David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Spring Quarter 2007

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

Mon, Apr 09
Analysis and modeling of whole-cell level metabolic networks
Elvind Almaas, PhD, Biomedical Scientist, Network Biology & Microbial Systems Group, Biosciences & Biotechnology Division, Lawrence Livermore National Laboratory
Contact & Intro: Chiara Sabatti
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ABSTRACT: Much effort has recently been focused on understanding the organization of whole-cell level metabolism. Recent insights gained from applying the tools of complex network analysis to cellular metabolism, where metabolites are represented as nodes and chemical reactions as links, suggest that cellular metabolism is an excellent model systems where computational predictions can be directly compared with experiments. In this presentation, I will describe the much used modeling approach of Flux Balance Analysis (FBA) and present results on the optimal organization of microbial metabolism using highly curated models of the bacterium E. coli and the yeast S. cerevisiae.

LITERATURE:
  1. Global organization of metabolic fluxes in the bacterium Escherichia coli. Almaas E, Kovacs B, Vicsek T, Oltvai ZN, Barabasi A-L. Nature 427:839 (2004).
  2. The activity reaction core and plasticity in metabolic networks. Almaas E, Oltvai ZN, Barabasi A-L. PLoS Computational Biology 1:e68 (2005).
  3. Genome-scale Models of Microbial Cells: Evaluating the consequences of constraints. Price ND, Reed JL, Palsson BO. Nature Reviews Microbiology 2:886-897 (2004).
Mon, Apr 16
Genetic Studies of Down Syndrome
Eleanor Feingold, PhD, Associate Professor, Departments of Human Genetics and Biostatistics, Graduate School of Public Health, University of Pittsburgh
Contact & Intro: Chiara Sabatti
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ABSTRACT: Trisomy is the leading cause of both mental retardation and pregnancy loss in humans. The most common autosomal trisomy is trisomy 21 (Down syndrome), which has an incidence of about 1 in 700 live births. A number of important issues can be studied by analyzing genotype data from trisomic individuals and their parents. For example, meiotic non-disjunction is highly correlated with altered recombination, although the detailed patterns of association are not yet clear. Another area of interest is mapping susceptibility genes for phenotypes such as heart defects that are common in individuals with Down syndrome. To perform these kinds of studies we need to extend standard statistical genetic analysis methods to handle individuals with three non-independent alleles. I will highlight some of the most important results we have achieved in the last 15 years of this work, and the statistical methods used to achieve them. I will emphasize aspects of the analysis that give us insight into standard disomic methods as well.

LITERATURE:
  1. Linkage Disequilibrium Mapping in Trisomic Populations: Analytical Approaches and an Application to Congenital Heart Defects in Down Syndrome. Kerstann KF, Feingold E, Freeman SB, Bean LJH, Pyatt R, Tinker S, Meltzer M, Jewel AH, Capone G, Sherman SL. Genetic Epidemiology 27:240-251, (2004).
  2. Association Between Maternal Age and Meiotic Recombination for Trisomy 21. Lamb NE, Yu K, Shaffer J, Feingold E, Sherman SL. American Journal of Human Genetics 76:91-99, 2005.
  3. Trisomy in Humans: Incidence, Origin, and Etiology. Hassold T, Hunt PA, Sherman S. Current Opinion in Genetics and Development 3:398-403 (1993).
  4. Recombinaton and nondisjunction in humans and flies. Koehler KE, Hawley RS, Sherman S, Hassold T. Human Molecular Genetics 5: 1495-1504 (1996).
Mon, Apr 23
Mostly Mendel
Jeanette Papp, PhD, Adjunct Assistant Professor, Department of Human Genetics, Director, Sequencing and Genotyping Core, UCLA
Contact & Intro: Chiara Sabatti
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ABSTRACT: There is a wide variety of laboratory and computational tools available to the modern geneticist for generating and analyzing genetic data. I will give an overview of some of the technology platforms in my lab available to the UCLA scientific community, and some computational tools we are developing for the efficient management, analysis, and visualization of genetic and phenotypic data. One important analysis tool we are involved with is the Mendel Software package for analysis of genetic traits in both pedigree and population data sets. I will give an overview of current and new features of Mendel 7.0, and describe MendelPro, a new graphical front end and database back end enabling data management, analysis, graphing and visualization using Mendel 7.0 as the computational engine. I will demonstrate the utility of the software using a linkage analysis of a posterior polymorphous corneal dystrophy dataset as an example.

