ABOUT THE COMPARATIVE MEDICINE INSTITUTE
The mission of the Comparative Medicine Institute (CMI) is to develop, foster, and assist multidisciplinary teams focused on translating basic research and scientific discovery into clinical/societal applications to improve the health of animals and humans.
In 2006, the Center for Comparative and Medicine and Translational Research (CCMTR) was established at NC State University as part of an effort to develop and support interdisciplinary research opportunities. Its role expanded considerably and in October 2015 the CCMTR was granted Institute status and is now recognized as the CMI.
The Institute strives to support interactions between the clinical and basic research groups within the university community by developing mechanisms that encourage and facilitate those collaborations. The CMI is comprised of interdisciplinary teams of more than 146 faculty from 21 departments and representing five colleges and seven universities. These closer interactions provided by the CMI, the focus on areas deemed to be of high relevance to the State and the Nation, and the considerable strengths already existing within NC State University ensure that the Institute will remain competitive.
An integral part of the Institute’s mission is to provide clinical and research opportunities to professional students, graduate students, clinical residents, and postdoctoral fellows. In addition, the Institute is a central component for enhancing and accelerating the development of the Centennial Biomedical Campus. All of these goals are relevant to the educational and research mission of NC State University, the UNC system, and the State of North Carolina.
The Comparative Medicine Institute (CMI) – Translational Genetics & Genomics Research Focus Area will have six different collaborative research projects between CMI members with expertise in basic research and CMI members with clinical expertise, spanning model organisms and companion animals, comparative genomics and phenotype prediction from genetic and genomic data. Seven positions will be offered to highly competitive undergraduate students majoring in the Genetics Program at NC State University. These positions are scheduled to begin in February 2017. All positions will be compensated for the summer research component with a stipend of $5,000 over a period of 12 weeks. All students that complete the summer research project will be required to present a poster on their research at the 2017 Summer Undergraduate Research Symposium; register for GN496 the following Fall 2017; and present their findings at the CMI poster presentation session in the Fall 2017. The topics and descriptions of these projects are available below.
- November 22, 2016
- The first day to apply.
- January 13, 2017
- Deadline to apply. All applications should be submitted by 5:00 pm.
- January 19, 2017, at 5:30 pm in the Stephens Room, 3503 Thomas Hall
- CMI Applicant Information Session (“Speed Dating” the CMI Projects and meeting the Principal Investigators) – All applicants who apply are strongly encouraged to attend. Refreshments will be provided. Please register for this event.
- Tentatively between February 16 – 28, 2017
- The final decision on applicants selected for the seven projects will be announced.
- March 1, 2017
- Trial period start-date for selected applicants. Students will begin working on their research project in the laboratory.
- May 15, 2017
- Research internship start date. Paid stipend begins.
- August 4, 2017
- Research internship end-date. Paid stipend ends.
A Translational Model for Canine Hereditary Ataxia in Drosophila
PIs: Robert Anholt, Natasha Olby, Mary Anna Carbone, Trudy Mackay
Neurodegenerative motion disorders have complex genetic risk factors. Multiple mutations have been associated with various forms of spinocerebellar ataxia. These genetic factors can give rise to diverse phenotypic spectra due to gene-gene interactions and gene-environment interactions. Ataxia can be modeled effectively in transgenic Drosophila melanogaster. Most studies in flies to date have focused on transgenic expression of ataxin, a member of the polyglutamine protein family with late onset neurodegeneration. A recent study identified a polymorphism in canine RAB24, associated with hereditary ataxia in two dog breeds, Old English Sheep dogs and Gordon Setters. Rab24 is a member of a family of small GTPases that regulate intracellular trafficking and vesicle fusion. It is encoded by a small gene of 4780 bp and a range of reagents, including DNA constructs and antibodies, are available. We propose to express wild-type and pathogenic allelic variants of canine Rab24 in transgenic Drosophila melanogaster using the GAL4-UAS binary expression system with a global neuronal elav-GAL4 driver as well as more specific GAL4 drivers that express the transgene in dopaminergic neurons or neurons in brain regions associated with locomotion, such as the central complex. We will observe open field locomotion of transgenic flies versus controls. Viable homozygous transgenic flies with locomotor deficits and their controls can be crossed to the sequenced inbred wild-derived lines of the Drosophila melanogaster Genetic Reference Panel to identify epistatic modifiers. Such modifiers, the transcriptional ensembles with which they are associated, and the neurons in which they are expressed can give insights into the mechanism by which RAB24 mutations give rise to locomotor deficits as a basis for further studies and as preliminary data for possible follow-up grant applications.
