Genetics and Genomics Commons^™

Systematic Assessment Of Accuracy Of Comparative Model Of Proteins Belonging To Different Structural Fold Classes, Subrata Chakrabarty, Dario Ghersi, Roberto Sanchez

Interdisciplinary Informatics Faculty Publications

In the absence of experimental structures, comparative modeling continues to be the chosen method for retrieving structural information on target proteins. However, models lack the accuracy of experimental structures. Alignment error and structural divergence (between target and template) influence model accuracy the most. Here, we examine the potential additional impact of backbone geometry, as our previous studies have suggested that the structural class (all-α, αβ, all-β) of a protein may influence the accuracy of its model. In the twilight zone (sequence identity ≤ 30%) and at a similar level of target-template divergence, the accuracy of protein models does indeed follow …

Computer Simulations Of Heterologous Immunity: Highlights Of An Interdisciplinary Cooperation, Claudia Calcagno, Roberto Puzone, Yanthe E. Pearson, Yiming Cheng, Dario Ghersi, Liisa K. Selin, Raymond M. Welsh, Franco Celada

Interdisciplinary Informatics Faculty Publications

The relationship between biological research and mathematical modeling is complex, critical, and vital. In this review, we summarize the results of the collaboration between two laboratories, exploring the interaction between mathematical modeling and wet-lab immunology. During this collaboration several aspects of the immune defence against viral infections were investigated, focusing primarily on the subject of heterologous immunity. In this manuscript, we emphasize the topics where computational simulations were applied in conjunction with experiments, such as immune attrition, the growing and shrinking of cross-reactive T cell repertoires following repeated infections, the short and long-term effects of cross-reactive immunological memory, and the …

The Differential Effect Of Toxoplasma Gondii Infection On The Stability Of Bcl2-Family Members Involves Multiple Activities, John Cherrington Carmen, Anthony Peter Sinai

Microbiology, Immunology, and Molecular Genetics Faculty Publications

The regulation of mitochondrial permeability, a key event in the initiation of apoptosis is governed by the opposing actions of the pro- and anti-apoptotic members of the BCL2-family of proteins. The BCL2-family can be classified further based on the number of BCL-homology (BH) domains they encode. Pathogen mediated modulation of BCL2-family members play a significant role in their ability to affect the apoptotic pathways in the infected host cell. The protozoan parasite Toxoplasma gondii establishes a profound blockade of apoptosis noted by a requirement for host NFκB activity and correlating with the selective degradation of pro-apoptotic BCL2-family members. In this …

Adventures In The Enormous: A 1.8 Million Clone Bac Library For The 21.7 Gb Genome Of Loblolly Pine., Zenaida V. Magbanua, Seval Ozkan, Benjamin D. Bartlett, Philippe Chouvarine, Christopher A. Saski, Aaron Liston, Richard C. Cronn, C. Dana Nelson, Daniel G. Peterson

CALS Publications

Loblolly pine (LP; Pinus taeda L.) is the most economically important tree in the U.S. and a cornerstone species in southeastern forests. However, genomics research on LP and other conifers has lagged behind studies on flowering plants due, in part, to the large size of conifer genomes. As a means to accelerate conifer genome research, we constructed a BAC library for the LP genotype 7-56. The LP BAC library consists of 1,824,768 individually-archived clones making it the largest single BAC library constructed to date, has a mean insert size of 96 kb, and affords 7.6X coverage of the 21.7 Gb …

Genome-Wide Characterization Of Centromeric Satellites From Multiple Mammalian Genomes, Can Alkan, Maria Francesca Cardone, Claudia Rita Catacchio, Francesca Antonacci, Stephen J. O'Brien, Oliver A. Ryder, Stefania Purgato, Monica Zoli, Evan E. Eichler, Mario Ventura

Biology Faculty Articles

Despite its importance in cell biology and evolution, the centromere has remained the final frontier in genome assembly and annotation due to its complex repeat structure. However, isolation and characterization of the centromeric repeats from newly sequenced species are necessary for a complete understanding of genome evolution and function. In recent years, various genomes have been sequenced, but the characterization of the corresponding centromeric DNA has lagged behind. Here, we present a computational method (RepeatNet) to systematically identify higher-order repeat structures from unassembled whole-genome shotgun sequence and test whether these sequence elements correspond to functional centromeric sequences. We analyzed genome …

Statistical Properties Of The Integrative Correlation Coefficient: A Measure Of Cross-Study Gene Reproducibility, Leslie Cope, Giovanni Parmigiani

Harvard University Biostatistics Working Paper Series

No abstract provided.