LITERATURE:
  1. Mendel 7.0 Documentation: A complete package for the exact genetic analysis of discrete traits in pedigree and population data sets. Lange K, Cantor R, Horvath S, Papp JC, Sabatti C, Sinsheimer J, Sobel E (2006). http://www.genetics.ucla.edu/software/mendel
  2. Detection and Integration of Genotyping Errors in Statistical Genetics. Sobel E, Papp JC, Lange K. The American Journal of Human Genetics 70: 496-508 (2002).
  3. Replication and Refinement of Linkage of Posterior Polymorphous Corneal Dystrophy to the PPCD1 Locus on Chromosome 20. Yellore VS, Papp J, Sobel E, Khan MA, Rayner SA, Farber DB, Aldave AJ. Genetics in Medicine 9: 228-234 (2007).
Mon, Apr 30
The Genetic Park of Ogliastra: unravelling complex traits in isolated populations
Mario Pirastu, PhD, Director, Institute of Population Genetics of the Italian National Research Council (CNR) and Scientific Director, Shardna Life Sciences, Sardinia, Italy
Contact & Intro: Chiara Sabatti
LITERATURE:
  1. Wright AF, Carothers AD, Pirastu M. Population choice in mapping genes for complex diseases. Nature Geneics 109:397-404 (1999).
  2. Gianfrancesco F, Esposito T, Ombra MN, Forabosco P, Maninchedda G, Fattorini M, Casula S, Vaccargiu S, Casu G, Cardia F, Deiana I, Melis P, Falchi M, Pirastu M. Identification of a novel gene and a common variant associated with uric acid nephrolithiasis in a Sardinian genetic isolate. American Journal of Human Genetics 72:1479-91 (2003).
  3. Fraumene C, Petretto E, Angius A, Pirastu M. Striking differentiation of sub-populations within a genetically homogeneous isolate (Ogliastra) in Sardinia as revealed by mtDNA analysis. Human Genetics 114:1-10 (2003).
Mon, May 07
New insights into the genetic mechanisms of inborn errors of metabolism
Jerry Vockley, MD, PhD, Professor of Pediatrics, School of Medicine, Professor of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Chief of Medical Genetics, Children's Hospital of Pittsburgh
Contact & Intro: Katrina Dipple
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ABSTRACT: The lack of consistent genotype/phenotype correlations for patients with inborn errors of metabolisms has refocused attempts to better understand the causes of phenotypic variation on other modifying factors. Genome sequencing projects have made it clear that the complexity at the protein level is much greater than can be explained by the number of genes identified in most organisms including humans. Much of this additional complexity is achieved by the generation of more than one functional protein from a single gene; however, protein-protein and pathway interactions expand the potential for a cascade of effects on cellular and organism function related to protein variation. Thus it is necessary to consider more than the loss of a specific enzymatic function when evaluating the clinical effects of single gene mutations causing inborn errors of metabolism. Genetic defects in energy metabolism provide compelling examples of the importance of these mechanisms. Many of the enzymes involved in mitochondrial fatty acid oxidation exist in more than one subcellular location and likely play different cellular roles in their various forms. In addition, these enzymes are active in the mitochondria as a multi-protein beta-oxidation complex that in turn interacts with the respiratory chain. Current research on these phenomena will be presented and its relevance to clinical variation will be discussed.

