Genetics and Genomics Commons^™

Loss-Based Estimation With Cross-Validation: Applications To Microarray Data Analysis And Motif Finding, Sandrine Dudoit, Mark J. Van Der Laan, Sunduz Keles, Annette M. Molinaro, Sandra E. Sinisi, Siew Leng Teng

U.C. Berkeley Division of Biostatistics Working Paper Series

Current statistical inference problems in genomic data analysis involve parameter estimation for high-dimensional multivariate distributions, with typically unknown and intricate correlation patterns among variables. Addressing these inference questions satisfactorily requires: (i) an intensive and thorough search of the parameter space to generate good candidate estimators, (ii) an approach for selecting an optimal estimator among these candidates, and (iii) a method for reliably assessing the performance of the resulting estimator. We propose a unified loss-based methodology for estimator construction, selection, and performance assessment with cross-validation. In this approach, the parameter of interest is defined as the risk minimizer for a suitable …

Comprehensive Analysis Of Class I And Class Ii Hla Antigens And Chronic Hepatitis B Virus Infection, Chloe L. Thio, David L. Thomas, Peter Karacki, Xiaojiang Gao, Darlene Marti, Richard A. Kaslow, James J. Goedert, Margaret Hilgartner, Steffanie A. Strathdee, Priya Duggal, Stephen J. O'Brien, Jacquie Astemborski, Mary Carrington

Biology Faculty Articles

Following an acute hepatitis B virus (HBV) infection, clearance or persistence is determined in part by the vigor and breadth of the host immune response. Since the human leukocyte antigen system (HLA) is an integral component of the immune response, we hypothesized that the highly polymorphic HLA genes are key determinants of viral clearance. HLA class I and II genes were molecularly typed in 194 Caucasian individuals with viral persistence and 342 matched controls who had cleared the virus. A single class I allele, A*0301 (odds ratio [OR], 0.47; 95% confidence interval [CI], 0.30 to 0.72; P = 0.0005) was …

Reconstructing The Genomic Architecture Of Mammalian Ancestors Using Multispecies Comparative Maps, William J. Murphy, Guillaume Bourque, Glenn Tesler, Pavel Pevzner, Stephen J. O'Brien

Biology Faculty Articles

Rapidly developing comparative gene maps in selected mammal species are providing an opportunity to reconstruct the genomic architecture of mammalian ancestors and study rearrangements that transformed this ancestral genome into existing mammalian genomes. Here, the recently developed Multiple Genome Rearrangement (MGR) algorithm is applied to human, mouse, cat and cattle comparative maps (with 311-470 shared markers) to impute the ancestral mammalian genome. Reconstructed ancestors consist of 70-100 conserved segments shared across the genomes that have been exchanged by rearrangement events along the ordinal lineages leading to modern species genomes. Genomic distances between species, dominated by inversions (reversals) and translocations, are …

Initial State Of The Drosophila Eye Before Dorsoventral Specification Is Equivalent To Ventral, Amit Singh, Kwang-Wook Choi

Biology Faculty Publications

Dorsoventral (DV) patterning is crucial for eye development in invertebrates and higher animals. DV lineage restriction is the primary event in undifferentiated early eye primordia of Drosophila. InDrosophila eye disc, a dorsal-specific GATA family transcription factor pannier (pnr) controls Iroquois-Complex (Iro-C) genes to establish the dorsal eye fate whereas Lobe (L), which is involved in controlling a Notch ligand Serrate (Ser), is specifically required for ventral growth. However, fate of eye disc cells before the onset of dorsal expression of pnr and Iro-C is not known. We show that L/Ser …

Unification Of Variance Components And Haseman-Elston Regression For Quantitative Trait Linkage Analysis, Wei-Min Chen, Karl W. Broman, Kung-Yee Liang