A Generalized Approach For Testing The Association Of A Set Of Predictors With An Outcome: A Gene Based Test, Benjamin A. Goldstein, Alan E. Hubbard, Lisa F. Barcellos

U.C. Berkeley Division of Biostatistics Working Paper Series

In many analyses, one has data on one level but desires to draw inference on another level. For example, in genetic association studies, one observes units of DNA referred to as SNPs, but wants to determine whether genes that are comprised of SNPs are associated with disease. While there are some available approaches for addressing this issue, they usually involve making parametric assumptions and are not easily generalizable. A statistical test is proposed for testing the association of a set of variables with an outcome of interest. No assumptions are made about the functional form relating the variables to the …

Reduced Mhc And Neutral Variation In The Galápagos Hawk, An Island Endemic, Jennifer Bollmer, Joshua Hull, Holly Ernest, José Sarasola, Patricia Parker

Biology Department Faculty Works

BackgroundGenes at the major histocompatibility complex (MHC) are known for high levels of polymorphism maintained by balancing selection. In small or bottlenecked populations, however, genetic drift may be strong enough to overwhelm the effect of balancing selection, resulting in reduced MHC variability. In this study we investigated MHC evolution in two recently diverged bird species: the endemic Galápagos hawk (Buteo galapagoensis), which occurs in small, isolated island populations, and its widespread mainland relative, the Swainson's hawk (B. swainsoni).ResultsWe amplified at least two MHC class II B gene copies in each species. We recovered only three different sequences from 32 Galápagos …

Minimal Art: Or Why Small Viral K+ Channels Are Good Tools For Understanding Basic Structure And Function Relations, Gerhard Thiel, Dirk Baumeister, Indra Schroeder, Stefan M. Kast, James L. Van Etten, Anna Moroni

James Van Etten Publications

Some algal viruses contain genes that encode proteins with the hallmarks of K+ channels. One feature of these proteins is that they are less than 100 amino acids in size, which make them truly minimal for a K+ channel protein. That is, they consist of only the pore module present in more complex K+ channels. The combination of miniature size and the functional robustness of the viral K+ channels make them ideal model systems for studying how K+ channels work. Here we summarize recent structure/function correlates from these channels, which provide insight into functional properties such as gating, pharmacology and …

Genetic Polymorphisms And The Treatment Outcome In Standard-Risk Pediatric Acute Lymphoblastic Leukemia, Qi Wei

Electronic Theses and Dissertations

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and accounts for 30 - 35% of all cancers in children. Significant improvement in the treatment of pediatric ALL has been achieved in recent years. Only 50 years ago, the disease was uniformly fatal with an Overall Survival (OS) rate < 5%. Modern-day, multi-drug chemotherapy is associated with an overall survival rate over 80%. Standard-risk ALL comprises the majority of ALL with an overall survival approaching 90%. Despite this success, children who relapse from this disease accounts for the majority of cancer-related deaths in children. The backbone of treatment protocols have incorporated somatic but not host genetic features in the treatment regimens. The current study examined 12 genetic polymorphisms affecting the pharmacodynamics of antileukemic drugs in an attempt to identify biologic markers related to the risk of disease relapse.

