David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Winter Quarter 2008

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

Mon, Jan 14
Haplotypes in the germline and in the soma: ancestral IBD segments and tumor amplification
Itsik Pe'er, PhD, Assistant Professor, Department of Computer Science & Center for Computational Biology & Bioinformatics, Columbia University
Contact & Intro: Chiara Sabatti, ext 49567
View details »

ABSTRACT: Whole genome association studies have recently proven an effective tool in exposing subtle genetic effects of germline single nucleotide polymorphisms on disease susceptibility by genotyping many thousands of individuals. We present two efforts to expand the methodology of genetic association to new domains:
(i) We present a novel, linear-time method for detecting Identity By Descent (IBD) between all pairs of individuals, facilitating analysis of shared, long range haplotypes across thousands of samples towards searching for rare, causal variants.
(ii) We extend the Transmission-Disequilibrium Test (TDT) from germline to somatic variation, and search for tumor-amplified genomic regions that select for the presence of a particular allele. We detect such allelic imbalance to be common across the genome in lung and breast cancer.

Mon, Jan 28
Genome-wide association studies for type 2 diabetes and diabetes-related traits
Michael Boehnke, PhD, Professor, Department of Biostatistics and Center for Statistical Genetics, University of Michigan
Contact & Intro: Chiara Sabatti, ext 49567
View details »

ABSTRACT: Genome-wide association studies (GWAS) provide an efficient means to identify common genetic variants that predispose to human disease or are responsible for variability in quantitative traits. In this seminar, I will discuss the design and initial results of a GWAS of type 2 diabetes we are carrying out as part of the Finland-United States Investigation of NIDDM Genetics (FUSION) Study.

  1. A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Scott L, Mohlke K, Bonnycastle L, Willer C, Li Y, Duren W, Erdos M, Stringham H, Chines P, Jackson A, Prokunina-Olsson L, Ding C, Swift A, Narisu N, Hu T, Pruim R, Xiao R, Li X-Y, Conneely K, Riebow N, Sprau A, Tong M, White P, Hetrick K, Barnhart M, Bark C, Goldstein J, Watkins L, Xiang F, Saramies J, Buchanan T, Watanabe R, Valle T, Kinnunen L, Abecasis G, Pugh E, Doheny K, Bergman R, Tuomilehto J, Collins F, Boehnke M. Science 316:1341-1345 (2007).
  2. Newly identified loci that influence lipid concentrations and risk of coronary artery disease. Willer C, Sanna S, Jackson A, Scuteri A, Bonnycastle L, Clarke R, Heath S, Timpson N, Najjar S, Stringham H, Strait J, Duren W, Maschio A, Busonero F, Mulas A, Albai G, Swift A, Morken M, Narisu N, Bennett D, Parish S, Shen H, Galan P, Meneton P, Hercberg S, Zelenika D, Chen W-M, Li Y, Sundvall J, Watanabe R, Nagaraja R, Ebrahim S, Lawlor D, Ben-Shlomo Y, Davey-Smith G, Shuldiner A, Collins R, Bergman R, Uda M, Tuomilehto J, Cao A, Collins F, Lakatta E, Lathrop M, Boehnke M, Schlessinger D, Mohlke K, Abecasis G. Nature Genetics: advance online publication (2008).
Mon, Feb 04
Activity patterns in biological networks: statistical analysis and network reconstruction
Daphne Koller, PhD, Professor, Department of Computer Science, Stanford University
Contact & Intro: Jake Lusis, ext 51359
View details »

ABSTRACT: Significant insight about biological networks arises from the study of network motifs: small wiring patterns that are overly abundant in the network. However, wiring patterns, like a street map, only reflect the set of potential routes within a cellular network, but not when and how they are used within different cellular processes. We study the functional behavior of networks by introducing the notion of 'activity motifs', which, like traffic flow, reflect dynamic and context-specific patterns in functional data that are abundant relative to the given network. The framework of activity motifs can be utilized to analyze properties of biological networks, and to inform algorithms that reconstruct the network structure. The talk will describe the framework of activity motifs and some of its applications to different networks and different types of functional data.

As one example, we use this framework to study the fine-grained timing of transcriptional regulation in Saccharomyces cerevisiae metabolism. We find that metabolic pathways are enriched for a variety of patterns, such as ordered activation or repression in linear chains; these patterns allow for efficient production and degradation in response to environment changes. To study the mechanism underlying fine-grained timing, we define activity motifs involving the binding strength of a single transcription factor to its targets. We find sequential binding motifs, where the genes in a linear chain have ordered binding strength to a single transcription factor. These binding motifs overlap significantly with the timed motifs, suggesting that fine gradations in transcription factor affinity provide one mechanism for ordered transcription. We then utilize the framework of activity motifs to define a novel method for the reconstruction of metabolic networks and show that its reconstruction accuracy is significantly better than that of previous methods.

