Research programs
Researchers in the VCU Department of Human Genetics attract local and federal grants and actively publish their results from their investigations in six main areas of human genetics research:
Genetics of inherited disorders
Many human diseases, genetic disorders and birth defects are a result of the heritable transmission of mutations. Identifying the specific genes and mutations predisposing individuals for these disorders will increase both our ability to detect them in utero through the creation of genetic tests and our understanding of the basis for the disease condition. Several principle investigators within this department are interested in identifying the genes associated with particular conditions.
Dr. Walter Nance and Dr. Arti Pandya are interested in defining the mutations associated with deafness. Their laboratory has an interest in studying the genetics of hearing loss. Specifically, they investigate the genes for non-syndromic hearing loss; mechanism of mitochondrial hearing loss; modifiers for deafness in Waardenburg syndrome Type I; and genotype/phenotype correlation of common genetic forms of deafness including Cx-26 deafness. Furthermore, they have developed a national repository of DNA from deaf probands.
Dr. Sarah Elsea focuses on the developmental disorder Smith-Magenis Syndrome. Her laboratory has recently identified a single gene from within 17p11.2, called RAI1 (retinoic acid induced 1), that when mutated causes the craniofacial and neurobehavioral abnormalities seen in SMS. A number of other genes within 17p11.2 are considered candidates for other features of the syndrome, including seizures, heart and kidney defects, and small stature. Studies in the laboratory are currently focused on the gene RAI1 and other genes within the chromosome 17p11.2 region.
Dr. Rita Shiang is currently working on cloning the second gene that causes Wolfram Syndrome, a devastating neurodegenerative disorder. She collaborates with Dr. Hatem El-Shanti from the University of Iowa; Dr. El-Shanti has provided DNA from families from nomadic tribes in Jordan.
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Genetics of psychiatric disorders
A group of researchers from the department are part of the Virginia Institute of Psychiatric and Behavioral Genetics. VIPBG's multidisciplinary research is organized around two mutually reinforcing principal themes: the development of methods for the analysis of genetic and environmental risk to complex traits (statistical genetics and genetic epidemiology) and the gathering of empirical data that permit the analysis of the causes of medically relevant normal behavioral variation and biomedical conditions with behavioral components (molecular, psychiatric and behavioral genetics). Currently, the institute is supported by 22 research grants totaling over $25 million from federal and private sources, including 25 R01's, two K awards and a T32. More than 500 papers in leading journals have been authored or co-authored by VIPBG faculty. In a recent survey of high-impact research in psychiatry, VCU was ranked second among federally funded U.S. universities. Three VIPBG researchers are ranked among the top 20 highly cited in psychiatry worldwide. Department of Human Genetics faculty members within VIPBG focus their research on child and adolescent development, substance use and abuse/dependence, and biomedical conditions.
Child and adolescent development
Dr. Lindon Eaves initiated this research program two decades ago to study the role of genes and environment in the development of normal and abnormal behavior in children and adolescents. A population-based sample of over 1,400 twin pairs, aged 8 through 16, and their parents participated in the original study called “Virginia Twin Study of Adolescent Behavioral Development.” This sample was contacted for up to four waves of data collection during adolescence and again as young adults as part of the YAFU project “Pathways to Adult Psychopathology: A Study of Etiological Factors” headed by Dr. Judy Silberg. An additional follow up with a focus on substance use is under way under the direction of Dr. Donna Miles.
Data analysis of the extensive longitudinal data is currently supported by the “Developmental Genetic Epidemiology of Psychopathology” grant, which is designed to yield a comprehensive understanding of the developmental interplay between genetic and social factors in the trajectory of mood and behavioral disorders from early adolescence into young adulthood. Co-investigators on this project include Dr. Hermine Maes and Dr. Debra Foley, who focused her research on “Genetic Epidemiology of Juvenile Anxiety Disorders.”
A spin-off of this line of research is the “Parental Effects on Depression and Disruptive Behavior in Children of Twins” project (PI: Dr. Judy Silberg). This “Children of Twins” study unravels the causal effects of parental treatment on offspring behavior from secondary genetic association between parents and children. It will allow the impact of specified putative environmental risk factors to be identified and estimated, including parental psycho-pathology, marital conflict, and impaired parenting on depression and anti-social behavior in children and adolescents. This line of work also is supported by a NARSAD award and the Carman Trust. Recently the National Institute for Child Health and Development awarded VIPBG $1.5 million for a study of infant twins in Puerto Rico. The grant, “Gene Environment Interplay in Infant Development,” represents a collaborative effort between VCU (Silberg and Eaves), Drs. Glorisa Canino and Vivian Febo at the University of Puerto Rico Behavioral Sciences Research Institute, and Dr. Helen Egger, a child psychiatrist at Duke University. The collaboration between UPR and VCU was originally established by VCU President Eugene P. Trani in 1999.
