Genetics Commons^™

Hereditary Sensory Autonomic Neuropathy Ii, A Rare Disease In A Large Pakistani Family, Fazal M. Arain, Prem Chand

Department of Paediatrics and Child Health

Hereditary Sensory Autonomic Neuropathy II (HSAN II) is a rare genetic disorder, characterized by severe loss of pain, temperature and touch sensation. Injuries in these patients can progress to necrosis and shedding of digits and limbs. Here we report two cases of HSAN II belonging to a Pakistani family. Individual 1, a forty five year old man, had complete loss of pain sensation since birth. Self-mutilation and complication of injuries resulted in the shedding of all the digits and right foot and surgical amputation of left leg. Individual 2, a five year old girl,had delay in healing of wounds and …

Molecular-Genetic And Behavioral Analysis Of The Functionality Of Patterning In The Trigeminal Neuraxis, Dana Bakalar

Dissertations, Theses, and Capstone Projects

A striking feature of the vibrissal representation in rodents is the presence; at brainstem (barrellettes), thalamic (barrelloids) and cortical levels (barrels) of a somatotopically organized pattern of neurons which is isomorphic, both morphologically and physiologically, to the pattern of vibrissae on the snout. The vibrissal system is required for several classes of behavior, including feeding and active vibrissal sensing, but the functional role of the patterning in these behaviors is unknown. We used two mutant animals lacking patterning in two areas of the vibrissal neuraxis to examine the functional role of patterning. We examined feeding behavior using a knockout of …

The Insulin/Igf Signaling Regulator Cytohesin/Grp-1 Modulates Sensitivity To Excitotoxicity In C. Elegans, Nazila Tehrani

Dissertations, Theses, and Capstone Projects

Excitotoxicity is a form of neurodegeneration that serves as the main underlying cause of brain damage in stroke/brain ischemia, and a contributing factor in a range of neurological diseases such as Epilepsy, ALS, Alzheimer, and Huntington's disease. In excitotoxicity, over-activation of glutamate receptors causes necrotic neuronal cell death. In spite of intense study of excitotoxicity, the molecular mechanisms that lead from glutamate receptor activation to necrotic death remain a mystery. Aging neurons are known to be more vulnerable to excitotoxicity and less likely to recover, but the underlying reasons for the increased cellular vulnerability are unknown. To gain insight into …

A Gene-Based Association Method For Mapping Traits Using Reference Transcriptome Data, Eric R. Gamazon, Heather Wheeler, Kaanan P. Shah, Sahar V. Mozaffari, Keston Aquino-Michaels, Robert J. Carroll, Anne E. Eyler, Joshua C. Denny, Gtex Consortium, Dan L. Nicolae, Nancy J. Cox, Hae Kyung Im

Bioinformatics Faculty Publications

Genome-wide association studies (GWAS) have identified thousands of variants robustly associated with complex traits. However, the biological mechanisms underlying these associations are, in general, not well understood. We propose a gene-based association method called PrediXcan that directly tests the molecular mechanisms through which genetic variation affects phenotype. The approach estimates the component of gene expression determined by an individual’s genetic profile and correlates ‘imputed’ gene expression with the phenotype under investigation to identify genes involved in the etiology of the phenotype. Genetically regulated gene expression is estimated using whole-genome tissue-dependent prediction models trained with reference transcriptome data sets. PrediXcan enjoys …

Drosophila Eye Model To Study Neuroprotective Role Of Creb Binding Protein (Cbp) In Alzheimer’S Disease, Timothy Cutler, Ankita Sarkar, Michael Moran, Andrew Steffensmeier, Oorvashi Roy Puli, Greg Mancini, Meghana Tare

Biology Faculty Publications

Background: The progressive neurodegenerative disorder Alzheimer’s disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (Aβ42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The Aβ42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for Aβ42 mediated neurodegeneration is yet to be fully understood.

Methodology/Principal Findings: We have utilized Gal4/UAS system to …

The Cababc Operon Essential For Biofilm And Rugose Colony Development In Vibrio Vulnificus, Jin Hwan Park, Youmi Jo, Song Yee Jang, Haenaem Kwon, Yasuhiko Irie, Matthew R. Parsek, Myung Hee Kim, Sang Ho Choi

Biology Faculty Publications

A transcriptome analysis identified Vibrio vulnificus cabABC genes which were preferentially expressed in biofilms. The cabABC genes were transcribed as a single operon. The cabA gene was induced by elevated 3′,5′-cyclic diguanylic acid (c-di-GMP) and encoded a calcium-binding protein CabA. Comparison of the biofilms produced by the cabA mutant and its parent strain JN111 in microtiter plates using crystal-violet staining demonstrated that CabA contributed to biofilm formation in a calcium-dependent manner under elevated c-di-GMP conditions. Genetic and biochemical analyses revealed that CabA was secreted to the cell exterior through functional CabB and CabC, distributed throughout the biofilm matrix, and produced …