LITERATURE:
  1. Human Acyl-CoA Dehydrogenase-9 Plays a Novel Role in the Mitochondrial B-Oxidation of Unsaturated Fatty Acids. Ensenauer R, He M, Willard JM, Goetzman ES, Corydon TJ, Vandahl BB, Mohsen A-W, Isaya G, Vockley, J. The Journal of Biological Chemistry 280: 32309–32316 (2005).
  2. Mini Review: Synergistic Heterozygosity: Disease Resulting from Multiple Partial Defects in One or More Metabolic Pathways. Vockley J, Rinaldo P, Bennett MJ, Matern D, Vladutiu GD. Molecular Genetics and Metabolism 71: 10–18 (2000).
  3. Synergistic heterozygosity in mice with inherited enzyme deficiencies of mitochondrial fatty acid beta-oxidation. Schuler AM, Gower BA, Matern D, Rinaldo P, Vockley J, Wood PA. Molecular Genetics and Metabolism 85: 7-11 (2005).
Mon, May 14
Overview of the Colorectal Cancer Family Registry and updates on the MMR-related etiological pathway
Robert W. Haile, PhD, Professor and Director, Genetic Epidemiology Program, USC Keck School of Medicine and Norris Comprehensive Cancer Center
Contact & Intro: Paivi Pajukanta
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ABSTRACT: The Colorectal Cancer Family registry (Colon CFR) is an NCI-supported consortium of research institutions in the U.S., Canada, and Australia established to facilitate the conduct of multi-institutional, multi-disciplinary research on the causes, prevention, and treatment of colorectal cancer (CRC). The Colon CFR has extensive data and biospecimens on over 10,000 population-based and 1,000 clinic-based families at increased risk of CRC. A comprehensive and integrated program of research is ongoing that includes studies of candidate gene pathways, linkage, genome-wide association, whole exon arrays (gene expression) and somatic mutations. Epigenetic and somatic events are used to address the issue of etiological heterogeneity. This program will be described and results regarding the mismatch repair pathway will be presented.

LITERATURE:
  1. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, Jass J, LeMarchand L, Grove J, Potter J, Newcomb P, Terdiman JP, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund K, Thibodeau SN, Boardman LA, Seminara D. Journal of the American Medical Association 293:1979-85 (2005).
  2. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Jass, JR. Histopathology 50: 113-130 (2007).
  3. Tumor Microsatellite Instability and Clinical Outcome in Young Patients with Colorectal Cancer. Gryfe R, Kim H, Hsieh ETK, Aronson MD, Holowaty EJ, Bull SB, Redston M, Gallinger S. New England Journal of Medicine 13:69-77 (2000).
Mon, May 21
At the crossroads of theory and application: Applying interaction models to studies of cardiovascular disease
Elizabeth Hauser, PhD, Associate Research Professor, Section of Medical Genetics, Department of Medicine, Duke University
Contact & Intro: Chiara Sabatti
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ABSTRACT: The identification of genetic risk factors for common complex diseases presents a challenging problem starting from choosing the best study design to providing functional evidence for the observed genetic effects. Our group has been performing genetic studies of coronary artery disease for the past 10 years. We have finally landed on some candidates of interest. Our studies have concentrated on chromosome 3q13 following identification of a large linkage peak in our family study (Hauser et al. AJHG 2004) and identification of the GATA2 (Connelly et al. PLos Genetics 2006) and the KALRN genes (Wang et al. AJHG 2007). The story does not end there with multiple genes in this and other regions showing evidence of association in multiple data sets. I will discuss these results along with our attempts to identify independent and interacting genes.

LITERATURE:
  1. Shah SH, Kraus WE, Crossman DC, Granger CB, Haines JL, Jones CJH, Mooser V, Huang L, Haynes C, Dowdy E, Vega GL, Grundy SM, Vance JM, Hauser ER. Serum Lipids in the GENECARD Study of Coronary Artery Disease Identify Quantitative Trait Loci and Phenotypic Subsets on Chromosomes 3q and 5q. Annals of Human Genetics 10:1469-1809 (2006).
  2. Wang L, Hauser ER, Shah SH, Pericak-Vance MA, Haynes C, Crosslin D, Harris II M, Nelson S, Hale AB, Granger CB, Haines JL, Jones CJH, Crossman D, Seo D, Gregory SG, Kraus WE, Goldschmidt-Clermont PJ, Vance JM. Peakwide Mapping on Chromosome 3q13 Identifies the Kalirin Gene as a Novel Candidate Gene for Coronary Artery Disease. The American Journal of Human Genetics 80: 650-663 (2007).
Fri, Jun 01
Talk is scheduled Friday, June 1, 12-1pm
Haplotype inference using an empirical linkage disequilibrium model
Sharon Browning, PhD, Lecturer, Department of Statistics, Faculty of Science, The University of Auckland
Contact & Intro: Chiara Sabatti
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ABSTRACT: In this talk I will address the problem of haplotype inference, with particular reference to the large whole genome association data sets that are currently being generated. Haplotypes are useful because they are the natural biological unit, and inferred haplotypes are needed by several good methods for testing for genetic association.

