ABNORMALITIES OF THE X CHROMOSOME IN TURNER SYNDROME AND ITS VARIANTS
Huntington F Willard, Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5P01HD032111-050004 from National Institute Of Child Health And Human Development
Abstract: Turner syndrome is a common chromosomal disorder associated with short stature, ovarian failure, and a collection of variable anatomical abnormalities including congenital webbed neck, shield chest, and cardiac and renal anomalies. This disorder is most commonly associated with a 45,X karyotype, but is found nearly half of the time in individuals carrying different types of structurally abnormal X chromosome. While a monosomy X karyotype implicates haploinsufficiency for X-linked genes in the pathogenesis of Turner syndrome, the latter karyotypes suggest that a more complex series of effects involving X chromosome inactivation and variable expression of X-linked genes are responsible. This revised project examines two of the most common structural abnormalities of the X chromosome associated with Turner syndrome -- isochromosomes for the X chromosome long arm detected in about 15-20% of patients with typical Turner syndrome and small X-derived centric fragments often associated with mental retardation, growth retardation, and dysmorphic facies. We propose a series of experiments to address the nature of these chromosome abnormalities, their molecular basis, and their phenotypic consequences. The data so obtained should be significant for the understanding of the molecular basis of chromosome abnormalities, for examining centromere structure and behavior, and for elucidating the genetic mechanisms responsible for a major syndrome affecting females throughout life. The specific experimental aims of the proposed research are 1. to determine the molecular structure and genetic origin of a series of patient-derived isochromosomes for the long arm, i(Xq); 2. to determine the molecular structure of a series of experimentally- derived isochromosomes for the short arm, i(Xq), using a newly developed system to select for formation of such chromosomes in cultured cells; 3. to map and clone breakpoints associated with various classes of isochromosome to test the hypothesis that specific DNA sequences are involved in the molecular formation of the isochromosome; 4. to test the hypothesis that both i(Xq) and i(Xp) isochromosomes that differ in their molecular structure also differ in their mitotic stability by measuring the segregation behavior of monocentric or dicentric isochromosomes in cultured cells; and 5. to identify genes from proximal Xp and Xq and to test the hypothesis that such genes are functionally disomic, due to a failure of X inactivation, in patients with small centric X fragments.
Keywords: Turner s syndrome, chromosome disorder, sex chromosome, centromere, chromatin, karyotype, artificial chromosome, genetic mapping, human subject, in situ hybridization, molecular cloning, polymerase chain reaction, pulsed field gel electrophoresis, tissue /cell culture
Sponsored Links Excellgen http://Excellgen.com
ABNORMALITIES OF THE X CHROMOSOME IN TURNER SYNDROME AND ITS VARIANTS
Huntington F Willard, Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5P01HD032111-040004 from National Institute Of Child Health And Human Development
Abstract: Turner syndrome is a common chromosomal disorder associated with short stature, ovarian failure, and a collection of variable anatomical abnormalities including congenital webbed neck, shield chest, and cardiac and renal anomalies. This disorder is most commonly associated with a 45,X karyotype, but is found nearly half of the time in individuals carrying different types of structurally abnormal X chromosome. While a monosomy X karyotype implicates haploinsufficiency for X-linked genes in the pathogenesis of Turner syndrome, the latter karyotypes suggest that a more complex series of effects involving X chromosome inactivation and variable expression of X-linked genes are responsible. This revised project examines two of the most common structural abnormalities of the X chromosome associated with Turner syndrome -- isochromosomes for the X chromosome long arm detected in about 15-20% of patients with typical Turner syndrome and small X-derived centric fragments often associated with mental retardation, growth retardation, and dysmorphic facies. We propose a series of experiments to address the nature of these chromosome abnormalities, their molecular basis, and their phenotypic consequences. The data so obtained should be significant for the understanding of the molecular basis of chromosome abnormalities, for examining centromere structure and behavior, and for elucidating the genetic mechanisms responsible for a major syndrome affecting females throughout life. The specific experimental aims of the proposed research are 1. to determine the molecular structure and genetic origin of a series of patient-derived isochromosomes for the long arm, i(Xq); 2. to determine the molecular structure of a series of experimentally- derived isochromosomes for the short arm, i(Xq), using a newly developed system to select for formation of such chromosomes in cultured cells; 3. to map and clone breakpoints associated with various classes of isochromosome to test the hypothesis that specific DNA sequences are involved in the molecular formation of the isochromosome; 4. to test the hypothesis that both i(Xq) and i(Xp) isochromosomes that differ in their molecular structure also differ in their mitotic stability by measuring the segregation behavior of monocentric or dicentric isochromosomes in cultured cells; and 5. to identify genes from proximal Xp and Xq and to test the hypothesis that such genes are functionally disomic, due to a failure of X inactivation, in patients with small centric X fragments.
