David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Fall Quarter 2009

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

Mon, Oct 05
Combining Co-expression Analysis with Genome-Wide Genetic Data to Identify Novel Candidate Genes in Autism
Samuel Strom, UCLA Department of Human Genetics
Contact & Intro: Stanley Nelson, ext 47981
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ABSTRACT: n/a

LITERATURE:

n/a

Mon, Oct 12
Association Studies Involving Rare Variants and Large-Scale DNA Sequence Data
Nicholas J. Schork, Ph.D., Director of Biostatistics and Bioinformatics, The Scripps Translational Science Institute, Professor, Molecular and Experimental Medicine, The Scripps Research Institute
Contact & Intro: Marc Suchard, ext 57442
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ABSTRACT: The growing availability of efficient DNA sequencing technologies is motivating geneticists to leverage these technologies in association studies focused on the identification of genetic variations that influence phenotypic expression and disease susceptibility. However, making sense of DNA sequence data in the context of association studies is problematic. Statistical methods that are appropriate for the analysis of common genetic variations of the type interrogated in contemporary single nucleotide polymorphism (SNP) genotyping chip-based genome-wide association (GWA) studies are not likely to be appropriate for DNA sequence-based association studies given that rare variations and non-SNP forms of variation must be considered. In fact, the identification and validation of these forms of variation from DNA sequencing runs are themselves problematic and need to be taken into account when analyzed in association studies. In addition, the analysis of rare variations will require genomic annotations (i.e., information about the location of functional elements in the genome) to help put into context their individual and collective biological effects. This talk will outline some general approaches to association analyses involving DNA sequence data, including leveraging local sequence similarity, 'collapsing' collections of rare variations to create 'genetic meta-factors', exploiting sophisticated in silico methods for sequence annotation, and running sophisticated, very high-dimensional regression and related data mining techniques for association testing purposes.

LITERATURE:
  1. Malo N, Libiger O, Schork NJ. Accommodating linkage disequilibrium in genetic-association analyses via ridge regression. Am J Hum Genet. 2008 Feb;82(2):375-85. PMID: 18252218
  2. Schork NJ, Wessel J, Malo N. DNA sequence-based phenotypic association analysis. Adv Genet. 2008;60:195-217. PMID: 18358322
  3. Schork NJ, Murray SS, Frazer KA, Topol EJ. Common vs. rare allele hypotheses for complex diseases. Curr Opin Genet Dev. 2009 Jun;19(3):212-9. Epub 2009 May 28. PMID: 19481926
  4. Torkamani A, Kannan N, Taylor SS, Schork NJ. Congenital disease SNPs target lineage specific structural elements in protein kinases. Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9011-6. Epub 2008 Jun 25. PMID: 18579784
  5. Torkamani A, Schork NJ. Predicting functional regulatory polymorphisms. Bioinformatics. 2008 Aug 15;24(16):1787-92. Epub 2008 Jun 18. PMID: 18562267
Mon, Oct 26
A Systems Genetic Approach for Understanding Cell Responses to Oxidized Phospholipids in Atherosclerosis
Casey Romanoski, UCLA Department of Human Genetics
Contact & Intro: Jake Lusis, ext 51359
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ABSTRACT: Atherosclerosis is the leading cause of heart attack and stroke that is caused by a complex combination of environmental and genetic factors. Atherosclerosis is an inflammatory disease that involves various cell types including endothelial cells. We have developed a human endothelial cell model system to study atherosclerosis using a systems genetics approach. Our approach utilizes natural genetic variation as well as perturbation by pro-inflammatory oxidized phospholipids to elucidate the relationships between genetic variation and molecular phenotypes. The goal of our studies is to identify genetic variations and biological pathways that lead to atherosclerosis in humans.

LITERATURE:

n/a

Mon, Nov 02
HNF4: New Roles for an Old Nuclear Receptor
Frances Sladek, Ph.D., Professor, Department of Biology and Neuroscience, UC Riverside
Contact & Intro: Christina Jamieson, ext 72469
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ABSTRACT: HNF4 is one of the most highly conserved members in the nuclear receptor superfamily. It is essential for early development and plays a major role in the adult gastrointestinal track in the liver, kidney, pancreas and intestine/colon. It is known to regulate hundreds of genes involved in intermediary metabolism, blood coagulation and xenobiotic and drug metabolism. Mutations in HNF4 and its target genes have been linked to human diseases including diabetes, atherosclerosis and hemophilia. We have recently identified the endogenous ligand for HNF4 – linoleic acid, an essential fatty acid – and are uncovering new roles for this ancient receptor in physiology and disease using high throughput genomics and other techniques