Johns Hopkins University, Dept. of Biostatistics Working Papers

Two of the major approaches for linkage analysis with quantitative traits in humans include variance components and Haseman-Elston regression. Previously, these have been viewed as quite separate methods. We describe a general model, fit by use of generalized estimating equations (GEE), for which the variance components and Haseman-Elston methods (including many of the extensions to the original Haseman-Elston method) are special cases, corresponding to different choices for a working covariance matrix. We also show that the regression-based test of Sham et al.(2002) is equivalent to a robust score statistic derived from our GEE approach. These results have several important implications. …

A Nested Unsupervised Approach To Identifying Novel Molecular Subtypes, Elizabeth Garrett, Giovanni Parmigiani

Johns Hopkins University, Dept. of Biostatistics Working Papers

In classification problems arising in genomics research it is common to study populations for which a broad class assignment is known (say, normal versus diseased) and one seeks to find undiscovered subclasses within one or both of the known classes. Formally, this problem can be thought of as an unsupervised analysis nested within a supervised one. Here we take the view that the nested unsupervised analysis can successfully utilize information from the entire data set for constructing and/or selecting useful predictors. Specifically, we propose a mixture model approach to the nested unsupervised problem, where the supervised information is used to …

The Hyperthermophilic Archaeon Sulfolobus: From Exploration To Exploitation, Stan J.J. Brouns, Thijs J.G. Ettema, Kenneth M. Stedman, Jasper Walther, Hauke Smith, Ambrosius P.L. Snijders, Mark Young, Rolf Bernander, Phillip C. Wright, Betina Siebers, John Van Der Oost

Biology Faculty Publications and Presentations

In the early 1970s, Sulfolobus was first isolated by Thomas Brock and co-workers from sulfur-rich acidic hot springs in Yellowstone National Park. Sulfolobus became one of the model organisms of Archaea in general, and of Crenarchaea in particular. Many of its unusual physiological characteristics have been investigated, and several of its thermostable enzymes have been studied in considerable detail. For fundamental reasons, and because of its potential for industrial applications, Sulfolobus has been selected for a genome sequence project. The recent completion of the Sulfolobus solfataricus genome has set the stage for a series of postgenome research lines that will …

Human Rights And Genetic Discrimination: Protecting Genomics' Promise For Public Health, Anita Silvers, Michael Ashley Stein

Faculty Publications

No abstract provided.

Tree-Based Multivariate Regression And Density Estimation With Right-Censored Data , Annette M. Molinaro, Sandrine Dudoit, Mark J. Van Der Laan

U.C. Berkeley Division of Biostatistics Working Paper Series

We propose a unified strategy for estimator construction, selection, and performance assessment in the presence of censoring. This approach is entirely driven by the choice of a loss function for the full (uncensored) data structure and can be stated in terms of the following three main steps. (1) Define the parameter of interest as the minimizer of the expected loss, or risk, for a full data loss function chosen to represent the desired measure of performance. Map the full data loss function into an observed (censored) data loss function having the same expected value and leading to an efficient estimator …

Sheep Updates 2003 - Posters, Maxine Brown, Gaye Krebs, Diana Fredorenko, Kathryn Edgerton-Warburton, Evan Burt, Nazrul Islam, Roy Butler, L. G. Butler, S. R. Brown, M. F. D'Antuono, J. C. Greeff, Ken Hart, Tanya Kilminster, Rachel Kirby, M. E. Ladyman, A. C. Schlink, I. H. Williams, P. E. Vercoe, Anyou Lui, Karen Smith, Martin Bent, Matthew Young

Sheep Updates

This session covers eleven papers from different authors:1 Sheep production on annual stubbles/pastures vs lucerne Maxine Brown Gaye Krebs Muresk Institute, Curtin University Diana Fedorenko Kathryn Egerton-Warburton Centre for Cropping Systems, Department of Agriculture Western Australia 2. The value chain of the Lake Grace livestock industry Evan Burt Nazrul Islam Department of Agriculture Western Australia 3. Native pastures, Dorper sheep and the 2002 drought Roy Butler Department of Agriculture Western Australia 4. Commercial sheep breeders can improve their sheep breeding program using wether trials L.G. Butler, S.R. Brown, M.F. D’Antuono, J.C. Greeff Department of Agriculture 5. Western Australia Linked ewe …