Substance use and abuse/dependence
In recent years research interest has increased dramatically in the area of substance use and abuse, which resulted in a number of funded projects. Dr. Donna Miles’ research focuses on examining sex differences in the etiology of substance abuse, both in role of genetic and environmental factors in the transition from initial substance use to substance dependence and in the relationship between childhood psycho-pathology and behavior with the development of adult substance use disorders. This work is supported by a Building Research Careers in Women’s Health fellowship and by the Virginia Youth Tobacco Project’s “Longitudinal Twin Study: Transitions to Substance Abuse.” Dr. Hermine Maes also is supported on the VYTP project, which addresses basic etiological questions regarding the transition from tobacco use to nicotine dependence; examines the role of genetic and environmental factors contributing to progression of tobacco use into nicotine dependence between adolescence and young adulthood; and uses molecular tools to identify individual genes that influence vulnerability to tobacco initiation and nicotine dependence. This research fits in with the priority areas of cancer control research set out by the National Cancer Institute and is encouraged through pre- and postdoctoral fellowships on the VCU Massey Cancer Center Cancer Control Training Program. Dr. Tim York, a fellow from this program was awarded an MCC Pilot Project Grant “Identification of Biomarkers for Tobacco Use: Normal Variation and the Control of Gene Expression in MZ and DZ Twins” to characterize genetic and environmental sources of individual variation in gene expression profiles and evaluate the role of gene expression in mediating the impact of known risk factors for cancer: tobacco use, alcohol use and obesity. Other funded substance use research includes a subcontract by Dr. Lindon Eaves to the “Multi-site Longitudinal Analysis – Psychiatric Risk of SUD” study into the impact of child psychopathology on subsequent substance use through a collaboration with Duke University and Dr. Michael Neale’s recently funded project “Psychometric and Genetic Assessments of Substance Use,” which looks at a number of issues involving substance use, including the development and testing of methods to investigate the assessment and classification of substance use and abuse patterns that include genetic item response theory models and genetic latent class models. Eaves also has a subcontract with Harvard University on “A Longitudinal Twin Study of Cognition and Aging” to shed light on the dynamic interplay of biological and psychosocial environmental factors that create age-associated changes in health, cognition and personality.
Biomedical conditions
General health information has been collected from large samples of twin pairs and their relatives from a population-based registry (the Mid-Atlantic Twin Registry) and volunteer-based sources (AARP) to study the relative importance of genes and environment and their interplay on a range of physical and mental health conditions and behaviors. Dr. Linda Corey’s research has focused on the genetic epidemiology of seizures and status epilepticus using data from large Virginian and Scandinavian twin registries to elucidate the importance of genetic, maternal and environmental factors in risk for epilepsy. This work has been funded by two projects: “A Genetic Study of Status Epilepticus in Twin Kindreds” and “Genetic Epidemiology of Seizures: A Twin Study.”
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Animal models of human disease
Mouse models of human disease
Animals provide indispensable model systems allowing us to investigate developmental biology, gene regulation, cancer oncogenes and many of the genetics causes of human disease and their associated pathologies. Dr. Jolene Windle is responsible for the VCU Massey Cancer Center transgenic core and is a key collaborator on several of these projects. Windle is interested in the role of several oncogenes in mouse mammary tumors and in a collaborative study with (XX) the study of osteoclasts from transgenic mice. Several principle investigators are using the powerful tool of mouse genetics to study several disease conditions. Dr. Rita Shiang[link to Shiang’s page] has developed a conditional knockout mouse model of Treacher Collins syndrome, a hereditary condition that primarily affects the structures of the head and face. Dr. Peter O’Connell and Windle are investigating the role of the protein metastasis associated protein 1 (MTA1) in breast cancer, specifically the genetic interaction between MTA1 with breast oncogenes. Lastly, Dr. Steven Townson in collaboration with Windle are developing a new transgenic model of mouse model of breast cancer metastasis and new technologies to aid in the temporal and spatial control of gene expression in transgenic mouse models.
