David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Fall Quarter 2015

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

Mon, Oct 12
Functional interpretation of genomes using biological networks
Kasper Lage, PhD, Assistant Professor, Harvard Medical School and Massachusetts General Hospital; Associate Member, The Broad Institute
Contact & Intro: Dan Geschwind, extension 46570
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ABSTRACT: The recent explosion in genome-wide association studies, exome-sequencing projecta have revealed many genetic variants likely to be involved in disease processes, but the composition and function of the molecular systems they affect remain largely obscure. This limits our progress towards biological understanding and therapeutic intervention. Computational analyses that systematically integrate biological networks (i.e., networks in which genes are connected if they are functionally associated in some experimental system) with genetic data have emerged as a powerful and scalable approach to functionally interpret large genomic data sets by enabling the identification of de novo pathways perturbed in disease. This talk will highlight approaches and methods being developed in this area, and exemplify how different network-based methods have been used to analyze common and rare genetic variants to deduce the molecular networks perturbed by genetics and environment in a wide range of diseases. Furthermore, as a general model for how in silico networks can be expanded, consolidated and validated, I will show how cardiac ion-channel networks involved in human arrhythmias were elucidated and validated by combining computational modeling, GWAS, quantitative interaction proteomics, and model organisms through rigorous statistical frameworks.

Mon, Oct 19
Genetic Analyses of Vitiligo and Facial Shape: A Tale of Two Complexities
Richard A. Spritz, MD, Professor and Director, Human Medical Genetics and Genomics Program University of Colorado School of Medicine
Contact & Intro: Esteban Dell'Angelica, extension 63749
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ABSTRACT: The autoimmune disease vitiligo and the normal trait facial shape represent two extremes of human complex traits. The first is a dichotomous disease trait, and the second is a universal set of interconnected quasi-continuous traits. Both have been approached by genomewide association studies that have begun to yield understanding of their underlying biology.

Mon, Oct 26
System wide analyses of transcriptional control in animals
Mark D. Biggin, PhD, Staff Scientist, Genomics Division, Lawrence Berkeley National Laboratory
Contact & Intro: Jessica Li, extension 68375
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ABSTRACT: In vivo, animal transcription factors each show a quantitative continuum of functional, quasi-functional, and nonfunctional DNA binding across thousands of genomic regions lying close to most genes. We are using computational analyses and experimental methods to elucidate the biochemical mechanisms that produce these patterns of DNA binding and how these messy combinations of transcription factors cooperate to generate precise spatial and temporal gene expression.

Over the last decade, many researches have suggested that post transcriptional regulation plays a larger role than transcriptional control in determining differences in protein expression between genes. We have critically reexamined this work and shown that once measurement error in the data is taken into account, transcriptional control is the dominant step, consistent with the classic view from decades past.

Mon, Nov 02
Assessing Human Genome Function In Vivo
Len A. Pennacchio, PhD, Senior Staff Scientist, Genomics Division & Deputy Director, Joint Genome Institute, Lawrence Berkeley National Laboratory
Contact & Intro: Nelson Freimer, extension 46427
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ABSTRACT: Dr Pennacchio's research is focused on understanding human genome function through studies in vivo. A major theme over the past decade has been identifying and understanding distant-acting gene regulatory sequences and exploring their role in human disease.

Mon, Nov 09
Large-scale genomic approaches to solving rare Mendelian diseases
Daniel MacArthur, PhD, Co-Director, Medical and Population Genetics, Broad Institute of Harvard and MIT
Contact & Intro: Leonid Kruglyak, extension 55486
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ABSTRACT: Despite the increasing availability of cheap sequencing, interpreting candidate disease-causing genetic variants identified in patient samples remains extremely challenging. In this talk I will describe the development of a massive resource of reference genetic variation, the Exome Aggregation Consortium, and the ways in which exome sequencing data from over 60,000 samples can be used to dramatically empower the identification of causal variants in rare disease patients. In addition, I will describe the application of whole-genome and transcriptome sequencing for the identification of causal variants missed by exome-based approaches.

Mon, Nov 16
Impact of gene mutations and polymorphisms on human B-cell tolerance
Eric Meffre , PhD, Associate Professor, Yale University, School of Medicine, Department of Immunobiology
Contact & Intro: Emmanuèle Delot, extension 51319
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ABSTRACT: Dr. Meffre's work focuses on the etiology of autoimmune diseases by identifying molecules and pathways involved in the establishment of B-cell tolerance through the investigation of rare patients with primary immunodeficiency (PID), enrolled at Yale and at Mount Sinai as well as through an international network. The replication of our observations in several autoimmune diseases favored by risk alleles reproducing abnormal tolerance features characterized in PID patients, demonstrates our relentless efforts to identify the cellular mechanisms underlying these diseases. An ultimate aim would be development of therapies targeting the causes of these disorders.

Mon, Nov 30
A global genetic interaction network: modeling a hierarchy of cell function and principles of inheritance
Charlie M. Boone, PhD, Professor, Donnelly Centre, University of Toronto
Contact & Intro: Leonid Kruglyak, extension 55486
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ABSTRACT: We generated a comprehensive genetic interaction network for the budding yeast, Saccharomyces cerevisiae. The genetic interaction profile for each gene enabled quantification of functional similarity and the assembly of a hierarchical model of cellular function. Negative genetic interactions connected functionally related genes, highlighted essential genes as network hubs that bridge a set of core bioprocesses, and defined pleiotropic genes that mediate connections between numerous different bioprocesses. Positive interactions, especially among essential genes, appeared to reflect more general regulatory mechanisms. The organizing principles of the yeast genetic network, whereby coherent sets of negative or positive interactions occur within and between genes encoding complexes and pathways, can be exploited to decipher genetic interactions in humans.

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