Keywords: Turner s syndrome, chromosome disorder, sex chromosome, centromere, chromatin, karyotype, artificial chromosome, genetic mapping, human subject, in situ hybridization, molecular cloning, polymerase chain reaction, pulsed field gel electrophoresis, tissue /cell culture
MECHANISMS OF HUMAN CHROMOSOME ABNORMALITIES
Huntington F Willard, Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5P01HD032111-05 from National Institute Of Child Health And Human Development IRG: SRC
Abstract: Abnormalities of chromosome structure or number are the most common identified class of genetic defect leading to mental retardation and/or other developmental anomalies. Chromosome defects are present in about 1 in 160 livebirths, most with significant physical or intellectual abnormalities. The longterm goal of this Program is to understand the molecular basis for chromosome abnormalities in humans, to relate the causes and specific nature of such abnormalities to phenotype, and to elucidate general features of chromosome structure and function that are relevant to the etiology of genetic disease. While extensive population cytogenetic studies have determined the incidence of various classes of chromosome abnormality, relatively little is known about the causes of either numerical or structural chromosome defects. In this revised application, we propose to use a combination of molecular and cytogenetic approaches to study the most common and clinically significant of these disorders. In studies of trisomy 21, we will utilize our well-established registry of over 1000 Down syndrome individuals to investigate the genesis of non-disfunction of chromosome 21, and we will use a novel gene mapping approach to identify genes involved in specific phenotype components of the syndrome. In studies of paternally- derived aneuploidy, we will use fluorescence in situ hybridization and single sperm PCR to analyze directly the male gametes, to study the incidence and etiology of paternal non-disfunction in trisomy 21 and in Klinefelter syndrome. In studies of Robertsonian translocations, the most common structural chromosome abnormality in humans, we will combine molecular and cytogenetic techniques to study the formation and meiotic behavior of these rearrangements. Finally, in studies of X chromosome abnormalities, we will determine the molecular nature of abnormal chromosomes detected in Turner syndrome and in variants of Turner syndrome with mental retardation and severe developmental effects, analyze the effect of different pericentromeric structures on mitotic chromosome segregation, and test a novel mechanism potentially important in the severe phenotypes seen associated with a subset of such chromosomes.
Keywords: chromosome aberration, chromosome disorder, molecular pathology, human genetic material tag
Project start date: 1995-05-10
Project end date: 2001-02-28
5P01HD032111-05 (1999): $946396
5P01HD032111-04 (1998): $909997
5P01HD032111-03 (1997): $943896
5P01HD032111-02 (1996): $904945
Grants awarded to Huntington F Willard
TRAINING IN THE GENOME SCIENCES AND THE HEMOGLOBINOPATHIES
Huntington F Willard, Director
Duke University, 2200 W. Main St., Suite 820, Durham, Nc 27705
Grant 5R90HG004150-05 from National Human Genome Research Institute
Abstract: _^__ the overall goal of the Duke University - University of North Carolina at Chapel Hill (UNC) Training Program in the Genome Sciences and the HemogloblnopathiesIs to train a cohort of both domestic and ´foreign postdoctoralfellows to be outstanding investigators of the basis for and treatment of the herhoglobinbpathies. using genomlcs and related large-scale and high-throughput approaches in the genome sciences. Whether each trainee´s chosen area of focus Is in genomics. proteomics or computational biology and whether one´s future research is basic, translations! or clinical, each fellow will be expected to gain a broad and comprehensiveunderstandingof the genome sciences as applied to ongoing research projects In the hemoglobinopathies. Training towards this goal will be achievedthrough advanced coursework; extensive rotations in genomics, proteomics, and computational laboratories; a weekly colloquium involving researchers in the genome sciences; researchin laboratories with active programs In herhbglbbihopathy research; and co-mentoring by training faculty with expertise both in the genome sciences and in the hemoglobinopathies in order to develop a full appreciation for the multidlsciplinary nature1of this training prograrn. The training programwill be directedjointly by the Director of the Duke Institute for Genome Sciences& Policy and by the Director of the Duke-UNC Comprehensive Sickle Cell Center. Outstandingfellows will be identified from among a strong pool of applicants to existing postdoctoral training opportunities at both Duke and UNG in hematology, transfusion medicine, medical genomics, vascular disease and the genome sciences; from applicantsto Individual mentorsat Duke and UNC; and from applicants identified by an international advisorygroup consisting of colleagues and collaboratorsin Tanzania and Thailand. Research opportunities will be providedby a group of more than 25 Duke and UNC faculty members with expertise in the genome sciences and in the hemoglobinopathies. We will develop a group of domestic andforeign colleagues who are dedicated to advance our understanding and treatment of the hemoglobinopathies. This network of investigators will form the basis for an ongoing series of internationalcollaborationsto reducethe pain and burden of these disorders