In the current research program, 125 standard-risk ALL patients who were treated at The Children's Hospital were enrolled in a retrospective study. Statistical analysis was performed to evaluate the association between genetic polymorphisms and risk of disease relapse in this study cohort. The GSTM1 null genotype was associated with a …

Functional Activation Of Cartilaginous Fish Melanocortin Receptors, Christina Lee Reinick

Electronic Theses and Dissertations

The evolution of the melanocortin receptor (MCR) gene family has been dictated by two genome duplication events (2R hypothesis). The gnathostomes are thus predicted to possess a minimum of four MCR genes. Previous studies on cartilaginous fish have shown evidence for the presence of only three MCRs. The purpose of this thesis is to functionally express the MC5R from the spiny dogfish (Squalus acanthias) and the putative MC2R and MC3R from the elephant shark (Callorhinchus milii); these receptors have not yet been fully characterized. In this study, SacMC5R was able to be expressed in CHO cells …

Linear Methods For Analysis And Quality Control Of Relative Expression Ratios From Quantitative Real-Time Polymerase Chain Reaction Experiments, Robert B. Page, Arnold J. Stromberg

Biology Faculty Publications

Relative expression quantitative real-time polymerase chain reaction (RT-qPCR) experiments are a common means of estimating transcript abundances across biological groups and experimental treatments. One of the most frequently used expression measures that results from such experiments is the relative expression ratio (R_E), which describes expression in experimental samples (i.e., RNA isolated from organisms, tissues, and/or cells that were exposed to one or more experimental or nonbaseline condition) in terms of fold change relative to calibrator samples (i.e., RNA isolated from organisms, tissues, and/or cells that were exposed to a control or baseline condition). Over the past decade, several …

Physiological And Genetic Correlates Of Boldness: Characterising The Mechanisms Of Behavioural Variation In Rainbow Trout, Oncorhynchus Mykiss, Jack S. Thomson, Phillip C. Watts, Tom G. Pottinger, Lynne U. Sneddon

Aquaculture Collection

Bold, risk-taking animals have previously been putatively linked with a proactive stress coping style whereas it is suggested shyer, risk-averse animals exhibit a reactive coping style. The aim of this study was to investigate whether differences in the expression of bold-type behaviour were evident within and between two lines of rainbow trout, Oncorhynchus mykiss, selectively bred for a low (LR) or high (HR) endocrine response to stress, and to link boldness and stress responsiveness with the expression of related candidate genes. Boldness was determined in individual fish over two trials by measuring the latency to approach a novel object. Differences …

Physiological And Genetic Correlates Of Boldness: Characterising The Mechanisms Of Behavioural Variation In Rainbow Trout, Oncorhynchus Mykiss, Jack S. Thomson, Phillip C. Watts, T. G. Pottinger, Lynne U. Sneddon

Ethology Collection

Bold, risk-taking animals have previously been putatively linked with a proactive stress coping style whereas it is suggested shyer, risk-averse animals exhibit a reactive coping style. The aim of this study was to investigate whether differences in the expression of bold-type behaviour were evident within and between two lines of rainbow trout, Oncorhynchus mykiss, selectively bred for a low (LR) or high (HR) endocrine response to stress, and to link boldness and stress responsiveness with the expression of related candidate genes. Boldness was determined in individual fish over two trials by measuring the latency to approach a novel object. Differences …

Functional Hak/Kup/Kt-Like Potassium Transporter Encoded By Chlorella Viruses, Timo Greiner, José Ramos, Maria C. Alvarez, James Gurnon, Ming Kang, James L. Van Etten, Anna Moroni, Gerhard Thiel

James Van Etten Publications

Chlorella viruses are a source of interesting membrane transport proteins. Here we examine a putative K+ transporter encoded by virus FR483 and related chlorella viruses. The protein shares sequence and structural features with HAK/KUP/KT-like K+ transporters from plants, bacteria and fungi. Yeast complementation assays and Rb+ uptake experiments show that the viral protein, termed HAKCV (high-affinity K+ transporter of chlorella virus), is functional, with transport characteristics that are similar to those of known K+ transporters. Expression studies revealed that the protein is expressed as an early gene during viral replication, and proteomics data indicate that it is not packaged in …

Positive Selection Shaped The Convergent Evolution Of Independently Expanded Kallikrein Subfamilies Expressed In Mouse And Rat Saliva Proteomes, Robert C. Karn, Christina M. Laukaitis

