Digital Commons Network^™

Cyclin-Dependent Kinase Inhibitor P1446a Induces Apoptosis In A Jnk/P38 Mapk-Dependent Manner In Chronic Lymphocytic Leukemia B-Cells, Cody Paiva, J. Claire Godbersen, Ryan S. Soderquist, Taylor Rowland, Sumner Kilmarx

Dartmouth Scholarship

CDK (cyclin-dependent kinase) inhibitors have shown remarkable activity in CLL, where its efficacy has been linked to inhibition of the transcriptional CDKs (7 and 9) and deregulation of RNA polymerase and short-lived pro-survival proteins such as MCL1. Furthermore, ER (endoplasmic reticulum) stress has been implicated in CDK inhibition in CLL. Here we conducted a pre-clinical study of a novel orally active kinase inhibitor P1446A in CLL B-cells. P1446A inhibited CDKs at nanomolar concentrations and induced rapid apoptosis of CLL cells in vitro, irrespective of chromosomal abnormalities or IGHV mutational status. Apoptosis preceded inactivation of RNA polymerase, and was accompanied by …

The Transcriptomic And Evolutionary Signature Of Social Interactions Regulating Honey Bee Caste Development, Svjetlana Vojvodic, Brian R. Johnson, Brock Harpur, Clement Kent, Amro Zayed, Kirk E. Anderson, Timothy A. Linksvayer

Faculty Scholarship for the College of Science & Mathematics

The caste fate of developing female honey bee larvae is strictly socially regulated by adult nurse workers. As a result of this social regulation, nurse-expressed genes as well as larval-expressed genes may affect caste expression and evolution. We used a novel transcriptomic approach to identify genes with putative direct and indirect effects on honey bee caste development, and we subsequently studied the relative rates of molecular evolution at these caste-associated genes. We experimentally induced the production of new queens by removing the current colony queen, and we used RNA sequencing to study the gene expression profiles of both developing larvae …

Yeast Integral Membrane Proteins Apq12, Brl1, And Brr6 Form A Complex Important For Regulation Of Membrane Homeostasis And Nuclear Pore Complex Biogenesis, Museer A. Lone, Aaron E. Atkinson, Christine A. Hodge, Stéphanie Cottier, Fernando Martínez-Montañés, Shelley Maithel, Laurent Mène-Saffrané, Cole Cole, Roger Schneiter

Dartmouth Scholarship

Proper functioning of intracellular membranes is critical for many cellular processes. A key feature of membranes is their ability to adapt to changes in environmental conditions by adjusting their composition so as to maintain constant biophysical proper- ties, including fluidity and flexibility. Similar changes in the biophysical properties of membranes likely occur when intracellular processes, such as vesicle formation and fusion, require dramatic changes in membrane curvature. Similar modifications must also be made when nuclear pore complexes (NPCs) are constructed within the existing nuclear membrane, as occurs during in- terphase in all eukaryotes. Here we report on the role of …

Parasite Manipulation Of The Invariant Chain And The Peptide Editor H2-Dm Affects Major Histocompatibility Complex Class Ii Antigen Presentation During Toxoplasma Gondii Infection, Louis-Philippe Leroux, Manami Nishi, Sandy El-Hage, Barbara A. Fox, David I Bzik, Florence Dzierszinsk

Dartmouth Scholarship

Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex class II (MHC-II) antigen presentation to attenuate CD4(+) T cell responses and establish persisting infections. Transcriptional downregulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, …

Large Scale Genetic Research On Neuropsychiatric Disorders In African Populations Is Needed, Shareefa Dalvie, Nastassja Koen, Laramie Duncan, Catherine Abbo, Dickens Akena, Lukoye Atwoli, Bonginkosi Chiliza, Kirsten A. Donald, Eugene Kinyanda, Christine Lochner

Internal Medicine, East Africa

In recent years there have been significant insights into the complex aetiologies of neurodevelopmental brain disorders. For example, neuropsychiatric genetics has achieved success with the identification of 108 loci for schizophrenia (Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). Furthermore, meta-analyses of genomewide association study (GWAS) results encompassing thousands of samples have been completed for other psychiatric disorders including attention-deficit/hyperactivity disorder (ADHD), autism

What Difference Does It Make? An Essay Review Of Beyond Versus: The Struggle To Understand The Interaction Of Nature And Nurture; James Tabery; Mit Press: Cambridge, Ma, 2014, Peter J. Taylor