We will also present preliminary results for the analysis and reconstruction of phosphorylation networks using a novel data set of genetic interactions.

Joint work with Gal Chechik, Eugene Oh, Oliver Rando, Jonathan Weissman, and Aviv Regev; Dorothea Fiedler, Gerard Cagney, Yanxin Shi, Kevan Shokat, and Nevan Krogan.

  1. Network motifs in the transcriptional regulation network of Escherichia coli. Shen-Orr SS, Milo R, Mangan S, Alon U. Nature Genetics 31:64-8 (2002).
  2. Just-in-time transcription program in metabolic pathways. Zaslaver A et al. Nature Genetics 36:486-91 (2004).
  3. Extensive low-affinity transcriptional interactions in the yeast genome. Tanay A. Genome Research 16:962-72 (2006).
Mon, Feb 11
Genome-wide ancestry analysis in admixed populations
Hua Tang, PhD, Assistant Professor, Department of Genetics, Stanford University School of Medicine
Contact & Intro: Chiara Sabatti, ext 49567
View details »

ABSTRACT: A chromosome in an individual of recently admixed ancestry resembles a mosaic of chromosomal segments, or ancestry blocks, each derived from a particular ancestral population. We consider the problem of inferring ancestry along the chromosomes in an admixed individual and thereby delineating the ancestry blocks. Using a simple population model, we infer gene-flow history in each individual. Compared with existing methods, which are based on a hidden Markov model, the Markov–hidden Markov model (MHMM) we propose has the advantage of accounting for the background linkage disequilibrium (LD) that exists in ancestral populations. We use simulations to illustrate the accuracy of the inferred ancestry as well as the importance of modeling the background LD; not accounting for background LD between markers may mislead us to false inferences about mixed ancestry in an indigenous population. The MHMM makes it possible to identify genomic blocks of a particular ancestry by use of any high-density SNP panels. I will discuss applications of this method in a study of Puerto Ricans.

  1. Reconstructing genetic ancestry blocks in admixed individuals. Tang H, Coram M, Wang P, Zhu X, Risch N. American Journal of Human Genetics. 79:1-12 (2006) Epub 2006 May 17. PMID: 16773560 [PubMed - indexed for MEDLINE]
  2. Recent genetic selection in the ancestral admixture of Puerto Ricans. Tang H, Choudhry S, Mei R, Morgan M, Rodriguez-Cintron W, Burchard EG, Risch NJ. American Journal of Human Genetics. 81:626-33 (2007) Epub 2007 Aug 1. PMID: 17701908 [PubMed - indexed for MEDLINE]
Mon, Feb 25
The role of Filamin B in skeletogenesis
Deborah Krakow, MD, Faculty, Division of Maternal-Fetal Medicine, Cedars-Sinai Medical Center and Associate Professor of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA
Contact & Intro: Paivi Pajukanta, ext 72011
View details »

ABSTRACT: Filamin B (FLNB) is a cytoskeleton protein involved in a variety of cellular processes including actin binding, cell division, cell migration, transport of cellular solutes, and provides a scaffold for signaling molecules. FLNB, and it paralogues, FLNA and FLNC are composed of two calponin homology domains (CHD1 and CHD2) and 24 highly homologous β-sheet repeats that are separated by two hinge regions. Filamin B homodimers localize juxtomembrane and it is hypothesized that the homodimers aid the extracellular matrix to communicate with intracellular processes. Mutations in FLNB underlie a variety of skeletal dysplasias; autosomal recessive spondylocarpotarsal syndrome (SCT) and the autosomal dominant disorders, Larsen syndrome (LS), atelosteogenesis I and III (AOI/AOIII) and Boomerang dysplasia (BD). SCT results from nonsense mutations scattered through the 24 repeat structures. The dominant disorders result from heterozygosity for conserved residues residing primarily in two domains, CHD2 and the repeat domains 14-17 that surround the first hinge of the molecule.

To further understand why mutations in FLNB, a ubiquitously expressed protein, results in skeletal dysplasias, a Flnb -/- mouse was generated using a fusion genetrap containing β-galactosidase. Studies of embryonic days 11-16 demonstrated that the expressed filamin B is highly expressed throughout the developing skeleton, especially condensing chondrocytes. Homozygous mice were statistically smaller than their wild type and heterozygous littermates. Analysis of the newborn (P1) skeletal preparations revealed aberrant mineralization in the neural arches leading to fusions between the individual vertebrae in the cervical and thoracic region. Analysis of P60 Flnb -/- mice showed progressive vertebrae fusions involving the ventral and dorsal vertebral bodies (neural arches and the centrum) in the cervical, thoracic and lumbar regions. Fusions also developed in the sternum. Micro-CT analysis of Flnb -/- mice demonstrated both vertebral and carpal fusions, closely phenocoping the human disorder. Analysis of sternal/rib chondrocytes from -/- animals demonstrated enhanced bone morphogenic activity (BMP) intrinsically and upon in-vitro stimulation with BMP2. Further enhanced BMP activity was seen with TGF-β stimulation suggesting enhanced BMP activity through two mechanisms. Further analysis of this animal model will provide insight into the mechanism of disease in SCT and will help determine the functional role of filamin B in the developing skeleton.