Scholarship and Professional Work - LAS

We performed proteomics studies of salivas from the genome mouse (C57BL/6 strain) and the genome rat (BN/SsNHsd/Mcwi strain). Our goal was to identify salivary proteins with one or more of three characteristics that may indicate that they have been involved in adaptation: 1) rapid expansion of their gene families; 2) footprints of positive selection; and/or 3) sex-limited expression. The results of our proteomics studies allow direct comparison of the proteins expressed and their levels between the sexes of the two rodent species. Twelve members of the Mus musculus species-specific kallikrein subfamily Klk1b showed sex-limited expression in the mouse saliva proteomes. …

Inflated Type I Error Rates When Using Aggregation Methods To Analyze Rare Variants In The 1000 Genomes Project Exon Sequencing Data In Unrelated Individuals: Summary Results From Group 7 At Genetic Analysis Workshop 17, Nathan L. Tintle, Hugues Aschard, Inchi Hu, Nora Nock, Haitian Wang, Elizabeth Pugh

Faculty Work Comprehensive List

As part of Genetic Analysis Workshop 17 (GAW17), our group considered the application of novel and standard approaches to the analysis of genotype-phenotype association in next-generation sequencing data. Our group identified a major issue in the analysis of the GAW17 next-generation sequencing data: type I error and false-positive report probability rates higher than those expected based on empirical type I error levels (as high as 90%). Two main causes emerged: population stratification and long-range correlation (gametic phase disequilibrium) between rare variants. Population stratification was expected because of the diverse sample. Correlation between rare variants was attributable to both random causes …

Identification Of Genetic Association Of Multiple Rare Variants Using Collapsing Methods, Yan V. Sun, Yun Ju Sung, Nathan L. Tintle, Andreas Ziegler

Faculty Work Comprehensive List

Next-generation sequencing technology allows investigation of both common and rare variants in humans. Exomes are sequenced on the population level or in families to further study the genetics of human diseases. Genetic Analysis Workshop 17 (GAW17) provided exomic data from the 1000 Genomes Project and simulated phenotypes. These data enabled evaluations of existing and newly developed statistical methods for rare variant sequence analysis for which standard statistical methods fail because of the rareness of the alleles. Various alternative approaches have been proposed that overcome the rareness problem by combining multiple rare variants within a gene. These approaches are termed collapsing …

Analysis Of Biological Features Associated With Meiotic Recombination Hot And Cold Spots In Saccharomyces Cerevisiae, Loren Hansen, Nak-Kyeong Kim, Leonardo Mariño-Ramírez, David Landsman

Mathematics & Statistics Faculty Publications

Meiotic recombination is not distributed uniformly throughout the genome. There are regions of high and low recombination rates called hot and cold spots, respectively. The recombination rate parallels the frequency of DNA double-strand breaks (DSBs) that initiate meiotic recombination. The aim is to identify biological features associated with DSB frequency. We constructed vectors representing various chromatin and sequence-based features for 1179 DSB hot spots and 1028 DSB cold spots. Using a feature selection approach, we have identified five features that distinguish hot from cold spots in Saccharomyces cerevisiae with high accuracy, namely the histone marks H3K4me3, H3K14ac, H3K36me3, and H3K79me3; …

Post-Transcriptional Regulation Of Afp And Igm Genes, Lilia M. Turcios

University of Kentucky Doctoral Dissertations

Gene expression can be regulated at multiple steps once transcription is initiated. I have studied two different gene models, the α-Fetoprotein (AFP) and the immunoglobulin heavy chain (IgM) genes, to better understand post-transcriptional gene regulation mechanisms. The AFP gene is highly expressed during fetal liver development and dramatically repressed after birth. There is a mouse strain-specific difference between adult levels of AFP, with BALB/cJ mice expressing 10 to 20-fold higher levels compared to other mouse strains. BALB/cJ mice express low levels of Zhx2 and thus incompletely repress AFP. Despite differences in steady state AFP mRNA levels in the adult liver …