Sheep Updates 2003 - Plenaries, Ashley Mercy, David Scobie, Neil Buchanan, Kevin Bell, John Milton, Graeme Martin, Bob Hall, Maurie Stephen, Rob Woodgate

Sheep Updates

This session covers eight papers from different authors:1. Biosecurity in the sheep industry will improve production and profits Ashley Mercy, Department of Agriculture, Western Australia 2. Easy care sheep David Scobie, AgResearch, PO Box 60 Lincoln, 8152, New Zealand 3. Targeting the market’s requirements - live sheep exports Neil Buchanan, Manager Animal Health Operations, Primary Industries & Resources, South Australia 4. Setting flock breeding objectives Kevin Bell, Sheep Management and Production Consultants, Kojonup WA 5. Future feeding of sheep in Western Australia John Milton and Graeme Martin, The University of Western Australia 6. Recipe for getting back into Sheep Bob …

Sheep Updates 2003 - Wool, Richard Coole, Stephen Gherardi, Chris Oldham, K. Curtis, J. Stanton, Johan Greeff, Chris Oldham, Mike Hyder, Beth Pagamoni, Andrew Thompson, Tom Plaisted, Kazue Tanaka, Mike Ferguson, Darren Gordon, Andrew Peterson, Peter Sommerville

Sheep Updates

This session covers six papers from different authors:1.‘Pastures from space’ - an opportunity to increase the profitability of sheep production Richard Coole Farmer Kojonup W.A. Stephen Gherardi Chris Oldham Department of Agriculture Western Australia 2. K. Curtis Department of Agriculture WA J. Stanton Department of Agriculture WA and Curtin University 3. Is selection of ewe hogget replacement on measurement profitable? Johan Greeff Department of Agriculture of Western Australia 4. Optimising the nutrition/grazing management of ewe flocks Chris Oldham Mike Hyder Beth Paganoni Department of Agriculture of Western Australia Andrew Thompson Department of Primary Industries, Hamilton, Victoria Tom Plaisted Kazue Tanaka …

Sheep Updates 2003 - Husbandry, Paul Barrett, Kevin Bell, J Greeff, L. Butler, S. Brown, K. Hart, A. Gray, John Karlsson, Paula Coombe, Ron Mctarrart, David Scobie, Sandy White

Sheep Updates

This session covers seven papers from different authors:1. Setting up a successful, low input feedlot Paul Barrett, ‘Bimberdong’ Jerramungup 2. Effective mineral supplementation of sheep Kevin Bell, Sheep Management and Production Consultants, Kojonup, WA 3. Genetic benchmarking for WA sheep producers J. Greeff, L. Butler, S. Brown, K. Hart and A. Gray Department of Agriculture Western Australia 4. Does selecting sheep for low WEC reduce scouring? John Karlsson, Johan Greeff and Paula Coombe, Department of Agriculture Western Australia 5. Summer quarters for sheep - stubbles Ron McTaggart, Department of Agriculture Western Australia, Albany 6. Thinking about breeding Easy Care Sheep? …

Some Environmental Relationships Of Undergrowth Species In Aspen Communities Of The Intermountain West, W F. Mueggler

Aspen Bibliography

This analysis results from an opportunity to explore plant-environmental relationships from data collected for a different purpose. Origin of the data is a study designed to develop an aspen community-type classification for southern Idaho, western Wyoming, Utah, and Nevada which resulted in the publication "Aspen Community Types of the Intermountain Region" GTR INT-250 by W.F. Mueggler (1988).

