David Geffen School of Medicine at UCLA
Department of Human Genetics

Speaker Series - Fall Quarter 2007

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

Mon, Oct 01
Stochastic demography, coalescents, and effective population size
Stephen Krone, PhD, Professor of Mathematics & Professor of Bioinformatics and Computational Biology, University of Idaho
Contact & Intro: Chiara Sabatti
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ABSTRACT: In population genetics, deviations from the “usual assumptions” (e.g., constant population size, panmixia, etc.) sometimes have no measurable effect on polymorphism data; in other cases, the effects can be substantial. The key to understanding the difference can be found in relative time scales in the setting of the coalescent. We will discuss conditions under which the genealogy for a (model of a) sample from a population that has stochastic demography or population structure can be characterized by the standard (Kingman) coalescent with a linear change in time scale. We argue that such conditions are necessary for a meaningful notion of effective population size. When these conditions are not met, we show that the appropriate genealogy is given by a stochastic nonlinear time change of the standard coalescent. We illustrate these ideas with simulations of Fu and Li’s F and Tajima’s D under models of stochastically fluctuating size and geographic structure.

  1. On the meaning and existence of an effective population size. Sjödin P, Kaj I, Krone S, Lascoux M, Nordborg M. Genetics 169:1061-1070 (2005).
  2. Separation of time scales and convergence to the coalescent in structured populations. Nordborg M, Krone S. Modern Developments in Theoretical Population Genetics. Slatkin M and Veuille M, editors. Oxford University Press: 194-232 (2002).
Mon, Oct 08
Noncompaction of the left ventricular myocardium
Michael Zaragoza, MD, PhD, Assistant Clinical Professor, Department of Pediatrics, Divison of Genetics and Metabolism, The Center for Mitochondrial and Molecular Medicine and Genetics, University of California, Irvine
Contact & Intro: Eric Vilain
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ABSTRACT: Noncompaction of the left ventricular myocardium (NCLV) is a primary genetic cardiomyopathy characterized by prominent trabeculae and deep intertrabecular recesses in the myocardial wall. NCLV is thought to arise from a block in the embryonic process in which myofibrils compact during cardiogenesis. This is thought to result in the characteristic two layers consisting of compacted and noncompacted myocardium. Clinical manifestations of NCLV are variable. Patients may develop ventricular dysfunction, heart failure, arrhythmia or complications due to thromboembolism whereas others remain asymptomatic. The genetic etiology of NCLV is heterogeneous. Mutations in TAZ on Xq28, DTNA on 18q12.1, LDB3 on 10q23.2 and LMNA on 1q22 have been described in patients. Genetic linkage to 11p15 has been reported in a single family. Despite these findings, the etiology of most NCLV is unknown. This presentation describes clinical and molecular studies of three unrelated families with NCLV. The first family consists of affected twin girls who carry a balanced translocation involving chromosomes 10 and 11. The second is a four-generation family with multiple affected members. The third family is a three-generation family with a recently diagnosed two year-old girl who presented with new onset heart failure. To identify the disease-causing gene, we mapped the chromosomal breakpoint in the first family and conducted genetic linkage analysis in the second family. By FISH using BACs and long range PCR-derived probes, the breakpoints on chromosome 10 and 11 have been localized. Linkage analysis using markers spanning the chromosomal regions demonstrate linkage with chromosome 11. Evaluation of the third family is in progress. Our results provide evidence for a common genetic etiology in the first two families and suggest that an additional locus for NCLV exists on chromosome 11. Determination of the genetic basis will enhance our understanding of NCLV and ventricular development.

