David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Spring Quarter 2009

Every 2nd and 4th Mondays, 11am - 12pm, Gonda Center Conference Room - Room 1357

Mon, Apr 06
Secular Trends in the Frequency of Deafness in the United States
Kathleen Arnos, Ph.D., Professor and Director, Genetics Program, Department of Biology, Gallaudet University, Washington, DC
Contact & Intro: Paivi Pajukanta, ext 72011
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ABSTRACT: In 1898, E.A. Fay, a professor at Gallaudet University, published an analysis of nearly 5,000 marriages of the deaf that occurred in America during the 19th century. The data included three-generation pedigrees of the offspring, siblings and parents of the proband-matings that have been reanalyzed during the past 100 years and remain unique because they were ascertained by complete selection through the deaf parents. It has recently been proposed that intense phenotypic assortative mating among the deaf may have greatly accelerated the slow response to relaxed genetic selection against deafness that began in many Western countries with the introduction of sign language and establishment of residential schools for the deaf. Simulation studies suggest that this mechanism specifically amplifies the frequency of the commonest form of recessive deafness in a population and may have doubled the frequency of connexin deafness (caused by mutations in GJB2 (connexin 26) and GJB6 (connexin 30)) in this country during the past 200 years. This hypothesis depends to a great extent on the value of a key statistic, i.e. the proportion of non-complementary matings among the deaf that had been estimated by segregation analysis of the Fay data. Non-complementary matings refer to marriages which are biologically incapable of producing hearing offspring because both parents are homozygous for the same recessive deafness genes and reflects both the overall and relative frequencies of different forms of recessive deafness in the population. If the absolute and relative frequency of connexin deafness has in fact increased during the past century, the frequency of non-complementary matings should also have increased. To test this prediction, we collected comparable pedigree data on contemporary marriages among the deaf ascertained by complete selection through the deaf parents. Segregation analysis of the resulting data revealed that the estimated proportion of non-complementary matings has increased by a factor of more than five in the past 100 years. Additional analysis of the frequency of pathologic connexin 26 mutations in probands partitioned into three 20-year birth cohorts shows a statistically significant linear increase in the frequency of connexin mutations during this time interval. These data are consistent with the increase in the frequency of connexin deafness predicted by our previous simulation studies and provide convincing evidence for the important influence that assortative mating can have on the frequency of common genes for deafness.

  1. A comparative analysis of the genetic epidemiology of deafness in the United States in two sets of pedigrees collected more than a century apart. Arnos KS, Welch KO, Tekin M, Norris VW, Blanton S, Pandya A, Nance WE. American Journal of Human Genetics 83:200-207 (2008).
  2. Relevance of connexin deafness (DFNB1) to human evolution. Nance WE, Kearsey MJ. American Journal of Human Genetics 74:1081-1087 (2004).
Mon, Apr 13
Learning mechanistic models of gene expression regulation from natural sequence variation
Harmen J. Bussemaker, Ph.D., Associate Professor, Biological Sciences, Columbia University, New York
Contact & Intro: Chiara Sabatti, ext 49567
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ABSTRACT: Our laboratory uses computation and quantitative modeling to understand the behavior of gene regulatory networks in terms of the underlying bio-molecular interactions. We focus on the function of transcription factors (TFs), which provide a crucial regulatory layer between signaling pathways and the genome. In this talk, we will describe how "hidden variables" related to the sequence specificity and condition-specific regulatory activity of TFs can be inferred through integrative analysis of functional genomics data of different type. We will also discuss a novel approach to mapping trans-acting sequence variation that infers segregant-specific TF activities, treat these as a quantitative trait, and then uses genetic linkage analysis to identify "aQTLs" harboring direct or indirect TF modulators.

  1. Predictive modeling of genome-wide mRNA expression: from modules to molecules. Bussemaker HJ, Foat BC, Ward LD. Annual Review of Biophysics and Biomolecular Structure 36:329-47 (2007).
  2. Profiling condition-specific, genome-wide regulation of mRNA stability in yeast. Foat BC, Houshmandi SS, Olivas WM, Bussemaker HJ. Proceedings of the National Academy of Sciences USA 102:17675-80 (2005). Epub Nov 29 (2005).
  3. Predicting functional transcription factor binding through alignment-free and affinity-based analysis of orthologous promoter sequences. Ward LD, Bussemaker HJ. Bioinformatics 24:i165-71 (2008).
Mon, Apr 27
Genetic Association Testing in pedigree data: issues and solutions
Hemant Tiwari, Ph.D., Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham
Contact & Intro: Chiara Sabatti, ext 49567
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ABSTRACT: A number of methods of association have been proposed for pedigree data and used to test for genetic association. All these methods can be characterized by five different types of approaches, namely, maximum-likelihood-based approach, mixed-model approaches, Generalized Estimating Equation (GEE) approach, Within-Cluster resampling approach, and methods based on MCMC. In this presentation, we compare some of these methods for their utility with respect to Type I error rates pertaining to genome-wide association studies, using comprehensive simulation study. In preliminary studies, we have found that mixed-model approach outperforms the other methods with respect to Type I error rates. However, it is computationally slow when number of families is large. In addition, we also discuss statistical approaches that provide valid and reliable estimates in the presence of missing familial data.