Allele-Specific Gene Expression in Animal Hybrids**
PIs: Drs David Aylor, Trudy Mackay, Kate Meurs,
Freya Mowat, Reade Roberts, Jeff Yoder
(** Two interns)
Hybrids are animals whose two parents are genetically distinct – from different strains, breeds, or species. Hybrids usually resemble both parents overall but often exhibit remarkable biology in specific traits for which they are unlike either parent. This phenomenon is called hybrid vigor when associated with favorable traits such as growth and fertility. However, hybridization can also have deleterious consequences such as sterility and disease susceptibility. The genetic causes of extreme trait values in hybrids have long been debated. One hypothesis posits new combinations of dominant alleles contributed by each parent. An alternative explanation is overdominance, a genetic mode of action in which heterozygotes at a specific gene have a more extreme phenotype than either homozygote. For complex traits, hybrid trait values are likely determined by a combination of both effects, plus gene-gene interactions. Allele-specific gene expression profiling can help us answer these long-standing questions by analyzing how each gene is expressed in the hybrid relative to its two parents. Multiple CMI investigators have research interests in hybrid biology and hybrid genetics across a wide range of organisms including mice, dogs, fish, and fruit flies. This project will be team-oriented and will involve two CMI undergraduate interns. One intern will primarily develop generalizable bioinformatic tools to enable allele-specific gene expression experiments across multiple organisms. Programming experience is desirable. The other intern will generate allele-specific gene expression data from a variety of animal samples.
Genetics of Host Resistance to Lethal Salmonella Infection
PIs: Drs. Johanna Elfenbein, Trudy Mackay
Salmonella enterica is the leading cause of bacterial foodborne gastroenteritis in the United States and causes more than 150 million cases worldwide each year. After ingestion, the bacterium invades the intestinal epithelium and elicits a robust immune response. Immunosuppressed individuals, children under 5 years of age, and the elderly develop an immune response that is insufficient to contain the bacterium to the intestine allowing systemic dissemination of the organism and frequently death of the infected individual. The full complement of host genes that are needed to survive lethal Salmonella infection are unknown. We developed a lethal Salmonella infection model using Drosophila melanogaster as a host organism. We used Wolbachia-negative flies outbred from the Drosophila Genetic Reference Panel with maximal heterozygosity at all loci to establish infection conditions whereby Drosophila are reliably killed by Salmonella infection. Flies are fed Salmonella and fly viability is monitored daily. We found that male flies die within 2-3 days of infection and females die within 8-9 days. This prior work, funded by the Comparative Medicine Institute, is the foundation for the current project. We will perform a large-scale genetic screen using the heterozygous fly population to establish the genotypes of animals surviving lethal salmonellosis. Flies will be separated by sex and fed either live or killed Salmonella. The genome sequence of 10% of the population of surviving flies will be compared with that of the starting population and those fed killed Salmonella, to control for starvation conditions. We will establish the Drosophila gene networks needed to survive lethal salmonellosis and these networks will be mined for mammalian homologues. After completion of the genetic screen, we will confirm the necessity of a subset of genes by creating mutant flies, using RNA interference to reduce gene expression, and/or overexpression of a given gene in a target tissue. The student selected to perform this project will gain experience in microbiology, DNA isolation from Drosophila, DNA sequence analysis, and advanced genetic manipulation of Drosophila (if time permits). This comparative medicine project will capitalize on the many genetic tools available in Drosophila to identify and characterize novel genes needed for survival in the face of Salmonella infection. Further work will translate the findings from our Drosophila infection model into vertebrate hosts including zebrafish, mice, and pigs.