LITERATURE:
  1. Hwang-Verslues and F.M. Sladek (2008) Nuclear receptor HNF4a1 competes with oncoprotein c-Myc for control of the p21/WAF1 promoter Molecular Endocrinology, 22:78-90
  2. Bolotin E, Schnabl J, Sladek F (Updated September, 2009). HNF4A (Homo sapiens). From the Transcription Factor Encyclopedia, http://www.cisreg.ca/tfe
  3. Xie, X, H. Liao, H. Dang,, W. Pang, Y. Guan, X. Wang, J. Y-J. Shyy, Y. Zhu, and F. M. Sladek (2009) Down regulation of hepatic HNF4alpha expression during hyperinsulinemia: involvement of SREBPs Molecular Endocrinology 23: 434-443. (*contributed equally)
  4. Yuan, X., T.C. Ta, M. Lin, J. Evans, Y. Dong, E. Bolotin, M. A. Sherman, B.M. Forman, F.M. Sladek (2009) Identification of an endogenous ligand bound to a native orphan nuclear receptor. PLoS ONE 4:e5609 (*contributed equally)
Mon, Nov 09
Treating metabolic disease and treating cancer, but I repeat myself
Barry Forman, Ph.D., M.D., Professor and Director, Gene Regulation and Drug Discovery, City of Hope
Contact & Intro: Christina Jamieson, ext 72469
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ABSTRACT: n/a

LITERATURE:

n/a

Mon, Nov 23
Mapping QTL to a phylogenetic tree
Karl Broman, Ph.D., Professor, Department of Biostatistics & Medical Informatics, University of Wisconsin, Madison
Contact & Intro: Marc Suchard, ext 57442
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ABSTRACT: The joint consideration of multiple crosses between related taxa (whether species or strains) offers the opportunity to identify the origin of a QTL allele on the phylogenetic tree that relates the taxa. We will discuss a formal method for combining multiple crosses to infer the location of a QTL on a tree, and will further discuss various experimental design issues for such endeavors, such as how many crosses are required and which sets of crosses are best.

LITERATURE:
  1. Broman K. W.. Review of statistical methods for QTL mapping in experimental crosses Laboratory Animals. 2001;30:44-52.
  2. Moyle Leonie C., Payseur Bret A.. Reproductive isolation grows on trees Trends in Ecology & Evolution. 2009.
Mon, Nov 30
Molecular Pathways for Schizophrenia: from Genes, Brain Circuitries, to Clinical Applications
Akira Sawa, M.D., Ph.D., Associate Professor of Psychiatry, Director, Program in Molecular Psychiatry, Johns Hopkins University
Contact & Intro: Esteban Dell'Angelica, ext 63749
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ABSTRACT: Biology for major mental disorders was hampered due to lack of molecular clues in the last century. However, for the past decade, identification of susceptibility genes for schizophrenia and related disorders has opened a window for neurobiological approaches for these disorders. Based on the genetic information, animal models have been generated and characterized. Meanwhile, a recent progress in stem cell biology utilizing human cells brings a major impact on the strategy of biological psychiatry. In this talk, a multifaceted approach for schizophrenia that integrates both genetic and stem cell approaches will be introduced, with an emphasis on its potential of translation and clinical application.

LITERATURE:

Sawa A, Snyder SH. Schizophrenia: diverse approaches to a complex disease. Science. 2002;296:692-695.

Sawa A, Cascella NG. Peripheral olfactory system for clinical and basic psychiatry: a promising entry point to the mystery of brain mechanism and biomarker identification in schizophrenia. Am J Psychiatry. 2009;166:137-139.

Jaaro-Peled H, Hayashi-Takagi A, Seshadri S, Kamiya A, Brandon NJ, Sawa A. Neurodevelopmental mechanisms of schizophrenia: understanding disturbed postnatal brain maturation through Neuregulin-1-ErbB4 and DISC1. Trends in Neurosci. 2009;32:485-495.

Mon, Dec 14
Targeted bisulfite sequencing revealed organization of DNA methylation in human pluripotent and adult cells
Kun Zhang, Ph.D., Assistant Professor, Department of Bioengineering, UCSD Jacobs School of Engineering
Contact & Intro: Guoping Fan x7-0439
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ABSTRACT: We developed a targeted bisulfite sequencing method for specific capture of an arbitrary subset of genomic targets for single molecule bisulfite sequencing, and for digital quantitation of DNA methylation at a single nucleotide resolution. We used this method to characterize the changes of DNA methylation during the nuclear reprogramming of human fibroblasts into hybrid stem cells, and into induced pluripotent stem (iPS) cells. We also extended the concept of linkage disequilibrium analysis to bisulfite sequencing data, and identified regions in which adjacent CpG sites are highly correlated in methylation level. A new type of cis-regulator that connects the genetic variations to the epigenome was identified.

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