Drosophila melanogasteras a model for human disease
Dr. Michael S. Grotewiel has introduced the department to the model organism Drosophila melanogaster as a tool for the investigation of human disease. His laboratory studies the molecular-genetic bases of nervous system function and aging in the fruit fly, Drosophila melanogaster. This organism serves as a model system for several reasons. First, there are many powerful genetic tools that can be used to manipulate the genome of fruit flies. Thus, it is possible to mutate genes of interest, alter their expression patterns, impair their function and search for other genes that function within a particular genetic pathway. Second, flies are capable of performing a number of behavioral tasks in the laboratory that can be quantitatively measured. Since these different behaviors depend on the function of distinct brain systems and typically decline with age, studying the behaviors provides insight into the function of specific regions of the nervous system within the context of aging. Finally, the fundamental aspects of neuron and gene function are conserved throughout the animal kingdom as are many aspects of aging. Thus, the information obtained from studies in fruit flies will facilitate a more global understanding of the molecular events underlying brain function and aging. In addition, Grotewiel and Dr. Sarah Elsea are using Drosophila to investigate the contribution of specific genes toward the phenotype of human Smith-Magenis patients. Lastly, Grotewiel and Dr. Ken Kendler have recently started to explore the use of Drosophila as a behavioral-genetic model for understanding schizophrenia in humans.
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Developmental genetics
The development of multicellular organisms from a fertilized embryo follows a genetic program requiring interactions between many different cell types. This multicellularity derives from a series of temporal and spatial signals that determine cell fate. Understanding these genetic interactions and pathways allows us to define the role of heritable mutations in development defects of organ systems and how control of these signaling pathways leads to tumorigenesis. Several different model systems are employed within the department to study different questions relating to mechanisms of development and aging.
Dr. Joyce Lloyd is collaboroating with Dr. Jack Haar and Dr. Joy Ware to investigate the genetic profile of mouse erythroid development. The goal of this project is to determine which genes are differentially expressed between these two populations of cells, to get a global sense of genes controlling erythroid development, and then use this information to develop strategies to re-initiate expression of embryonic globin genes in sickle-cell anemia and beta-thalassemia. Lloyd has developed a technique to isolate erythroid cells from the developing mouse embryo, using laser capture microdissection. Primitive erythroid cells can be isolated from the yolk sac, and definitive erythroid cells can be collected from the fetal liver. RNA from these cells is isolated and used microarray hybridizations to identify differential gene expression patterns.
Dr. Jim Lister uses the zebrafish (Danio rerio) (refer to The Zebrafish Information Network for more information) to study the role of the mitf transcription factor in pigment cell development from the neural crest cell lineage. Grotewiel uses the fruit fly Drosophilamelanogaster to study age-related effects on learning and memory. The focus of his laboratory is on the role of integrins in nervous system function and the genetic basis for aging. This is achieved using RNA interference technology in conjunction with Drosophila genetics to knock-down the expression of individual integrin genes to better understand how they participate in the function or development of the olfactory system. In addition, several aging-related genes are being characterized that were identified through genetic screens focused on understanding the mechanisms of aging on learning and memory.
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Gene regulation
Understanding how genes are regulated is one of the key tenants of biology. Defining the mechanisms that regulate the expression of a particular protein is an important step in understanding the genetic pathways directing the development of multicellular organisms and how these pathways contribute to human disease. Several faculty members are investigating the fundamental mechanisms of gene regulation using a variety of in vitro and in vivo systems.
The laboratory of Dr. Joyce Lloyd is interested in developmental gene regulation and uses globin switching as a model system. In the human, beta-like globin expression switches from the embryonic (epsilon-) to the fetal (gamma-) to the adult (beta-) globin genes. Epsilon and gamma-globin have an ameliorating effect on sickle cell anemia and beta-thalassemia, so a basic understanding of how switching occurs will lead to novel therapeutic strategies. The major focus of this research project has been to identify the DNA regulatory elements and transcription factors involved in globin gene switching. Recently, we have shown using knock-out/transgenic mice that KLF2, a zinc finger transcription factor, regulates epsilon globin gene expression. Therefore, KLF2 may be a good candidate for use in gene therapy strategies. The current questions which Lloyd is addressing the role of KLF2 in erythroid cells, its action on the epsilon globin promoter, and its interaction with the related protein, EKLF/KLF1. Lloyd is collaborating with several researchers on these questions including Dr. Gordon Ginder from the VCU Massey Cancer Center, Dr. Jerry Lingrel, University of Cincinnati, Dr. Karin Gaensler, University of California, San Francisco, and Dr. Kenneth Peterson, University of Kansas.