  1. Disruption of planar cell polarity signaling results in congenital heart defects and cardiomyopathy attributable to early cardiomyocyte disorganization. Phillips HM, Rhee HJ, Murdoch JN, Hildreth V, Peat JD, Anderson RH, Copp AJ, Chaudhry B, Henderson DJ. Circulation Research 101:137-45 (2007).
  2. A molecular pathway including Id2, Tbx5, and Nkx2-5 required for cardiac conduction system development. Moskowitz IP, Kim JB, Moore ML, Wolf CM, Peterson MA, Shendure J, Nobrega MA, Yokota Y, Berul C, Izumo S, Seidman JG, Seidman CE. Cell 129:1365-76 (2007).
  3. Nkx2-5 pathways and congenital heart disease; loss of ventricular myocyte lineage specification leads to progressive cardiomyopathy and complete heart block. Pashmforoush M, Lu JT, Chen H, Amand TS, Kondo R, Pradervand S, Evans SM, Clark B, Feramisco JR, Giles W, Ho SY, Benson DW, Silberbach M, Shou W, Chien KR. Cell 117:373-86 (2004).
Mon, Oct 15
Genetic and epigenetic analyses of non-Hodgkin lymphoma
Joseph G. Hacia, PhD, Associate Professor, Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California
Contact & Intro: Paivi Pajukanta
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ABSTRACT: While gene expression, genomic copy number, and mutational analyses have provided key insights into the genetic basis for the extensive pathologic and biologic heterogeneity in diffuse large B-cell lymphoma (DLBCL), considerably less is known about its epigenetic underpinnings. Here, we evaluated the DNA methylation levels of over 500 unique gene-associated CpG islands in DLBCL tumors using McrBC-based CpG island microarray, MethyLight, and bisulfite sequencing analyses. Although we observed variation in DNA methylation across all DLBCL, we identified twelve CpG islands showing significant methylation in greater than 85% of the tumors surveyed. In addition, we compared the methylation and expression status of sixty-seven genes located within 500-bp of our methylation assays. Our observations are more consistent with the potential involvement of DNA methylation in the maintenance relative to the initiation of gene silencing. Nevertheless, the proportional reductions in expression of seven genes with increasing CpG island methylation suggests that epigenetic processes could be causally involved in the initial stages of gene silencing. Overall, the genes highlighted in our analyses warrant further investigation into their roles in the development and progression of DLBCL and potential as clinical biomarkers.

  1. Comparisons of PCR-based genome amplification systems using CpG island microarrays. Pike BL, Groshen S, Hsu YH, Shai RM, Wang X, Holtan N, Futscher BW, Hacia JG. Human Mutation 27: 589-596 (2006).
  2. Motexafin Gadolinium disrupts zinc metabolism in human cancer cell lines. Magda D, Lecane P, Miller RA, Lepp C, Miles D, Mesfin M, Biaglow JE, Ho VV, Chawannakul D, Nagpal S, Karaman MW, Hacia JG. Cancer Research 65: 3837-3845 (2005).
  3. Mutation and genomic deletion status of ataxia telangiectasia mutated (ATM) and p53 confer specific gene expression profiles in mantle cell lymphoma. Greiner TC, Dasgupta C, Ho VV, Weisenburger DD, Smith LM, Lynch JC, Vose JM, Fu K, Armitage JO, Braziel RM, Campo E, Delabie J, Gascoyne RD, Jaffe ES, Muller-Hermelink HK, Ott G, Rosenwald A, Staudt LM, Im MY , Karaman MW, Pike BL, Chan WC, Hacia JG. Proceedings of the National Academy of Sciences 103:2352-2357 (2006).
Mon, Oct 22
Unraveling the genetics of celiac disease: a genomics approach
Cisca Wijmenga, PhD and Lude Franke, MSc, Genetics Department, University Medical Center Gronigen, Gronigen and University Medical Center Utrecht, Utrecht
Contact & Intro: Jake Lusis
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ABSTRACT: Celiac disease is a common (1% prevalence) chronic inflammatory disease of the small intestine, caused by an immune response to dietary wheat, rye and barley that are present in a (Western) daily diet. Genetic predisposition to CD is complex and includes the HLA-DQA105/ DQB102 and HLA-DQA0301/DQB0302 genes as major factors; these are estimated to explain some 40% of the heritability of the disease. The other 60% of the genetic susceptibility to CD is shared between an unknown number of non-HLA genes, each of which is estimated to contribute only a small risk effect. Previously, linkage studies were the only cost-effective way to map and isolate non-HLA genes contributing to CD. Using a linkage strategy we identified the MYO9B gene which encodes an unconventional myosin molecule that has a role in actin remodeling of epithelial enterocytes. This result is suggestive of a primary impairment of the intestinal barrier in the etiology of CD, which may explain why immunogenic gluten peptides are able to pass through the epithelial barrier. This suggestion is in line with results obtained form a large-scale genomics study using gene expression profiling of small intestinal biopsies. More recently we have performed a genome-wide association study and genotyped >300,000 SNPs in 778 CD cases and 1422 population controls. An extended region of highly significant association was seen around the HLA locus (χ2=769.1, P<10-19, OR 7.04 [95% CI 6.08 - 8.15]). Excluding the HLA region, we observed one other SNP that remained significant after permutation testing (P=2.0 x 10-7, empirical genome-wide significance P=0.045). This finding was independently confirmed in two other collections (meta-analysis P=3.8 x 10-11, OR 0.66 [95% CI 0.58 - 0.74]). This SNP maps at the IL2/IL21 locus, a biologically plausible candidate gene and genetic variation in this gene may predispose CD patients towards unwanted immune responses to cereal antigens. It seems plausible, based on the current genetic and functional studies, that causal genes for CD play a role in the barrier function as well as in the immune systems.