Working Papers on Science in a Changing World

Beyond versus makes its contribution to the thriving industry of books that clarify or recast nature-nurture issues through seven conceptual moves. The first is to posit a divide between sociological and philosophical inquiry. As Tabery depicts them, commentators on the science invoked in nature-nurture debates often focus on the racist or other political views of disputants or on their flawed understanding of scientific concepts. Tabery, in contrast, as a philosopher of science, explains past and present disagreements as stemming from “a disagreement concerning how explanation works in science.” (The other moves include explanatory and terminological divides, connecting associations to mechanisms, …

Bypassing Iron Storage In Endodermal Vacuoles Rescues The Iron Mobilization Defect In The Natural Resistance Associated-Macrophage Protein3natural Resistance Associated-Macrophage Protein4 Double Mutant, Viviane Mary, Magali Schnell Ramos, Cynthia Gillet, Amanda L. Socha, Jerome Giraudat, Astrid Agorio, Sylvain Merlot, Colin Clairet, Sun A. Kim, Tracy Punshon, Mary Lou Guerinot, Sebastien Thomine

Dartmouth Scholarship

To improve seed iron (Fe) content and bioavailability, it is crucial to decipher the mechanisms that control Fe storage during seed development. In Arabidopsis (Arabidopsis thaliana) seeds, most Fe is concentrated in insoluble precipitates, with phytate in the vacuoles of cells surrounding the vasculature of the embryo. NATURAL RESISTANCE ASSOCIATED-MACROPHAGE PROTEIN3 (AtNRAMP3) and AtNRAMP4 function redundantly in Fe retrieval from vacuoles during germination. When germinated under Fe-deficient conditions, development of the nramp3nramp4 double mutant is arrested as a consequence of impaired Fe mobilization. To identify novel genes involved in seed Fe homeostasis, we screened an …

Diagnostics Need Not Apply, Rebecca S. Eisenberg

Articles

Diagnostic testing helps caregivers and patients understand a patient's condition, predict future outcomes, select appropriate treatments, and determine whether treatment is working. Improvements in diagnostic testing are essential to bringing about the long-heralded promise of personalized medicine. Yet it seems increasingly clear that most important advances in this type of medical technology lie outside the boundaries of patent-eligible subject matter. The clarity of this conclusion has been obscured by ambiguity in the recent decisions of the Supreme Court concerning patent eligibility. Since its 2010 decision in Bilski v. Kappos, the Court has followed a discipline of limiting judicial exclusions from …

Development Of The Crispr/Cas9 System For Targeted Gene Disruption In Aspergillus Fumigatus, Kevin Fuller, Shan Chen, Jennifer J. Loros, Jay C. Dunlap

Dartmouth Scholarship

Low rates of homologous recombination have broadly encumbered genetic studies in the fungal pathogen Aspergillus fumigatus. The CRISPR/Cas9 system of bacteria has recently been developed for targeted mutagenesis of eukaryotic genomes with high effi- ciency and, importantly, through a mechanism independent of homologous repair machinery. As this new technology has not been developed for use in A. fumigatus, we sought to test its feasibility for targeted gene disruption in this organism. As a proof of principle, we first demonstrated that CRISPR/Cas9 can indeed be used for high-efficiency (25 to 53%) targeting of the A. fu- migatus polyketide synthase gene (pksP), …

Role Of The Dna Sensor Sting In Protection From Lethal Infection Following Corneal And Intracerebral Challenge With Herpes Simplex Virus 1, Zachary M. Parker, Aisling A. Murphy, David. A. Leib

Dartmouth Scholarship

STING is a protein in the cytosolic DNA and cyclic dinucleotide sensor pathway that is critical for the initiation of innate responses to infection by various pathogens. Consistent with this, herpes simplex virus 1 (HSV-1) causes invariable and rapid lethality in STING-deficient (STING(-/-)) mice following intravenous (i.v.) infection. In this study, using real-time bioluminescence imaging and virological assays, as expected, we demonstrated that STING(-/-) mice support greater replication and spread in ocular tissues and the nervous system. In contrast, they did not succumb to challenge via the corneal route even with high titers of a virus that was routinely lethal …