An Exploration Of The Phylogenetic Placement Of Recently Discovered Ultrasmall Archaeal Lineages, Jeffrey M. O'Brien

Honors Scholar Theses

In recent years, several new clades within the domain Achaea have been discovered. This is due in part to microbiological sampling of novel environments, and the increasing ability to detect and sequence uncultivable organisms through metagenomic analysis. These organisms share certain features, such as small cell size and streamlined genomes. Reduction in genome size can present difficulties to phylogenetic reconstruction programs. Since there is less genetic data to work with, these organisms often have missing genes in concatenated multiple sequence alignments. Evolutionary Biologists have not reached a consensus on the placement of these lineages in the archaeal evolutionary tree. There …

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), …

Impact Of Estrogen Receptor Alpha On Sle1-Induced Loss Of Tolerance, Shayla D. Yoachim

Theses & Dissertations

The autoimmune disease lupus shows a significant female sex bias. This sex bias may be due to the ability of estrogens to promote loss of tolerance to chromatin, the initial loss of tolerance event in lupus. Previously, we demonstrated that the ability of estrogens to promote lupus in (NZBxNZW) F1 mice is dependent on signaling via estrogen receptor alpha (ERα). The Sle1 lupus susceptibility allele controls loss of tolerance to chromatin, and C57BL/6 (B6) mice carrying the Sle1 lose tolerance and develop anti-chromatin autoantibodies and spontaneously activated immune cells. Loss of tolerance occurs earlier and with a higher penetrance in …

Role Of The C-Terminus Of The Catalytic Subunit Of Translesion Synthesis Polymerase Ζ (Zeta) In Uv-Induced Mutagensis, Hollie M. Siebler

Theses & Dissertations

Cellular DNA is under constant attack by endogenous and exogenous DNA damaging agents that threaten genome integrity. Unrepaired DNA lesions often stall replicative DNA polymerases and are bypassed by translesion synthesis (TLS) to prevent replication fork collapse. TLS mechanisms are lesion- and species-specific, with prominent roles of specialized DNA polymerases with relaxed active sites. After incorporation of nucleotide(s) across from the lesion, the distorted primer termini are typically extended by DNA polymerase ζ (Pol ζ). As a result, Pol ζ is responsible for most DNA damage-induced mutations. Mechanisms of sequential polymerase switches and regulation of Pol ζ access to DNA …

Functional Characterization Of The Roles Of Endocytic Recycling Regulator Ehd1 Using In Vivo And In Vitro Analyses, Priyanka Arya

Theses & Dissertations

Endocytic recycling is a fundamental cellular process that allows the precise regulation of the membrane components and receptors at the cell surface. Recent studies have established that the C-terminal Eps15 homology domain-containing (EHD) proteins function as key regulators of this process. Four highly-conserved members of the EHD protein family in mammals, EHD1-EHD4, play shared as well as unique roles in endocytic trafficking. Studies presented here demonstrate a critical role of EHD1 in the normal ocular development in mice. Ehd1 knockout mice generated in our laboratory displayed gross ocular phenotypes including the anophthalmia, microphthalmia, and congenital cataracts. Hematoxylin and eosin (H&E) …

Using The Intact Method To Study Pickle In Individual Cell Types, Jacqueline L. Phipps, Daniela N. Martir, Ben Carter, Joe Ogas

The Summer Undergraduate Research Fellowship (SURF) Symposium

Cell differentiation is an essential part of development in multicellular organisms. Cells with identical genomic DNA are able to differentiate into a variety of tissues due to selective expression and repression of genes. This tissue-specific gene expression is enabled in part by proteins called chromatin remodelers, which can move, remove, or restructure histone proteins to restrict or allow physical access to genomic DNA. PICKLE (PKL) is a member of the CHD family of ATP-dependent chromatin remodelers that promotes cellular identity in the plant model organism Arabidopsis thaliana. PKL promotes cell identity by silencing embryonic genes during seed germination by promoting …

Captive Breeding Protocols And Their Impact On Genetic Diversity In White-Footed Mice (Peromyscus Leucopus): Implications For Threatened And Endangered Species, Maureen C. Lamb, Janna R. Willoughby, J. Andrew Dewoody

The Summer Undergraduate Research Fellowship (SURF) Symposium

Captive breeding protocols used in zoos often are aimed at increasing population sizes and retaining genetic diversity of endangered species. However, captive breeding causes genetic adaptation to captivity that can lead to an overall decrease in genetic diversity and reduce chances of a successful reintroduction to the wild. In this study, we assess how 3 different breeding protocols—random mating, preferential breeding of individuals with the lowest mean kinship scores, and selection for docility—affect the variability of mitochondrial DNA in white-footed mice (Peromyscus leucopus). We used mice that were captured from the wild but were mated for up to …

Using High Throughput Genomic Sequencing To Predict Ecological Impacts On Sea Turtle Populations, Lesley Anderson