To enhance our understanding in the disease process we perform gene expression studies on intestinal biopsy samples of celiac patients. In addition, we employ bioinformatics tools to further aid in our understanding of the molecular pathways involved in disease pathogenesis.

  1. A genome-wide association study for celiac disease identifies risk variants in the region harboring IL2 and IL21. van Heel DA, Franke L, Hunt KA, Gwilliam R, Zhernakova A, Inouye M, Wapenaar MC, Barnardo MCNM, Bethel G, Holmes GKT, Feighery C, Jewell D, Kelleher D, Kumar P, Travis S, Walters JRF, Sanders DS, Howdle P, Swift J, Playford RJ, McLaren WM, Mearin ML, Mulder CJ, McManus R, McGinnis R, Cardon LR, Deloukas P, Wijmenga C. Nature Genetics 39:827-829 (2007).
  2. Neutrophil recruitment and barrier impairment in celiac disease: a genomic study. Diosdado B, Van Bakel H, Strengman E, Franke L, Van Oort E, Mulder CJ, Wijmenga C, Wapenaar MC. Clinical Gastroenterology and Hepatology. In press (2007).
  3. Reconstruction of a functional human gene network, with an application for prioritizing positional candidate genes. Franke L, van Bakel H, Fokkens L, de Jong ED, Egmont-Petersen M, Wijmenga C. The American Journal of Human Genetics Volume 78:1011-1025.
Mon, Oct 29
A multisample change-point model for DNA copy number analysis
Nancy Zhang, PhD, Assistant Professor, Department of Statistics, Stanford University
Contact & Intro: Chiara Sabatti
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ABSTRACT: The DNA copy number of an individual can be viewed as a change-point process along the chromosome, with a ”normal” level at 2 and ”aberrations” being locations where the copy number deviates from normal. Chromosomal aberrations occur naturally in the human population, and are a common source of genetic variation. High throughput genomic profiling technologies have been developed to measure DNA copy number at a fine scale along the chromosome. Given this data for a sample of individuals from the population, how do we statistically detect locations of shared aberration across individuals?

We discuss the properties of this type of data and propose a mixture model for its analysis, where at each change-point, the sample is composed of a mixture of individuals who have the change and those who do not. We have experimented with several statistics for detection of shared change-points. For some of the statistics, large sample tail approximations for significance evaluation can be derived. We compare the performance of these statistics in the context of DNA copy number detection using replicate samples from the same individual and from parent-child trios.