  1. George V, Elston RC. Testing the association between polymorphic markers and quantitative traits in pedigrees. Genet Epidemiol 4:193-201 (1987).
  2. Hoffman EB, Sen PK, Weinberg CR. Within cluster resampling. Biometrika 88:1121-1134 (2001).
  3. Follmann D, Proschan M, Leifer E. Multiple outputation Inference for complex clustered data by averaging analyses from independent data. Biometrics 59 (2):420-429 (2003).
Mon, May 04
Neuron-glia interactions: mechanisms and roles in development and disease
Gabriel Corfas, Ph.D., Professor, F.M. Kirby Neurobiology Center, Children's Hospital Boston and Departments of Neurology and Otolaryngology, Harvard Medical School
Contact & Intro: Esteban Dell'Angelica, ext 63749
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  1. Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Chen S, Rio C, Ji RR, Dikkes P, Coggeshall RE, Woolf CJ, Corfas G. Nature Neuroscience 6:1186-1193 (2003).
  2. Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for the pathogenesis of neuropsychiatric disorders. Roy K, Murtie JC, El-Khodor BF, Edgar N, Sardi SP, Hooks BM, Benoit-Marand M, Chen C, Moore H, O'Donnell P, Brunner D, Corfas G. Proceedings of the National Academy of Sciences USA 104:8131-8136 (2007).
  3. Presenilin-dependent erbB4 nuclear signaling regulates the timing of astrogenesis in the developing cerebral cortex. Sardi SP, Patten BA, Murtie J, Corfas G. Cell 127:185-197(2006).
Mon, May 11
A Systems Genetics Approach to Familial Combined Hyperlipidemia
Chris Plaisier, Dept. of Human Genetics
Contact & Intro: Paivi Pajukanta, ext 72011
Mon, May 18
Rabs and myosins in lacrimal acinar secretory vesicle exocytosis
Sarah F. Hamm-Alvarez, Ph.D., Gavin S. Herbert Professor and Chair, Department of Pharmacology and Pharmaceutical Sciences, USC School of Pharmacy
Contact & Intro: Esteban Dell'Angelica, ext 63749
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ABSTRACT: Tears are a complex biological mixture consisting of a mucin phase, an aqueous protein and electrolyte rich phase as well as a lipid phase. The secretion of diverse tear proteins from the lacrimal gland to constitute the aqueous phase sustains the health and refractivity of the cornea while protecting the entire ocular surface from pathogens. The principal secretory cell within the lacrimal gland, an exocrine gland, is the lacrimal gland acinar cell, a secretory epithelial cell that maintains an abundant array of large (~1-2 micrometer) heterogenous secretory vesicles that are exocytosed at the apical plasma membrane to release tear proteins in response to diverse stimuli. Like other secretory cells, lacrimal gland acinar cells express members of the rab3 and rab27 families of secretory rabs that are thought to be critical for elements of secretory vesicle exocytosis. Moreover, the myosin V motor protein, Myo5c, is implicated in acinar secretory vesicle exocytosis, as is Myo5a in melanocytes and neurons. However, comparison of functional studies in acinar cells in vitro to studies with knockout mice yield conflicting data about how these rab proteins actually function in acinar cell secretory vesicle exocytosis relative to exocytosis in other cell types, as well as raise questions about the use of a common protein toolkit for exocytosis in distinctly different cellular environments.

  1. Jerdeva G, Wu K, Yarber FA, Rhodes CJ, Kalman D, Schechter JE, Hamm-Alvarez SF. Actin and non-muscle myosin II facilitate apical exocytosis of tear proteins in rabbit lacrimal acinar epithelial cells. J Cell Sci 118:4797-4812 (2005).
  2. Evans E, Zhang W, Jerdeva G, Chen, C-Y, Chen X, Hamm-Alvarez SF, Okamoto CT. Direct interaction between rab3D and the polymeric immunoglobulin receptor may regulate its trafficking through regulated secretory vesicles in lacrimal gland acinar cells. Am J Physiol (Cell Physiol) 294:C662-674 (2008).
  3. Marchelletta RR, Jacobs D, Schechter JE, Cheney R, Hamm-Alvarez SF. Myosin 5c facilitates actin filament remodeling and compound fusion of mature secretory vesicles during exocytosis in lacrimal acini. Am J Physiol (Cell Physiol)195:C13-28 (2008).
Mon, Jun 01
Daphna Weissglas, Ph.D., Dept. of Human Genetics
Contact & Intro: Paivi Pajukanta, ext 72011
Fri, Jun 19
David L. Rimoin Lecture in Genetics Education: 11am - 12pm, Neuroscience Research Building Auditorium
Evolution: a context for medicine
David Valle, M.D., Henry J. Knott Professor and Director of the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Contact & Intro: David Rimoin, 323-423-4461

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