David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Winter Quarter 2006

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

Tue, Jan 17
Talk is scheduled for Tuesday, January 17
Candidate Malarial Genes in Papua New Guinea
Melanie Bahlo, Ph.D., Special Fellow, The Walter and Eliza Hall Institute of Medical Research, Division of Bioinformatics, Parkville, Victoria, Australia
Contact & Intro: Chiara Sabatti, Ph.D., ext 49567
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ABSTRACT: Papua New Guinea (PNG) is inhabited by a Melanesian population with little western influence. Malaria is endemic in coastal areas and represents a significant health challenge for the inhabitants. We have examined three candidate malaria susceptibility loci: glycophorin C (GYPC), erythropoietin (EPO) and the Duffy (FY) blood group locus by carrying out genetic investigations, including linkage disequilibrium (LD) and haplotype surveys using both microsatellite and SNP markers surrounding these loci. The Melanesian population has a well known GYPC polymorphism, an exon 3 deletion, known as the Gerbich polymorphism. This polymorphism is very frequent in lowland PNG (46.5%) yet contradictory evidence exists regarding its functional significance for malaria. This is also borne out in the genetic data with extended homozygosity (~8cM) surrounding GYPC, regardless of exon 3 deletion genotype, in both lowland and highland populations. GYPC sequencing discovered several SNP polymorphisms that are in strong LD with the exon 3 deletion with almost all exon 3 deletion homozygotes (0.90-1.0 frequency of the associated haplotype) and are present at a much lower frequency (0.4-0.5) in exon 3 deletion heterozygotes and wild types, highland PNG and Caucasian samples. We postulate that the excess homozygosity surrounding GYPC is maintained for reasons other than the exon 3 deletion. Furthermore these flanking SNPs are putative malarial susceptibility polymorphisms, however given the extended homozygosity surrounding GYPC there are likely to be additional genetic causes which are currently unknown. The strong malarial selection pressures in PNG potentially provide LD mapping opportunities with extended LD observed however the causal polymorphism(s) may be difficult to identify.

LITERATURE:
  1. Screening for recently selected alleles by analysis of Human Haplotype similarity. Hanchard et al. American Journal of Human Genetics 78:153-159 (2006).
  2. Detecting recent positive selection in the human genome from haplotype structure. Sabeti et al. Nature 419:832-837 (2002).
  3. How Malaria has affected the human genome and what human genetics can teach us about malaria. Kwiatkowski D. American Journal of Human Genetics 77:171-192 (2005).
Mon, Jan 23
Selection Pressures on Microbial Proteins
Joshua B. Plotkin, Ph.D., Harvard Society of Fellows, Harvard University
Contact & Intro: Chiara Sabatti, Ph.D., ext 49567
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ABSTRACT: Microbial proteins evolve at vastly different rates, in response to different selection pressures. In this seminar, I will discuss classical and novel methods to measure the selection pressures on proteins. I will apply these techniques to the genomes of human pathogens, and to species of yeast. For pathogens, our analysis helps to identify potential therapeutic targets. In the case of yeast, we hope to elucide what forces determine the rate of protein evolution.

LITERATURE:
  1. A single determinant for the rate of yeast protein evolution. Drummond DA, Raval A, Wilke CO. (unpublished)
  2. Four responses to "Plotkin JB, Dushoff J, Fraser HB. Nature 428:942–945 (2004)". Nature 433:E5-E8 (2005).
  3. Detecting selection using a single genome sequence of M. tuberculosis and P. falciparum. Plotkin JB, Dushoff J, Fraser HB. Nature 428:942-945 (2004). With supplementary methods 1-3.  
Mon, Jan 30
Blood Vessels and Organs - 'The chicken or the egg'?
Andras Nagy, Ph.D., Senior Scientist, Mount Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, Canada
Contact & Intro: Guoping Fan, ext 70439
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ABSTRACT: Vascular Endothelial Growth Factor: a double edged sword
The VEGF-A gene encoding for Vascular Endothelial Growth Factor-A is complex and produces numerous isoforms that carry different biological properties. Understanding the spatial and temporal control of VEGF-A expression during organogenesis and adult function is fundamental for finding out its role in normal and disease processes. The purpose of this talk is to discuss the advantages and disadvantages of recent genetic models that focus on the role of VEGF-A in normal development and physiology.
Therapeutic interventions that deliver VEGF-A to hypoxic tissues have shown great promise in patients with cardiac or peripheral vascular disease permitting the growth of new blood vessels. In contrast, production of VEGF-A by solid tumours induces neovascularization required for tumour growth. Given these results, it is no surprise that VEGF has received great attention in the fight against cancer. The use this factor or its antagonists in treating patients, however, should be approached with caution, due to the pivotal role of proper VEGF-A activity necessary for essential physiological functions.