This is joint work with David Siegmund and Jun Li.

  1. STAC: A method for testing the significance of DNA copy number aberrations across multiple array-CGH experiments. Diskin SJ, Eck T, Greshock J, Mosse YP, Naylor T, Stoeckert Jr. CJ, Weber BL, Maris JM, Grant GR. Genome Research 16:1149–1158 (2006).
  2. Global variation in copy number in the human genome. Redon R, Ishikawa S, Fitch KR, Feuk L, Perry GH, Andrews TD, Fiegler H, Shapero MH, Carson AR, Chen W, Cho EK, Dallaire S, Freeman JL, Gonzalez JR, Gratacos M, Huang J, Kalaitzopoulos D, Komura D, MacDonald JR, Marshall CR, Mei R, Montgomery L, Nishimura K, Okamura K, Shen F, Somerville MJ, Tchinda J, Valsesia A, Woodwark C, Yang F, Zhang J, Zerjal T, Zhang J, Armengol L, Conrad DF, Estivill X, Tyler-Smith C, Carter NP, Aburatani H, Lee C, Jones KW, Scherer SW, Hurles ME, Nature 444:444-454 (2006).
Tue, Oct 30
Neuroscience Research Building Auditorium
Rapid identification of regulatory variants using large-scale transcriptional profiling
John Blangero, Scientist, Department of Genetics, Southwest Foundation for Biomedical Research
Contact & Intro: Chiara Sabatti
Mon, Nov 05
Kernel machines, mixed models and genomic studies
Debashis Ghosh, PhD, Associate Professor, Department of Statistics and Huck Institute of Life Sciences, Penn State University
Contact & Intro: Chiara Sabatti
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ABSTRACT: With the proliferation of genomewide association studies, an important scientific question is how to incorporate the effects of multiple genetic markers in understanding genotype-phenotype associations. In this talk, we discuss application of a class of techniques developed in the machine learning community, known as kernel machines. The most famous example of a kernel machine is the support vector machine. We then characterize an equivalence between the kernel machines with mixed effects models that allow us to fit kernel machines using standard statistical software. Finally, we show how the kernel machine can be applied to the analysis of genetic association studies and pathway analyses. Examples using simulated and real data will be given.

  1. Nonparametric tests of association of multiple genes with human disease. Schaid DJ, McDonnell SK, Hebbring SJ, Cunningham JM, Thibodeau SN. American Journal of Human Genetics 76:780-93 (2005). Epub 2005 Mar 22.
  2. Improved power by use of a weighted score test for linkage disequilibriummapping. Wang T, Elston RC. American Journal of Human Genetics 80:353-60 (2007). Epub 2006 Dec 21.
Mon, Nov 19
Sparse partial least squares regression with applications to transcription factor activity analysis and eQTL mapping
Sunduz Keles, PhD, Assistant Professor, Departments of Statistics and Biostatistics & Medical Informatics, University of Wisconsin
Contact & Intro: Chiara Sabatti
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ABSTRACT: Analysis of modern biological data often involves ill-posed problems due to high dimensionality and multicollinearity. Partial Least Squares (PLS) regression has been an alternative to ordinary least squares for handling multicollinearity in several areas of scientific research since 1960s (Wold, 1966). At the core of the PLS methodology lies a dimension reduction technique coupled with a regression model. Although PLS regression has been shown to achieve good predictive performance, it is not particularly tailored for variable/feature selection and therefore often produces linear combinations of the original predictors that are hard to interpret due to high dimensionality. In this talk, we investigate the known asymptotic properties of the PLS estimator under special case of normality and show that its consistency breaks down with the very large p and small n paradigm. We, then, propose a sparse partial least squares (SPLS) formulation which aims to simultaneously achieve good predictive performance and variable selection by producing sparse linear combinations of the original predictors. We provide an efficient implementation of SPLS based on the LARS algorithm (Efron et al. 2004). An additional advantage of the SPLS algorithm is that it naturally handles multivariate responses. We illustrate the methodology in a joint analysis of gene expression and genome-wide binding data and provide preliminary results on an application to eQTL mapping.

