in the domeless locus, which encodes a JAK-STAT pathway receptor. Our goal is to characterize the genetic determinants of cell differentiation in this population of lymph gland precursors. To define the signals required for maintenance of medullary zone precursors, our studies have focused on the role of the Posterior Signaling Center (PSC). Previous work demonstrated the existence of a third region termed the Posterior Signaling Center (PSC) within the lymph gland that displays the ligand Serrate to activate the Notch signaling pathway. We will present results which suggest that the PSC behaves like a stem cell niche, as it is required for maintenance of the medullary zone in the larval lymph gland. Homeodomain-containing transcription factors are necessary for specification of the cells within the niche. These cells in turn provide a microenvironment that through reciprocal signaling interactions endows MZ precursors with the ability to self renew and persist in a non-differentiated state. Through the use of molecular genetic approaches and cell transplantation techniques we are dissecting candidate signaling pathways involved in the establishment, maintenance, and cell fate of medullary zone precursors.

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