LITERATURE:
  1. VEGFA is necessary for chondrocyte survival during bone development. Zelzer E, Mamluk R, Ferrara N, Johnson RS, Schipani E, Olsen BR. Development 131: 2161-71 (2004).
  2. Cortical and retinal defects caused by dosage dependent reductions in VEGF-A. Haigh JJ, Gerhardt H, Morelli P, Haigh K, Tsien J, Damert A, Miquerol L, Muhlner U, Klein R, Ferrara N, Wagner EF, Betsholtz C, and Nagy A. Dev Biol 262: 225-241 (2003).
  3. Glomerular-specific alterations of VEGF-A expression lead to distinct congenital and acquired renal diseases. Eremina V, Sood M, Haigh J, Nagy A, Lajoie G, Ferrara N, Gerber HP, Kikkawa Y, Miner JH, Quaggin SE.
    J Clin Invest 111: 707-716 (2003).
Mon, Feb 06
Assessing Genome-wide SNP Platforms Using Multilocus Linkage Disequilibrium
Dan L. Nicolae, Ph.D., Assistant Professor, Department of Statistics, University of Chicago
Contact & Intro: Chiara Sabatti, ext 49567
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ABSTRACT: Genome-wide association studies aim to detect the genetic variation responsible for common diseases in humans. The challenges in analyzing the data generated by these studies come from the complexity of both the phenotypes and of the genetic data. The analysis and interpretation of the genetic data can be greatly improved by detailed information on how the SNPs included in the genotyped set interrogate all known variation across the genome. I will exemplify by showing the coverage and characteristics of the Affymetrix GeneChip Mapping Array 100K SNP Set, and I will discuss strategies for genome-wide analyses.

LITERATURE:
  1. Optimal selection of SNP markers for disease association studies. Halldórsson BV, Istrail S, De La Vega FM. Hum Hered 58:190-202 (2004).
  2. Determinants of the success of whole-genome association testing. Clark AG, Boerwinkle E, Hixson J, Sing CF. Genome Res 15:1463-1467 (2005).
Mon, Feb 13
Optical Mapping and Its Applications to Discovering Structural Variations in Genomes
Anton Valouev, Graduate student, Department of Mathematics, University of Southern California
Contact & Intro: Chiara Sabatti, ext 49567
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ABSTRACT: Optical Mapping is a powerful high-throughput genome wide restriction mapping technology in which restriction maps of single DNA molecules can be acquired using light microscopy and an array of software tools which include image analysis, whole-genome assembler, and variation caller. In this talk I will give an overview of Optical Mapping technology and will explain some statistical aspects associated with calling structural variants in genomes which include insertions/deletions, differences at restriction sites, inversions, translocations.

LITERATURE:
  1. A Microfluidic System for Large DNA Molecule Arrays. Dimalanta ET, Lim A, Runnheim R, Lamers C, Churas C, Forrest DK, de Pablo JJ, Graham MD, Coppersmith SN, Goldstein S, and Schwartz DC. Anal. Chem. 76: 5293-5301 (2004).
Mon, Feb 27
Circulating Mesenchymal Progenitor Cells in Promoting Pulmonary Fibrosis
Robert M. Strieter, M.D., Professor and Chair, Division of Pulmonary and Critical Care Medicine, Vice Chair, Department of Medicine, Professor of Pathology and Pediatrics, David Geffen School of Medicine at UCLA
Contact & Intro: Esteban Dell' Angelica, ext 63749
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ABSTRACT: Historically, tissue repair was thought to be primarily related to local cellular events with the exception of platelet degradation and recruitment of leukocytes during the coagulation and inflammatory phases of repair. However, recent studies have challenged this paradigm, and have demonstrated the existence of populations of circulating adult stem cells that behave as progenitor cells that can differentiate into endothelial cells, muscle cells, neural cells, hepatic cells, osteoblasts, myofibroblasts. The mesenchymal stem cells are believed to reside primarily in the bone marrow and are mobilized to enter the pool of circulating blood cells when exposed to specific environmental cues, traffic to specific tissue sites, and within their new tissue microniche and in response to specific environmental cues differentiate into specific cellular lineages. The function of these cells may be critical for maintenance of homeostasis of peripheral organs, or they can be recruited to participate in repair following tissue injury. Our presentation will focus on a circulating pool of cells that are mesenchymal stem cells with evidence for plasticity to differentiate into myofibroblasts, adipocytes, and osteoblasts. Our findings demonstrate that under conditions of evolving pulmonary fibrosis and in response to TGF-β, these cells can differentiate into myofibroblasts and play a major role in promoting fibrosis. However, if these cells are exposed to different microenvironmental cues and in the absence of TGF-beta, they can differentiate into adipocytes and form adipose tissue, which is relevant to their contribution to form adipose tissue related to metabolic syndrome. These findings support the notion that developing strategies to target the trafficking of these cells to specific tissue sites may serve as novel therapeutic intervention to attenuate their role in promoting fibrosis and adiposity.