  1. Supervised PCR Prediction by Supervised Principal Components. Bair E, Hastie T, Paul D, Tibshirani R. Journal of the American Statistical Association 473:119-137 (2006).
  2. Partial least squares: a versatile tool for the analysis of high-dimensional genomic data. Boulesteix A-L, Strimmer K. Briefings in Bioinformatics 8:32-44 (2007).
  3. Gene expression & ChIP-chip: Group SCAD regression analysis for microarray time course gene expression data. Wang L, Chen G, Li H. Bioinformatics 23:1486-1494 (2007).
Mon, Dec 03
A multi-faceted approach to understanding the role of the 5-lipoxygenase pathway in cardiovascular and metabolic diseases
Hooman Allayee, PhD, Assistant Professor, Department of Preventive Medicine, Director, Molecular Genetics Laboratory, General Clinical Research Center, Keck School of Medicine, University of Southern California
Contact & Intro: Paivi Pajukanta
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ABSTRACT: The 5-Lipoxygenase (5-LO) pathway, which generates pro-inflammatory leukotrienes (LTs) from arachidonic acid, is known to play an important role in asthma but has recently garnered a great deal of attention for its potential involvement in cardiovascular disease (CVD). This stems from a series of studies over the last few years ranging from biochemical, genetic, and pharmacological studies in both mice and humans, which collectively have provided strong evidence for the pro-atherogenic role of LTs. For example, we previously used an integrative genetics approach with inbred strains, genetically targeted mice, and microarray profiling to demonstrate that 5-LO deficiency leads to a profound resistance to atherosclerosis as well as metabolic disturbances such as obesity and impaired insulin secretion. In humans, we and others have reported findings consistent with the mouse models, particularly with respect to the notion that the 5-LO/LT pathway participates in atherosclerotic processes. For example, individuals carrying variant alleles of a 5-LO promoter polymorphism have significantly increased carotid atherosclerosis. This pro-atherogenic effect was exacerbated in the context of high dietary arachidonic acid levels whereas high dietary omega-3 fatty acids, which are also substrates for 5-LO but generate non-inflammatory LTs, blunted this effect. More recently, we have confirmed these initial genetic and gene-dietary interactions with a more clinically relevant phenotype, such as MI, in a large Costa Rican cohort. These latter results also reveal a significant nutri-genetic association between the shorter promoter alleles, dietary arachidonic acid, and risk of MI, and demonstrate that the associated alleles lead to increased 5-LO expression. Consistent with these observations are large-scale genetic studies from other groups, which have reported association between other 5-LO pathway genes and various CVD traits. An overview of these combined mouse-human studies and the role of the 5-LO pathway in CVD and diabetes-related traits will be presented.

  1. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. Dwyer JH, Allayee H, Dwyer KM, Fan J, Huiyun W, Mar R, Lusis AJ, Mehrabian M. The New England Journal of Medicine 350:29-37 (2004).
  2. Integrating genotypic and expression data in a segregating mouse population to identify 5-lipoxygenase as a susceptibility gene for obesity and bone traits. Mehrabian M, Allayee H, Stockton J, Lum PY, Drake T, Castellani LW, Suh M, Armour C, Edwards Lamb J, Lusis AJ, Schadt EE. Nature Genetics 37:1224-1233 (2005).
  3. Nonconventional genetic risk factors for cardiovascular disease. Tymchuk CN, Hartiala J, Patel PI, Mehrabian M, Allayee H. Current Atherosclerosis Reports 8:184-192 (2006).
  4. The effect of Montelukast and low-dose Theophylline on cardiovascular disease risk factors in asthmatics. Allayee H, Hartiala J, Lee W, Mehrabian M, Irvin CG, Conti DV, Lima JJ. CHEST 132:868–874 (2007).

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