The role of filamin B in skeletogenesis. Merrill-Brugger A, Farrington-Rock C, Cohn DH, Krakow D.

  1. Mutations in the gene encoding filamin B disrupt vertebral segmentation, joint formation and skeletogenesis. Krakow D, Robertson SP, King LM, Morgan T, Sebald ET, Bertolotto C, Wachsmann-Hogiu S, Acuna D, Shapiro SS, Takafuta T, Aftimos S, Kim CA, Firth H, Steiner CE, Cormier-Daire V, Superti-Furga A, Bonafe L, Graham Jr JM, Grix A, Bacino CA, Allanson J, Bialer MG, Lachman RS, Rimoin DL, Cohn DH. Nature Genetics 36: 405-410 (2004).
  2. Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome. Farrington-Rock C, Kirilova V, Dillard-Telm L, Borowsky AD, Chalk S, Rock MJ, Cohn DH, Krakow D. HMG Advance Access published July 17, 2007.
  3. FLNB caused by mutations in a molecular and clinical study of Larsen syndrome. Cohn DH, Krakow D, Robertson SP, Shafeghati Y, Rump P, Alanay Y, Alembik Y, Al-Madani N, Firth H, Karimi-Nejad MH, Kim CA, Leask K, Maisenbacher M, Moran E, Pappas JG, Prontera P, de Ravel T, Fryns J-P, Sweeney E, Fryer A, Unger S, Wilson LC, Lachman RS, Rimoin DL, Cohn DH, Krakow D, Robertson SP. Journal of Medical Genetics 44:89-98 (2007) Originally published online 26 June 2006.
Mon, Mar 03
Transmission of parentally shared human leukocyte antigen alleles and the risk of preterm delivery
De-Kun Li, MD, PhD, Senior Research Scientist, Division of Research, Kaiser Foundation Research Institute, Kaiser Permanente, Oakland
Contact & Intro: Christina Jamieson, ext 62597
View details »

OBJECTIVE: Our objective was to examine our hypothesis that the transmission of parentally shared human leukocyte antigen (HLA) alleles to offspring increases the risk of preterm delivery.
METHODS: A population-based family study with participating children and their parents was conducted in Kaiser Permanente Medical Care Program, an integrated healthcare delivery system, in the Northern California Region. A total of 234 participants from 78 families with early preterm deliveries (35 weeks of gestation or less) and 60 participants from 20 families with full-term births were included in the study. Buccal cells were collected from the first-born preterm cases and their parents to determine HLA-B (class I) and DRB1 (class II) types and the transmission of parental alleles to the offspring. The buccal samples were also collected from full-term deliveries to rule out possible segregation distortion at the studied HLA loci.
RESULTS: Compared with the expected transmission probability based on Mendel’s laws (25%), transmission of parentally shared HLA-B or DRB1 alleles from both heterozygous parents to offspring (48% of 23 heterozygous parents) was associated with a more than 5-fold increased risk of preterm delivery (odds ratio 5.5; 95% confidence interval 1.2–51). Transmission of parentally shared HLA alleles from heterozygous mothers (83%) appears to be more important in the etiology of preterm delivery than transmission from fathers (57%). The transmission pattern of parentally shared HLA alleles in our full-term controls was almost identical to the expected pattern based on Mendel’s laws and demonstrated no segregation distortion at those HLA loci.
CONCLUSION: Our findings provide evidence that the transmission of parentally shared HLA alleles may be an underlying mechanism for preterm delivery.

  1. Changing paternity and the risk of preterm delivery in the subsequent pregnancy. Li D-K. Epidemiology 10:148-152 (1999).
  2. Maternal placental abnormality and the risk of sudden infant death syndrome. Li D-K, Wi S. American Journal of Epidemiology 149:608-11 (1999).
  3. Transmission of parentally shared human leukocyte antigen alleles and the risk of preterm delivery. Li D-K, Odouli, R, Liu L, Vinson M, Trachtenberg E. The American College of Obstetricians and Gynecologists 104:594-600 (2004).
Mon, Mar 10
Talk scheduled 12-1pm, Neuroscience Research Building Auditorium
Roles of coregulators, protein-protein interactions, and protein methylation in transcriptional regulation by nuclear receptors
Michael Stallcup, PhD, Professor and Chair, Department of Biochemistry & Molecular Biology, Norris Comprehensive Cancer Center, University of Southern California
Contact & Intro: Christina Jamieson, ext 62597
View details »