Cluster Stability Scores For Microarray Data In Cancer Studies, Mark Smolkin, Debashis Ghosh

The University of Michigan Department of Biostatistics Working Paper Series

A potential benefit of profiling of tissue samples using microarrays is the generation of molecular fingerprints that will define subtypes of disease. Hierarchical clustering has been the primary analytical tool used to define disease subtypes from microarray experiments in cancer settings. Assessing cluster reliability poses a major complication in analyzing output from these procedures. While much work has been done on assessing the global question of number of clusters in a dataset, relatively little research exists on assessing stability of individual clusters. A potential benefit of profiling of tissue samples using microarrays is the generation of molecular fingerprints that will …

Comparative Genome Organization Of Human, Murine, And Feline Mhc Class Ii Region, Naoya Yuhki, Thomas W. Beck, Robert M. Stephens, Yoko Nishigaki, Kymberly Newmann, Stephen J. O'Brien

Biology Faculty Articles

To study comparative molecular dynamics in the genesis of the major histocompatibility complex (MHC), we determined a complete nucleotide sequence spanning 758,291 bp of the domestic cat (Felis catus) extended and classical class II region. The feline class II MHC includes 44 genes (31 predicted to be expressed) which display DNA sequence homology and ordered gene synteny with human HLA and mouse H2, in extended class II and centromere proximal regions (DM to DO) of the classical class II region. However, remarkable genomic alterations including gene gain and loss plus size differentials of 250 kb are …

Life Cycle Of A Torrenticolous Hawaiian Chironomid (Telmatogeton Torrenticola): Stream Flow And Microhabitat Effects, M. Eric Benbow, Albert J. Burky, Carl M. Way

Biology Faculty Publications

In this study we documented the instar densities and life cycle of Telmatogeton torrenticola Terry (Chironomidae : Telmatogetoninae) from Kinihapai Stream, Maui, Hawaii. Greatest larval densities of this midge are found on substrates of high velocity, shallow flows of cascades, and splash zones of waterfalls, with lower densities in riffles. In the summer of 1994 we compared the effects of two microhabitats (termed optimal and suboptimal) on inter-instar density and relative abundance. In a second year (1995), we evaluated the effect of long-term reduced stream flow on these variables only in optimal microhabitats. A significant reduction in stream flow from …

Natural Selection On Protein Polymorphism In The Rodent Genus Peromyscus: Evidence From Interlocus Contrasts, Jay F. Storz, Michael W. Nachman

Jay F. Storz Publications

The effects of natural selection are generally locus-specific, whereas migration, drift, and inbreeding are expected to have relatively uniform effects across the entire genome. This suggests that multilocus surveys of multiple populations can be used to distinguish selection from demographic effects. The purpose of this study was to test for evidence of selection on protein polymorphism in natural populations of mice in the genus Peromyscus. We analyzed published data from geographic surveys of allozyme variation and used a coalescent- based simulation model to identify specific loci that deviated from neutral expectations. Observed F_ST values generally exhibited a remarkably …

Supervised Detection Of Regulatory Motifs In Dna Sequences, Sunduz Keles, Mark J. Van Der Laan, Sandrine Dudoit, Biao Xing, Michael B. Eisen

U.C. Berkeley Division of Biostatistics Working Paper Series

Identification of transcription factor binding sites (regulatory motifs) is a major interest in contemporary biology. We propose a new likelihood based method, COMODE, for identifying structural motifs in DNA sequences. Commonly used methods (e.g. MEME, Gibbs sampler) model binding sites as families of sequences described by a position weight matrix (PWM) and identify PWMs that maximize the likelihood of observed sequence data under a simple multinomial mixture model. This model assumes that the positions of the PWM correspond to independent multinomial distributions with four cell probabilities. We address supervising the search for DNA binding sites using the information derived from …

A Bt Transgene Reduces Herbivory And Enhances Fecundity In Wild Sunflowers, A. A. Snow, Diana Pilson, L. H. Rieseberg, M. J. Paulsen, N. Pleskac, M. R. Reagon, D. E. Wolf, S. M. Selbo