Dr. Steven Townson studies the role of the estrogen receptor 1 (ESR1) coactivator and corepressor proteins in breast cancer. ESR1, a member of the steroid-binding nuclear receptor family of transcription factors, is responsible for mediating the oncogeneic effects of the hormone estrodiol in breast cancer. ESR1 is both a prognostic and predictive factor in breast cancer and over 70 percent of tumors express this protein. Thus, by understanding the role of ESR1 and proteins that regulate its function, breast tumorigenesis can better be understood. His laboratory is investigating the role of the Ret finger protein in defining ESR1-regulated pathways of tumorigenesis and performing a structure/function analysis of RFP as a transcription factor.
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Cancer genetics
Cancer is one of the leading causes of mortality and morbidity in developed societies and many of the mechanisms leading to a variety of different cancers have not been elucidated. The combination of environmental, behavioral and genetic factors all impact an individual’s susceptibility to cancer. Defining the genetic changes associated with tumor development and progression will enable us to develop clinical assays to prescribe appropriate treatments and predict tumor progression, thus increasing overall patient survival. In this department investigators are unraveling the genetic changes associated with two of the most common types of cancers, breast and prostrate.
Dr. Peter O’Connell has several collaborative projects related to cancer genetics. O’Connell and colleagues at Baylor College of Medicine, Drs. Jenny Chang and Mike Lewis, hypothesize that patterns of gene expression exist that will distinguish primary breast cancers that are sensitive or resistant to specific chemotherapies. This project will establish gene expression parameters of response for two mainline chemotherapies for breast cancer: Taxotere (T) and Adriamycin (doxorubicin) plus cyclophosphamide (AC). They use cDNA microarrays and allied technologies, e.g., quantitative real time PCR and immunohistochemistry to identify and confirm patterns of gene expression associated with sensitivity or resistance to these two therapies.
A collaborative project with Drs. Lynn Penberthy, Diane Wilson, Cathy Dumur and Kelly Archer is investigating obesity, ethnicity and disparities in breast cancer outcome. Breast tumors from lean versus overweight patients of African and European descent are compared to identify obesity- and/or ethnicity-associated tumor-genetic differences that contribute to disparities in breast cancer survival.
A collaborative project on prognostic markers of risk of invasive progression of ductal carcinoma in situ with Dr. Craig Allred at Baylor College of Medicine. Here, gene expression differences are compared between DCIS (non-invasive breast cancer) and invasive breast cancers to identify a prognostic index for estimating the risk of DCIS progression to invasive breast cancer.
Predicting tumor response to chemotherapy is a critical aim of improving patient survival and O’Connell is investigating gene expression-based predictors of breast tumor chemotherapy response. Differences in pre-treatment breast tumor gene expression profiles are correlated with differences in tumor chemoresponses (shrinkage) of patients receiving main-line neoadjuvant chemotherapies (treatment prior to surgical resection). The team has identified, and is validating gene-based predictors of TaxotereR (docetaxel), Adiamycin-Cytoxan (AC) chemoresponse (coming soon – HerceptinR). The team consists of Drs. Harry Bear, Cathy Dumur, Carleton Garret, Kelly Archer, Jenny Chang (BCM) and Craig Allred (BCM).
The metastasis-associated protein 1 (MTA1) protein is important for breast metastasis. O’Connell has used immunohistochemistry to show that overexpression of metastasis-associated 1 (MTA1, a steroid hormone co-repressor protein) is both a prognostic and a predictive factor for breast cancer treatment. The only problem is that MTA1 has 27 different isoforms. The team consists of Drs. Harry Bear, Cathy Dumur, Carleton Garret, Jenny Chang (BCM) and Craig Allred (BCM).
Lastly, a project with Dr. Steven Townson is defining genetic differences that occur between primary and recurrent breast tumors, and primary and contralateral breast tumors.
A cancer hallmark is the presence of chromosomal aberrations and Dr. Colleen Jackson-Cook is a cytogeneticist investigating cancer-related chromosomal aberrations. Professor Joy Ware uses functional genomics approaches to determine the role of networks of macromolecules and proteins in prostrate cancer development. Here, single gene products are studied in a global context, rather than one gene product at a time.
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