Maternal Psychiatric Disease And Epigenetic Evidence Suggest A Common Biology For Poor Fetal Growth, Timothy H. Ciesielski, Carmen J. Marsit, Scott M. Williams

Dartmouth Scholarship

We sought to identify and characterize predictors of poor fetal growth among variables extracted from perinatal medical records to gain insight into potential etiologic mechanisms. In this process we reevaluated a previously observed association between poor fetal growth and maternal psychiatric disease. We evaluated 449 deliveries of >36 weeks gestation that occurred between 9/2008 and 9/2010 at the Women and Infants Hospital in Providence Rhode Island. This study group was oversampled for Small-for-Gestational-Age (SGA) infants and excluded Large-for-Gestational-Age (LGA) infants. We assessed the associations between recorded clinical variables and impaired fetal growth: SGA or Intrauterine Growth Restriction (IUGR) diagnosis. After …

Two Novel Genetic Variants In The Mineralocorticoid Receptor Gene Associated With Spontaneous Preterm Birth, Inge Christiaens, Q. Wei Ang, Lindsay N. Gordon, Xin Fang, Scott Williams

Dartmouth Scholarship

Background: Preterm birth is the leading cause of mortality and morbidity in newborn infants. Its etiology is multifactorial with genes and environmental factors, including chronic maternal stress, contributing to its risk. Our objective was to investigate whether single nucleotide polymorphisms (SNPs) in genes involved in the stress response are associated with spontaneous preterm birth using a candidate gene approach.

Methods: A total of 210 cases (singleton spontaneous preterm birth at <37 >weeks) and 412 controls (singleton term birth at 38–42 weeks without a history of preterm birth) were studied. High quality maternal DNA was available from saliva samples of 190 cases …

Polyq-Dependent Rna–Protein Assemblies Control Symmetry Breaking, Changhwan Lee, Patricia Occhipinti, Amy S. Gladfelter

Dartmouth Scholarship

Dendritic growth in fungi and neurons requires that multiple axes of polarity are established and maintained within the same cytoplasm. We have discovered that transcripts encoding key polarity factors including a formin, Bni1, and a polarisome scaffold, Spa2, are nonrandomly clustered in the cytosol to initiate and maintain sites of polarized growth in the fungus Ashbya gossypii. This asymmetric distribution requires the mRNAs to interact with a polyQ-containing protein, Whi3, and a Pumilio protein with a low-complexity sequence, Puf2. Cells lacking Whi3 or Puf2 had severe defects in establishing new sites of polarity and failed to localize Bni1 protein. Interaction …

Selective Involvement Of The Checkpoint Regulator Vista In Suppression Of B-Cell, But Not T-Cell, Responsiveness By Monocytic Myeloid-Derived Suppressor Cells From Mice Infected With An Immunodeficiency-Causing Retrovirus, Kathy A. Green, Li Wang, Randolph J. Noelle, William R. Green

Dartmouth Scholarship

Inhibition of T-cell responses in tumor microenvironments by myeloid-derived suppressor cells (MDSCs) is widely accepted. We demonstrated augmentation of monocytic MDSCs whose suppression of not only T-cell, but also B-cell, responsiveness paralleled the immunodeficiency during LP-BM5 retrovirus infection. MDSCs inhibited T cells by inducible nitric oxide synthase (iNOS)/nitric oxide (NO), but uniquely, inhibition of B cells was ~50% dependent each on iNOS/NO and the MDSC-expressed negative-checkpoint regulator VISTA. Blockade with a combination of iNOS/NO and VISTA caused additive or synergistic abrogation of MDSC-mediated suppression of B-cell responsiveness.

A Self-Lysis Pathway That Enhances The Virulence Of A Pathogenic Bacterium, Kirsty A. Mcfarland, Emily L. Dolben, Michele Leroux, Tracy K. Kambara, Kathryn Ramsey, Robin Kirkpatrick, Joseph Mougous, Deborah Hogan, Simon Dove

Dartmouth Scholarship

In mammalian cells, programmed cell death (PCD) plays important roles in development, in the removal of damaged cells, and in fighting bacterial infections. Although widespread among multicellular organisms, there are relatively few documented instances of PCD in bacteria. Here we describe a potential PCD pathway in Pseudomonas aeruginosa that enhances the ability of the bacterium to cause disease in a lung infection model. Activation of the system can occur in a subset of cells in response to DNA damage through cleavage of an essential transcription regulator we call AlpR. Cleavage of AlpR triggers a cell lysis program through de-repression of …