Diana Pilson Publications

Gene flow from transgenic crops can introduce novel traits into related species, but the ecological importance of this process is unknown. Here, we report the first empirical evidence that wild plants can benefit from a bacterial transgene under uncaged, natural conditions. Cultivated sunflower (Helianthus annuus) is known to hybridize frequently with wild sunflower (H. annuus) in the western and midwestern United States. We studied a crop-developed Bacillus thuringiensis (Bt) transgene, cry1Ac, in backcrossed wild sunflower populations. Lepidopteran damage on transgenic plants was strongly reduced relative to control plants at our two study sites, while damage …

Blackwell Publishing Ltd. Chondrocranial, Hyobranchial And Internal Oral Morphology In Larvae Of The Basal Bufonid Genus Melanophryniscus (Amphibia: Anura), Peter M. Larson, Rafael O. De Sá, Diego Arrieta

Biology Faculty Publications

Melanophryniscus is a genus of small toads inhabiting the southern portion of South America. This genus is considered basal within the family Bufonidae. Data on larval chondrocranial morphology do not exist for the genus and larval internal oral anatomy has only been described for a single species. Here, we describe chondrocranial and internal oral morphology in Melanophryniscus montevidensis, M. orejasmirandai and M. sanmartini. Chondrocranial morphology is similar among the species examined. Comparisons with other bufonids and with outgroup taxa suggest that the following chondrocranial characters may represent synapomorphies for the Bufonidae: free (or absent) ceratobranchial IV, a reduced …

Ets-2 And Components Of Mammalian Swi/Snf Form A Repressor Complex That Negatively Regulates The Brca1promoter, Kimberly M. Baker, Guo Wei, Alicia E. Schaffner, Michael C. Ostrowski

Science and Mathematics Faculty Publications

Ets-2 is a transcriptional activator that can be modulated by ras-dependent phosphorylation. Evidence is presented indicating that ets-2 can also act as a transcriptional repressor. In the breast cancer cell line MCF-7, exogenous ets-2 repressed the activity of a BRCA1promoter-luciferase reporter dependent on a conserved ets-2-binding site in this promoter. Conditional overproduction of ets-2 in MCF-7 cells resulted in repression of endogenousBRCA1 mRNA expression. To address the mechanism by which ets-2 could act as a repressor, a biochemical approach was used to identify proteins that interacted with the ets-2 pointed domain. From this analysis, components of the …

Simple Parallel Statistical Computing In R, Anthony Rossini, Luke Tierney, Na Li

UW Biostatistics Working Paper Series

Theoretically, many modern statistical procedures are trivial to parallelize. However, practical deployment of a parallelized implementation which is robust and reliably runs on different computational cluster configurations and environments is far from trivial. We present a framework for the R statistical computing language that provides a simple yet powerful programming interface to a computational cluster. This interface allows the development of R functions that distribute independent computations across the nodes of the computational cluster. The resulting framework allows statisticians to obtain significant speed-ups for some computations at little additional development cost. The particular implementation can be deployed in heterogeneous computing …

Literate Statistical Practice, Anthony Rossini, Friedrich Leisch

UW Biostatistics Working Paper Series

Literate Statistical Practice (LSP, Rossini, 2001) describes an approach for creating self-documenting statistical results. It applies literate programming (Knuth, 1992) and related techniques in a natural fashion to the practice of statistics. In particular, documentation, specification, and descriptions of results are written concurrently with writing and evaluation of statistical programs. We discuss how and where LSP can be integrated into practice and illustrate this with an example derived from an actual statistical consulting project. The approach is simplified through the use of a comprehensive, open source toolset incorporating Noweb, Emacs Speaks Statistics (ESS), Sweave (Ramsey, 1994; Rossini, et al, 2002; …

Comparison Of Methods For Dna Isolation From Food Samples For Detection Of Shiga Toxin-Producing Escherichia Coli By Real-Time Pcr, Loree C. Heller, Carisa R. Davis, K. Kealy Peak, David Wingfield, Andrew C. Cannons, Philip T. Amuso, Jacqueline Cattani

Bioelectrics Publications

In this study, food samples were intentionally contaminated with Escherichia coli O157:H7, and then DNA was isolated by using four commercial kits. The isolated DNA samples were compared by using real-time PCR detection of the Shiga toxin genes. The four kits tested worked similarly.