BACKGROUND AND OBJECTIVES: DNA-bound nuclear receptors recruit many coactivator proteins to remodel chromatin and activate transcription. We identified a new coactivator and investigated its role in the function of estrogen receptor α (ER) and estrogen-dependent growth of breast cancer cells. We also investigated the mechanism by which it enhances ER function.
METHODOLOGY: Coactivator activity was investigated with transient transfection assays. Endogenous coactivator function was examined by using siRNA to reduce the endogenous coactivator level and measuring hormone induced levels of mRNAs by quantitative polymerase chain reaction. Localization of proteins on the promoter of the pS2 gene (an endogenous target gene of ER) in MCF-7 cells was accomplished by chromatin immunoprecipitation assays.
RESULTS: Here we report that the protein called cell cycle and apoptosis regulator 1 (CCAR1) binds to and functions as a coactivator for ER and several other nuclear receptors. CCAR1 binds to ER and to CoCoA, which is part of the p160 coactivator complex. Over-expression of CCAR1, either alone or in combination with CoCoA and p160 coactivators, enhanced the hormone-dependent and hormone-independent activity of ER in transient reporter gene assays. In MCF-7 breast cancer cells, endogenous CCAR1 localized to the promoter of the endogenous pS2 gene in a hormone dependent manner. Furthermore, reduction of endogenous CCAR1 levels reduced the induction of pS2 gene expression by estradiol and inhibited the estrogen-dependent growth of MCF-7 cells. The mechanism of CCAR1 coactivator function was investigated by examining the recruitment of ER, various coactivators, and RNA polymerase II to the pS2 promoter in cells with reduced levels of CCAR1. Normal hormone dependent recruitment of ER, p160 coactivator AIB1, and coactivator CoCoA were observed when CCAR1 levels were reduced. In contrast, hormone-dependent recruitment of RNA polymerase II and several components of the Mediator complex (an important coactivator complex involved in recruitment of RNA polymerase II) was substantially inhibited in cells with reduced CCAR1 levels. CCAR1 binds to several Mediator subunits as well as components of the p160 coactivator complex.
CONCLUSIONS: We therefore propose that CCAR1 coordinates the hierarchy of recruitment and the activities of two critical coactivator complexes: the p160 coactivator complex, which is recruited directly by the DNA-bound ER; and the Mediator complex, which requires CCAR1 for its recruitment to the promoter.

  1. The roles of protein-protein interactions and protein methylation in transcriptional activation by nuclear receptors and their coactivators. Stallcup MR, Kim JH, Teyssier C, Lee Y-H, Ma H, Chen D. The Journal of Steroid Biochemistry and Molecular Biology 85:139-145 (2003).
  2. CoCoA, a nuclear receptor coactivator which acts through an N-terminal activation domain of p160 coactivators. Kim JH, Li H, Stallcup MR. Molecular Cell 12:1537-1549 (2003).
  3. Downstream signaling mechanism of the C-terminal activation domain of transcriptional coactivator CoCoA. Kim JH, Yang CK, Stallcup MR. Nucleic Acids Research 34:2736-2750 (2006).
Mon, Mar 17
Epigenetic mechanisms in human diseases
Taiping Chen, PhD, Laboratory Head & Research Investigator, The Epigenetics Program, Novartis Institutes for Biomedical Research
Contact & Intro: Guoping Fan, ext 70439
View details »

ABSTRACT: Epigenetic mechanisms such as DNA methylation and histone modifications coordinately regulate gene expression and chromatin structure. Aberrant changes in epigenetic modifications are associated with a variety of human diseases, including cancer, neurological disorders, and immunological disorders. The reversibility of epigenetic modifications makes epigenetic factors an attractive class of targets for therapeutic intervention. The focus of our research is to understand the role of epigenetic mechanisms in various diseases and to validate epigenetic factors as therapeutic targets for these diseases. In this seminar, I intend to discuss the following topics: 1) DNA methylation in cancer, 2) the lysine demethylase LSD1 in mouse development and epigenetic regulation, and 3) generation of mouse models for Rett syndrome.

  1. Establishment and maintenance of DNA methylation patterns in mammals. Chen T, Li E. Current Topics in Microbiology and Immunology 301:179-201 (2006).
  2. Complete inactivation of DNMT1 leads to mitotic catastrophe in human cancer cells. Chen T, Hevi S, Gay F, Tsujimoto N, He T, Zhang B, Ueda Y, Li E. Nature Genetics 39:391-396 (2007).

Previous Quarters