A Genetic Porcine Model Of Cancer, Lawrence B. Schook, Tiago V. Collares, Wenping Hu, Ying Liang, Fernanda M. Rodrigues, Laurie A. Rund, Kyle M. Schachtschneider, Fabiana K. Seixas, Kuldeep Singh, Kevin D. Wells, Eric M. Walters, Randall S. Prather, Christopher M. Counter

Toxicology and Cancer Biology Faculty Publications

The large size of the pig and its similarity in anatomy, physiology, metabolism, and genetics to humans make it an ideal platform to develop a genetically defined, large animal model of cancer. To this end, we created a transgenic "oncopig" line encoding Cre recombinase inducible porcine transgenes encoding KRAS^G12D and TP^53R167H, which represent a commonly mutated oncogene and tumor suppressor in human cancers, respectively. Treatment of cells derived from these oncopigs with the adenovirus encoding Cre (AdCre) led to KRAS^G12D and TP^53R167H expression, which rendered the cells transformed in culture and tumorigenic when engrafted into …

Deletion Of Nfnab In Thermoanaerobacterium Saccharolyticum And Its Effect On Metabolism, Jonathan Lo, Tianyong Zheng, Daniel G. Olson, Natalie Ruppertsberger, Shital Tripathi, Adam Guss, Lee Lynd

Dartmouth Scholarship

NfnAB catalyzes the reversible transfer of electrons from reduced ferredoxin and NADH to 2 NADP⁺. The NfnAB complex has been hypothesized to be the main enzyme for ferredoxin oxidization in strains of Thermoanaerobacterium saccharolyticum engineered for increased ethanol production. NfnAB complex activity was detectable in crude cell extracts of T. saccharolyticum. Activity was also detected using activity staining of native PAGE gels. The nfnAB gene was deleted in different strains of T. saccharolyticum to determine its effect on end product formation. In wild-type T. saccharolyticum, deletion of nfnAB resulted in a 46% increase in H₂ formation but …

Links Between Anr And Quorum Sensing In Pseudomonas Aeruginosa Biofilms, John H. Hammond, Emily F. Dolben, T. Jarrod Smith, Sabin Bhuju, Deborah Hogan

Dartmouth Scholarship

In Pseudomonas aeruginosa, the transcription factor Anr controls the cellular response to low oxygen or anoxia. Anr activity is high in oxygen-limited environments, including biofilms and populations associated with chronic infections, and Anr is necessary for persistence in a model of pulmonary infection. In this study, we characterized the Anr regulon in biofilm-grown cells at 1% oxygen in the laboratory strain PAO1 and in a quorum sensing (QS)-deficient clinical isolate, J215. As expected, transcripts related to denitrification, arginine fermentation, high-affinity cytochrome oxidases, and CupA fimbriae were lower in the Δanr derivatives. In addition, we observed that transcripts associated with quorum …

Origins Of An Unmarked Georgia Cemetery Using Ancient Dna Analysis, Andrew T. Ozga, Raúl Y. Tito, Brian M. Kemp, Hugh Matternes, Alexandra Obregon-Tito, Leslie Neal, Cecil M. Lewis, Jr.

Human Biology Open Access Pre-Prints

Determining the origins of those buried within undocumented cemeteries is of incredible importance to historical archaeologists and in many cases, the nearby communities. In the case of Avondale Burial Place, a cemetery in Bibb County, Georgia, in use from 1820 to 1950, all written documentation of those interred within it has been lost. Osteological and archaeological evidence alone could not describe, with confidence, the ancestral origins of the 101 individuals buried there. In the present study, we utilize ancient DNA extraction methods to investigate the origins of Avondale Burial Place through the use of well-preserved skeletal fragments from 20 individuals …

Exceptionally High Levels Of Genetic Diversity In Wheat Curl Mite (Acari: Eriophyidae) Populations From Turkey, W. Szydło, Gary L. Hein, E. Denizhan, A. Skoracka

Department of Entomology: Faculty Publications

Recent research on the wheat curl mite species complex has revealed extensive genetic diversity that has distinguished several genetic lineages infesting bread wheat (Triticum aestivum L.) and other cereals worldwide. Turkey is the historical region of wheat and barley (Hordeum vulgare L.) domestication and diversification. The close relationship between these grasses and the wheat curl mite provoked the question of the genetic diversity of the wheat curl mite in this region. The scope of the study was to investigate genetic differentiation within the wheat curl mite species complex on grasses in Turkey. Twenty-one wheat curl mite populations from …