Ibd Configuration Transition Matrices And Linkage Score Tests For Unilineal Relative Pairs, Sandrine Dudoit

U.C. Berkeley Division of Biostatistics Working Paper Series

Properties of transition matrices between IBD configurations are derived for four general classes of unilineal relative pairs obtained from the grand-parent/ grand-child, half-sib, avuncular, and cousin relationships. In this setting, IBD configurations are defined as orbits of groups acting on a set of inheritance vectors. Properties of the transition matrix between IBD configurations at two linked loci are derived by relating its infinitesimal generator to the adjacency matrix of a quotient graph. The second largest eigenvalue of the infinitesimal generator and its multiplicity are key in determining the form of the transition matrix and of likelihood-based linkage tests such as …

Expression And Localization Of Estrogen Receptor-Alpha Protein In Normal And Abnormal Term Placentae And Stimulation Of Trophoblast Differentiation By Estradiol, A Bukovsky, Maria Cekanova Ms, Rndr, Phd, Mr Caudle, J Wimalasena, Js Foster, Dc Henley, Rf Elder

Faculty Publications and Other Works -- Biochemistry, Cellular and Molecular Biology

Estrogens play an important role in the regulation of placental function, and 17-beta-estradiol (E2) production rises eighty fold during human pregnancy. Although term placenta has been found to specifically bind estrogens, cellular localization of estrogen receptor alpha (ER-alpha) in trophoblast remains unclear. We used western blot analysis and immunohistochemistry with h-151 and ID5 monoclonal antibodies to determine the expression and cellular localization of ER-alpha protein in human placentae and cultured trophoblast cells. Western blot analysis revealed a ~65 kDa ER-alpha band in MCF-7 breast carcinoma cells (positive control). A similar band was detected in five normal term placentae exhibiting strong …

Selecting Differentially Expressed Genes From Microarray Experiments, Margaret S. Pepe, Gary M. Longton, Garnet L. Anderson, Michel Schummer

UW Biostatistics Working Paper Series

High throughput technologies, such as gene expression arrays and protein mass spectrometry, allow one to simultaneously evaluate thousands of potential biomarkers that distinguish different tissue types. Of particular interest here is cancer versus normal organ tissues. We consider statistical methods to rank genes (or proteins) in regards to differential expression between tissues. Various statistical measures are considered and we argue that two measures related to the Receiver Operating Characteristic Curve are particularly suitable for this purpose. We also propose that sampling variability in the gene rankings be quantified and suggest using the “selection probability function”, the probability distribution of rankings …

Microbial Genomics: Tropical Treasure?, Craig Stephens

Biology

A Brazilian consortium has unveiled the genomic DNA sequence of the purple-pigmented bacterium Chromobacterium violaceum, a dominant component of the tropical soil microbiota. The sequence provides insight into the abundant potential of this organism for biotechnological and pharmaceutical applications.

Life Span Extension Of Drosophila Melanogaster: Genetic And Population Studies, Lawrence G. Harshman

Lawrence G. Harshman Publications

During the past two decades, genetic studies of model organisms have been the most important tool underlying advances in understanding the biological basis of aging and longevity. Drosophila melanogaster, the geneticist's "fruit fly," is a model organism because it has been the focus of genetic studies for more than 90 years. This review argues that studies on D. melanogaster will make an especially important contribution to the field of aging and longevity at the intersection of research on genetics, complex traits, and fly populations.

Five approaches have been used to study the genetics of longevity of D. melanogaster: …