LITERATURE:
  1. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Ying Xue Y, Belperio JA, Keane MP, Strieter RM. The Journal of Clinical Investigation. 114:438-446 (2004).
  2. Pulmonary fibrosis: thinking outside of the lung. Garantziotis S, Steele MP, Schwartz DA. The Journal of Clinical Investigation. 114:319-321 (2004).
  3. Characterization of human fibrocytes as circulating adipocyte progenitors and the formation of human adipose tissue in SCID mice. Hong KM, Burdick MD, Phillips RJ, Heber D, Strieter, RM. FASEB Journal express article 10.1096/fj.05-4295fje. Published online (2005).
  4. Circulating Fibrocytes: Collagen-secreting Cells of the Peripheral Blood. Quan TE, Cowper S, Wu S-P, Bockenstedt L, Bucala R. The International Journal of Biochemistry & Cell Biology. 36:598–606 (2004).
  5. Fibrocytes: a unique cell population implicated in wound healing. Metz, CN. CMLS Cellular and Molecular Life Sciences. 60:1342–1350 (2003).
Mon, Mar 06
Evidence for Ancestral Structure in Human Populations
Jeffrey Wall, Ph.D., Assistant Professor, Program in Molecular and Computational Biology, University of Southern California
Contact & Intro: Chiara Sabatti, Ph.D., ext 49567
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ABSTRACT: Determining the evolutionary relationships between fossil hominid groups such as Neanderthals and modern humans has been a question of enduring interest in human evolutionary genetics. Here we present a new method for addressing whether archaic human groups contributed to the modern gene pool (called ancient admixture) using the patterns of linkage disequilibrium in contemporary human populations. Our method improves on previous work by explicitly accounting for recent population history before performing the analyses. Using sequence data from the Environmental Genome Project, we find strong evidence for ancient admixture in both a European and a West African population (p < 10-8), with contributions to the modern gene pool of at least 7%. While Neanderthals form an obvious archaic source population candidate in Europe, there is not yet a clear source population candidate in West Africa.

LITERATURE:
  1. Detecting Ancient Admixture in Humans Using Sequence Polymorphism Data. Wall, JD. Genetics 154:1271-1279 (2000).
Tue, Mar 07
Talk is scheduled 12-1pm
Common Genetic Variants Modulates Cardiac Repolarization (QT Interval)
Aravinda Chakravarti, Ph.D., Henry J. Knott Professor and Director, McKusick - Nathans Institute of Genetics Medicine, Johns Hopkins University School of Medicine
Contact & Intro: Chiara Sabatti, ext 49567
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ABSTRACT: When extreme, the QT interval, a measure of cardiac repolarization, is associated with increased cardiovascular mortality. We performed a genome-wide association study of the QT interval distribution to identify common variants modulating this trait. At least one of the targets is CAPON, a regulator of neuronal NOS, but many more such gene variants remain to be discovered.

LITERATURE:
  1. Genomics in Sudden Cardiac Death. Arking DE, Chugh SS, Chakravarti A, Spooner PM. Circulation Reviews 94: 712 - 723, 2004.
  2. A Haplotype Map of the Human Genome. The International HapMap Consortium (includes A. Chakravarti). Nature 437: 1299-1320, 2005.
Mon, Mar 13
Novel Mechanisms of Neurodegeneration-Insights from Mouse Cerebellar Mutants
Susan L. Ackerman, Ph.D., Investigator and Staff Scientist, Howard Hughes Medical Institute, The Jackson Laboratory, Bar Harbor, Maine
Contact & Intro: Guoping Fan, Ph.D., ext 70439
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ABSTRACT: Abnormal protein aggregation is common to many neurodegenerative and other pathological conditions. Although some of these abnormally folded proteins result from mutations in genes encoding the disease-associated protein, the in vivo mechanisms that are non-intrinsic to misfolded proteins remain largely unknown. Using a phenotype-driven or forward genetic approach, our lab has identified two genes that when disrupted cause neuronal accumulation of misfolded proteins and subsequent degeneration. In addition to this work, I will discuss genetic strategies for identifying novel genes that suppress the formation of protein aggregates and neuron loss.

LITERATURE:
  1. The harlequin mouse mutation down-regulates apoptosis-inducing factor. Klein JA, Longo-Guess CM, Rossmann MP, Seburn KL, Hurd RE, Frankel WN, Bronson RT, Ackerman SL. Nature 419:367-374 (2002).
  2. Protein accumulation and neurodegeneration in the woozy mutant mouse is caused by disruption of SIL1, a cochaperone of BiP. Zhao L, Longo-Guess C, Harris BS, Lee J-W, Ackerman SL. Nature Genetics 37:974-979 (2005).

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