Host Genetic Control of Human Skin Microbiota
PIs: Drs. Julie Horvath, Reade Roberts
The human microbiota consists of microscopic ecosystems in and on the human body, and has been increasingly associated with a variety of human health conditions. Despite the clinical importance of human microbiota, and strong evidence for host genetic modulation of the microbiota, few specific links have been identified between variation in the human genome and the composition of microbial communities on the human body. We recently found that alleles of the ABCC11 gene are significantly correlated with composition of apocrine gland associated microbiota in the ear canal and armpit. Notably, clinically relevant bacterial species appear to be modulated by ABCC11 variation. One of these species is Propionibacterium acnes, linked to acne and other health conditions, including eye disease. The proposed CMI project will sample microbiota from participants’ face pores, and potentially eye secretions and other sites; individuals will be genotyped for ABCC11 alleles using a sequencing assay. High-throughput 16S rRNA (bacteria) and ITS (fungi) sequencing libraries will be produced from the microbiota samples for analysis using Illumina MiSeq genome sequencing technology. The microbiota bacterial and fungal profiles produced will be correlated to ABCC11 genotype, body site, and varied participant data.
Whole Genome Sequence Analysis of Red Wolves to
Identify Genetic Mutations Causing Blindness
PIs: Drs. Freya Mowat, Matthew Breen
Would you like the opportunity to be part of a real wolfpack? Red wolves are a critically endangered species, extinct in the wild. A captive breeding population based on 14 founders is maintained in multiple collections throughout the USA. We have discovered a suspected X-linked form of hereditary blindness in three male red wolves, and are continuing to explore the prevalence of the disease by performing eye examinations of wolves in collections throughout the USA. The ultimate goal of this research is to develop a genetic test to screen for affected/carrier animals and provide appropriate genetic counseling to the species managers. Our goal for the summer project is to perform whole genome sequencing on two affected male wolves. The student will perform bioinformatic sequence analysis to identify and explore sequence similarities between the two genomes (and a previously sequenced suspected carrier female) to narrow down the list of candidate genes. PCR and Sanger sequencing of strong candidate genes may be performed. We will also perform frozen sectioning of affected and unaffected wolf eyes during the summer, the student will be able to perform histologic assessment of the tissue. There will be opportunity to participate in red wolf eye screening examinations as they are scheduled and to extend the project beyond the summer, pending external funding.
A Solution to Peto’s Paradox:
p53 Copy Number in Large-Bodied Marine Mammals
PIs: Drs. Jason Somarelli, Seth Faith
Cancer kills nearly 8 million people worldwide each year. However, cancer is not a disease restricted to humans. In fact, it seems as though cancer is an affliction that is common to almost all multicellular organisms. And yet, some large-bodied organisms get cancer at rates that are much lower than expected given the numbers of cell divisions that would have to occur to form their immense body sizes. If we assume that any dividing cell is capable of becoming cancerous, then the number of cells in an organism should correlate with the amount of cancer that a species gets. However, this correlation does not exist in nature. This lack of correlation between body size (i.e. cell number) and cancer rate is known as Peto’s Paradox. Peto’s Paradox suggests that large-bodied animals might have a series of protective mechanisms in place that prevent them from getting cancer as frequently as they should. For example, we now know that elephants have 20 copies of the tumor suppressor, p53, while humans have just two copies of this essential tumor suppressing gene. We hypothesize that other large-bodied mammals have increased copies of p53 and/or other protective mechanisms that enable them to grow to such large sizes without developing cancer. We will test our hypothesis by analyzing p53 gene copy number in a cohort of large-bodied marine mammals. This work could help pinpoint mechanisms of protection against cancer to help prevent human and animal cancers alike.
Please complete the application below to be considered for one of the seven CMI project positions.
- Supplemental Documents:
Submission of your CV or resume (PDF format) and a copy of your unofficial transcript (PDF, PNG, or JPG format) is required.
- Any information that you submit to apply for the CMI – Translational Genetics and Genomics application will be made available to the CMI faculty. All application materials will be reviewed by members of the CMI.
If you have any questions regarding your application submission form, please contact Melissa Robbins via email at firstname.lastname@example.org.