STAR Program Research Presentations

Marine turtles are long-lived, migratory vertebrates that encounter a variety of human and natural stressors throughout their lives. Understanding the biology and threats of these animals is challenging because they are hard to observe, and can migrate across whole ocean basins. Minimally invasive sampling techniques (e.g., blood samples) allow us to learn about their physiology, genetics, and the environmental conditions they have experienced. In this project, we developed a novel method to extract the RNA from whole green and loggerhead turtle blood from animals inhabiting a variety of sites across the Pacific Ocean. Some habitats are more pristine, while others …

Characterization Of Putative Wnt3a-Inducible Enhancers, Katelynn C. Lee, Nicholas Hum, Aimy Sebastian, Gabriela Loots

STAR Program Research Presentations

The Wnt signaling pathway has been previously shown to play a major role in regulating bone metabolism and it is emerging as a target for the therapeutic intervention of bone thinning disorders such as osteoporosis. Several Wnt proteins have been shown to be expressed in bone and mutations in Wnt pathway members such as Wnt co-receptor Lrp5 and Wnt inhibitor Sost have been shown to be associated with low or high bone mass disorders, however, very little is known about specific roles played by different Wnt ligands in bone development, repair and remodeling. To identify downstream targets of Wnt signaling …

Differential Regulation Of The Two Grp170 Paralogues Of Caenorhabditis Elegans, Antonio L. Rockwell

Biology Theses

Abstract of a Thesis

Differential Regulation of the Two grp170 Paralogues of Caenorhabditis elegans

Caenorhabditis elegans has two loci encoding the large eukaryotic molecular chaperone Grp170, grp170a (T24H7.2) and grp170b (T14G8.3). To investigate expression of the two C. elegans grp170 loci during ER stress, the Unfolded Protein Response (UPR) was induced with the glycosylation inhibitor tunicamycin. Levels of grp170a mRNA did not significantly change in response to tunicamycin treatment while the levels of grp170b mRNA increased 6-fold. ER stress induction of grp170b was unaffected in worms defective for the ATF6 and PERK-1 UPR signal transduction pathways. However, worms defective …

Beyond Bivariate Correlations: Three-Block Partial Least Squares Illustrated With Vegetation, Soil, And Topography, Daehyun Kim, Thomas J. Dewitt, César S. B. Costa, John A. Kupfer, Ryan W. Mcewan, J. Anthony Stallins

Biology Faculty Publications

Ecologists, particularly those engaged in biogeomorphic studies, often seek to connect data from three or more domains. Using three-block partial least squares regression, we present a procedure to quantify and define bi-variance and tri-variance of data blocks related to plant communities, their soil parameters, and topography. Bi-variance indicates the total amount of covariation between these three domains taken in pairs, whereas tri-variance refers to the common variance shared by all domains. We characterized relationships among three domains (plant communities, soil properties, topography) for a salt marsh, four coastal dunes, and two temperate forests spanning several regions in the world. We …

Identification Of Familial Wilms Tumor Predisposition Genes Using Whole Genome Sequencing, Timothy B. Palculict

Dissertations and Theses (Open Access)

Wilms tumor, a childhood tumor arising from undifferentiated renal mesenchyme, is diagnosed in North America at a frequency of 1 in 10,000 live births and accounts for 5% of all pediatric cancers. The etiology of Wilms tumor is heterogeneous with multiple genes known to have an effect on Wilms tumor development; however, these genes are rarely associated with familial Wilms tumor. Gene mutations in WT1, WTX, CTNNB1 and TP53 are observed in a third of sporadic tumors, while the causative gene(s) responsible for familial Wilms tumor are largely unknown. Approximately 2% of Wilms tumor patients have a family …

In Vivo Significance Of The Mdm4 And P73 Interaction During Development And Tumorigenesis, Mehrnoosh Tashakori

Dissertations and Theses (Open Access)

The tumor suppressor protein p53 is negatively regulated by Mdm4 protein. The significance of such regulation was determined from mouse models. Mdm4-deficient mice are embryonic lethal at E7.5 in a p53-dependent manner. p73, a member of the p53-family, is a transcription factor with tumor suppressor activity. In vitro studies show that Mdm4 binds to p73 and, further, comprehensive biochemical studies revealed that Mdm4 has higher affinity for p73 than p53. However, little is known about the significance of the Mdm4 and p73 interaction in vivo. This study aimed to elucidate the biological consequences of this interaction during embryogenesis …

Germline Mutation Detection In Next Generation Sequencing Data And Tp53 Mutation Carrier Probability Estimation For Li-Fraumeni Syndrome, Gang Peng

Dissertations and Theses (Open Access)

Next generation sequencing technology has been widely used in genomic analysis, but its application has been compromised by the missing true variants, especially when these variants are rare. We proposed a family-based variant calling method, FamSeq, integrating Mendelian transmission information with de novo mutation and sequencing data to improve the variant calling accuracy. We investigated the factors impacting the improvement of family-based variant calling in simulation data and validated it in real sequencing data. In both simulation and real data, FamSeq works better than the single individual based method.

In FamSeq, we implemented four different methods for the Mendelian genetic …