Cofactor Specificity Of The Bifunctional Alcohol And Aldehyde Dehydrogenase (Adhe) In Wild-Type And Mutant Clostridium Thermocellum And Thermoanaerobacterium Saccharolyticum, Tianyong Zheng, Daniel G. Olson, Liang Tian, Yannick J. Bomble, Michael Himmel, Jonathan Lo, Shuen Hon, A. Joe Shaw, Johannes P. Van Dijken, Lee Lynd

Dartmouth Scholarship

Clostridium thermocellum and Thermoanaerobacterium saccharolyticum are thermophilic bacteria that have been engineered to produce ethanol from the cellulose and hemicellulose fractions of biomass, respectively. Although engineered strains of T. saccharolyticum produce ethanol with a yield of 90% of the theoretical maximum, engineered strains of C. thermocellum produce ethanol at lower yields (∼50% of the theoretical maximum). In the course of engineering these strains, a number of mutations have been discovered in their adhE genes, which encode both alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) enzymes. To understand the effects of these mutations, the adhE genes from six strains of C. …

Biological Significance Of Photoreceptor Photocycle Length: Vivid Photocycle Governs The Dynamic Vivid-White Collar Complex Pool Mediating Photo-Adaptation And Response To Changes In Light Intensity, Arko Dasgupta, Chen-Hui Chen, Changhwan Lee, Amy S. Gladfelter, Jay C. Dunlap, Jennifer J. Loros

Dartmouth Scholarship

Most organisms on earth sense light through the use of chromophore-bearing photoreceptive proteins with distinct and characteristic photocycle lengths, yet the biological significance of this adduct decay length is neither understood nor has been tested. In the filamentous fungus Neurospora crassa VIVID (VVD) is a critical player in the process of photoadaptation, the attenuation of light-induced responses and the ability to maintain photosensitivity in response to changing light intensities. Detailed in vitro analysis of the photochemistry of the blue light sensing, FAD binding, LOV domain of VVD has revealed residues around the site of photo-adduct formation that influence the stability …

Clustered Regularly Interspaced Short Palindromic Repeat-Dependent, Biofilm-Specific Death Of Pseudomonas Aeruginosa Mediated By Increased Expression Of Phage-Related Genes, Gary E. E. Heussler, Kyle C. Cady, Katja Koeppen, Sabin Bhuju, Bruce A. Stanton, George A. O’Toole

Dartmouth Scholarship

The clustered regularly interspaced short palindromic repeat (CRISPR)/CRISPR-associated (CRISPR/Cas) system is an adaptive immune system present in many archaea and bacteria. CRISPR/Cas systems are incredibly diverse, and there is increasing evidence of CRISPR/Cas systems playing a role in cellular functions distinct from phage immunity. Previously, our laboratory reported one such alternate function in which the type 1-F CRISPR/Cas system of the opportunistic pathogen Pseudomonas aeruginosa strain UCBPP-PA14 (abbreviated as P. aeruginosa PA14) inhibits both biofilm formation and swarming motility when the bacterium is lysogenized by the bacteriophage DMS3. In this study, we demonstrated that the presence of just the DMS3 …

Telomere Dna Recognition In Saccharomycotina Yeast: Potential Lessons For The Co-Evolution Of Ssdna And Dsdna-Binding Proteins And Their Target Sites, Olga Steinberg-Neifach, Neal F. Lue

Publications and Research

In principle, alterations in the telomere repeat sequence would be expected to disrupt the protective nucleoprotein complexes that confer stability to chromosome ends, and hence relatively rare events in evolution. Indeed, numerous organisms in diverse phyla share a canonical 6 bp telomere repeat unit (5′-TTAGGG-3′/5′-CCCTAA-3′), suggesting common descent from an ancestor that carries this particular repeat. All the more remarkable, then, are the extraordinarily divergent telomere sequences that populate the Saccharomycotina subphylum of budding yeast. These sequences are distinguished from the canonical telomere repeat in being long, occasionally degenerate, and frequently non-G/C-rich. Despite the divergent telomere repeat sequences, studies to …

Sex-Specific Parental Effects On Offspring Lipid Levels, Irene M. Predazzi, Rafal S. Sobota, Serena Sanna, William S. Bush, Jacquelaine Bartlett, Jessica S. Lilley, Macrae F. Linton, David Schlessinger, Francesco Cucca, Sergio Fazio, Scott M. Williams

Dartmouth Scholarship

Background:

Plasma lipid levels are highly heritable traits, but known genetic loci can only explain a small portion of their heritability.