A person inherits one copy of each autosomal chromosome from each of his/her parents. Genotypic data give unordered pairs of alleles (variants) at genetic markers. The sequence of alleles along a single chromosome copy is a “haplotype”. Alleles that are located at neighboring positions on a chromosome tend to be correlated (this is known as linkage disequilibrium), thus it is possible to statistically infer haplotypes from the genotype data.

I will review several existing methods for haplotype inference, and present a new method based on an empirical model for linkage disequilibrium. This new method has proved to be much faster than competing existing methods, which is important for application to large-scale data sets, and has accuracy comparable with the most accurate of existing methods.

Mon, Jun 04
Steroid-regulated signaling pathways in bone formation
Laura P. Zanello, PhD, Assistant Professor, Department of Biochemistry, University of California-Riverside
Contact & Intro: Esteban Dell’Angelica
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ABSTRACT: The development of new therapies for treatment and prevention of bone mass loss depends, at least in part, on a full understanding of the molecular mechanisms by which osteoblasts produce and secrete bone, and their regulation by bone anabolic hormones. Research in my laboratory focuses on molecular mechanisms of action of steroid hormones in bone cells. More specifically, we study signaling networks underlying membrane-initiated responses of 1α,25-dihydroxyvitamin D3 (1,25D) in osteoblasts, the bone-forming cells. One aspect of our research studies steroid-induced modulation of calcium and chloride channel activities and ATP exocytosis in relation with bone formation. In addition, we investigate 1,25D effects on osteoblast cell cycle and survival. We found that 1,25D-induced protection against apoptosis and anti-proliferative actions depend on the intensity and duration of the hormone stimulus, and involve a PI3K/Akt cascade and a JNK/AP-1/p21 pathway, respectively. A major aim of our studies is to contribute to the understanding and treatment of some human clinical disorders of the skeleton characterized by decreased mineralization and bone mass loss, such as rickets and osteoporosis.

A side project in my laboratory studies the use of carbon nanotubes (CNTs) as an adequate 3D-scaffold material for the growth and proliferation of bone cells and formation of functional bone tissue. More specifically, we investigate morphological changes, cell proliferation, and integrity of the plasma membrane of osteoblasts grown on chemically functionalized CNTs. Bone structure and function depend intimately on the arrangement of cellular and non-cellular components at the nanoscale level. Our studies apply to bone bioengineering, which is aimed at creating artificial nanostructures with the capacity to increment or replace the natural tissue.

LITERATURE:
  1. 1α,25(OH)2-vitamin D3 antiproliferative actions involve vitamin D receptor-mediate activation of MAPK pathways and AP-1/p21waf1 upregulation in human osteosarcoma. Wu W, Zhang X, Zanello LP. Cancer Letters (in press, 2007).
  2. 1α,25(OH)2-vitamin D3 membrane-initiated calcium signaling modulates exocytosis and cell survival. Zhang X., Biswas P, Owraghi M, Zanello LP. J. Steroid Biochemistry and Molecular Biology [Epub ahead of print]
  3. Bone cell proliferation on carbon nanotubes. Zanello LP, Zhao B, Hu H, Haddon RC. Nano Letters 6: 562-567 (2006).
  4. Rapid modulation of osteoblast ion channel responses by 1α,25(OH)2-vitamin D3 requires the presence of a functional vitamin D nuclear receptor. Zanello LP, Norman AW. Proceedings of the National Academy of Science USA 101:1589-1594 (2004).
Fri, Jun 15
Intercampus Medical Genetics Training Program Graduation, The David L. Rimoin Lecture in Genetics Education, 11am-12pm, Neuroscience Research Building Auditorium
"Marfan Syndrome and Related Disorders: From Molecules to Medicines"
Harry (Hal) Dietz, MD, Victor A. McKusick Professor of Medicine and Genetics, Institute of Genetic Medicine, Departments of Pediatrics, Medicine, Molecular Biology, Genetics, and Neurosurgery, Investigator, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine
Contact & Intro: David Rimoin, 310-423-4461

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