Methods and Results:

In this study, we analyzed the role of parental levels of total cholesterol (TC), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), and triglycerides (TGs) in explaining the values of the corresponding traits in adult offspring. We also evaluated the contribution of nongenetic factors that influence lipid traits (age, body mass index, smoking, medications, and menopause) alone and in combination with variability at the genetic loci known to associate with TC, LDL‐C, HDL‐C, and TG levels. …

An Inquiry-Infused Introductory Biology Laboratory That Integrates Mendel's Pea Phenotypes With Molecular Mechanisms, Philip Kudish, E. Schlag, Nicholas J. Kaplinsky

Biology Faculty Works

We developed a multi-week laboratory in which college-level introductory biology students investigate Mendel's stem length phenotype in peas. Students collect, analyze and interpret convergent evidence from molecular and physiological techniques. In weeks 1 and 2, students treat control and experimental plants with Gibberellic Acid (GA) to determine whether uncharacterized short mutant lines are GA responsive. These data allow students to place the mutation in the GA signal transduction pathway. During weeks 2 and 3, plants are genotyped for Mendel's "le" mutation using a derived cleaved polymorphic sequences (dCAPS) PCR assay. This laboratory allows students to make a direct connection between …

Origins Of An Unmarked Georgia Cemetery Using Ancient Dna Analysis, Andrew T. Ozga, Raul Y. Tito, Brian M. Kemp, Hugh Matternes, Alexandra J. Obregon-Tito, Leslie Neal, Cecil M. Lewis Jr.

Biology Faculty Articles

Determining the origins of those buried within undocumented cemeteries is of incredible importance to historical archaeologists and, in many cases, the nearby communities. In the case of Avondale Burial Place, a cemetery in Bibb County, Georgia, in use from 1820 to 1950, all written documentation of those interred within it has been lost. Osteological and archaeological evidence alone could not describe, with confidence, the ancestral origins of the 101 individuals buried there. In the present study, we used ancient DNA extraction methods in well-preserved skeletal fragments from 20 individuals buried in Avondale Burial Place to investigate the origins of the …

An Approach For Determining And Measuring Network Hierarchy Applied To Comparing The Phosphorylome And The Regulome, Chao Cheng, Erik Andrews, Koon-Kiu Yan, Matthew Ung, Daifeng Wang, Mark Gerstein

Dartmouth Scholarship

Many biological networks naturally form a hierarchy with a preponderance of downward information flow. In this study, we define a score to quantify the degree of hierarchy in a network and develop a simulated-annealing algorithm to maximize the hierarchical score globally over a network. We apply our algorithm to determine the hierarchical structure of the phosphorylome in detail and investigate the correlation between its hierarchy and kinase properties. We also compare it to the regulatory network, finding that the phosphorylome is more hierarchical than the regulome.

50 Whys To Look For Genes: Pros And Complications, Peter J. Taylor

Working Papers on Science in a Changing World

“Treating the audience as capable of thinking about the complexities that surround the application of genetic knowledge” was the tagline of a series of daily blog posts made over seven weeks in the fall of 2014, posts that included extended quotes from the recently published Nature-Nurture? No (Taylor 2014). This working paper is a compilation of those posts.

Spectral Gene Set Enrichment (Sgse), H Robert Frost, Zhigang Li, Jason H. Moore

Dartmouth Scholarship

Gene set testing is typically performed in a supervised context to quantify the association between groups of genes and a clinical phenotype. In many cases, however, a gene set-based interpretation of genomic data is desired in the absence of a phenotype variable. Although methods exist for unsupervised gene set testing, they predominantly compute enrichment relative to clusters of the genomic variables with performance strongly dependent on the clustering algorithm and number of clusters. We propose a novel method, spectral gene set enrichment (SGSE), for unsupervised competitive testing of the association between gene sets and empirical data sources. SGSE first computes …