Keywords: Area; Clinical; Computational Biology; Disease; Disorder; Faculty; Future; Genome; Genomics; Goals; Hematology; Hemoglobinopathies; Hemoglobinopathies / Iron Metabolism; Individual; Institutes; International; Investigators; Laboratories; Medical; Medicine; Mentors; North Carolina; Pain; Painful; Policies; Programs (PT); Programs [Publication Type]; Proteomics; R01 Mechanism; R01 Program; RPG; Research; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Researchers; Rotation; Science; Science of Medicine; Series; Sickle Cell; TRNSF; Tanzania; Thailand; Training; Transfusion; Translations; United Republic of Tanzania; Universities; Vascular Diseases; Vascular Disorder; base; blood vessel disorder; cohort; disease/disorder; drepanocyte; member; post-doctoral training; postdoctoral training; programs; sickle RBC; sickle erythrocyte; sickle red blood cell
Project start date: 2006-05-01
Project end date: 2011-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: RFA-HG-05-002
5R90HG004150-05 (2010): $78518
INACTIVATION PROFILE OF X CHROMOSOME--A GENOMIC STUDY
Huntington F Willard, Director
Geneticscase Western Reserve University
10900 Euclid Ave
cleveland, Oh 44106
Grant 5R01GM060672-02 from National Institute Of General Medical Sciences IRG: GNM
Abstract: X chromosome inactivation is the process whereby one of the two X chromosomes in somatic cells of mammalian females is inactivated early in embryogenesis. While the essential features of X inactivation have been known for over 30 years, the genomic context within which this long-range chromosomal control mechanism operates remains unclear. The human X chromosome contains an estimated several thousand genes, and the genomic resources to support systematic and comprehensive analyses of gene expression on a chromosome scale are becoming increasingly available. We have developed two complementary approaches to examine the inactivation status of any X-linked gene that is expressed in fibroblast strains or in fibroblast-derived somatic cell hybrids. Our previous work has examined the inactivation status of over 200 X-linked genes and expressed sequence tags (ESTs), has revealed the existence of at least four distinct types, classified according to their response to X inactivation, and has provided strong evidence that the organization of the chromosome itself plays a significant role in determining the X inactivation profile of its genes. These data provide a framework for a systematic approach designed to examine the genomic and chromosomal basis for these differences and to integrate a comprehensive X inactivation profile of the X chromosome with the growing gene map and nucleotide sequence of the human X chromosome. The experiments described in this application have two specific aims (i) to determine the expression of at least 1,500 X-linked genes or ESTs in a panel of mouse x human somatic cell hybrids containing active or inactive human X chromosomes; and (ii) to determine the expression of at least 500 X-linked genes or ESTs in a panel of human diploid fibroblasts demonstrating non-random X inactivation by evaluating the mono- or biallelic expression of a series of expressed polymorphisms. The proposed experiments should provide a comprehensive view of the expression of genes on the human X chromosome in the context of its reponse to the process of X inactivation. These genomic data, which we view as an essential part of the X chromosome genome project, will be of substantial value to those in the fields of human and medical genetics and will, in addition, provide the basis for future insights into the chromosomal, epigenetic and molecular mechanisms by which cis-limited control of X-linked gene expression is achieved
Keywords: early embryonic stage, gene expression, gene induction /repression, genome, sex chromosome fibroblast, gene dosage, sequence tagged site animal tissue, fluorescence resonance energy transfer, human tissue, hybrid cell, polymerase chain reaction
Project start date: 2000-01-01
Project end date: 2002-12-31
5R01GM060672-02 (2001): $479023
1R01GM060672-01 (2000): $465071
MOLECULAR GENETICS OF HUMAN X CHROMOSOME INACTIVATION
Huntington F Willard, Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5R01GM045441-09 from National Institute Of General Medical Sciences IRG: MGN
Abstract: X chromosome inactivation is the process whereby one of the two X chromosomes in somatic cells of mammalian females is inactivated early in embryogenesis, presumably as a means of dosage compensation between females, with two X chromosomes, and males, with one. While the essential features of X inactivation have been known for over 30 years, the precise molecular, genetic, and developmental details of this lone- range chromosomal control mechanism remain unclear. Over the past few years, substantial progress has been made in the definition and understanding of the various steps involved in X inactivation initiation early in development through the action of the X inactivation center, promulgation of the inactivation signal and establishment of the inactive state along the chromosome in a strictly cis-limited manner, and maintenance of the various epigenetic states through subsequent cell divisions. A strong candidate for a gene involved in X inactivation, XIST, was described by us in 1991. Since then, significant genetic and developmental evidence has been presented in both humans and mice that supports a role for XIST in the initiation and perhaps establishment of the X inactivation signal. These data provide a framework for further experiments designed to test the hypothesis that the XIST gene, with its regulatory sequences, both controls the initial choice of which X chromosome to inactivate and subsequently establishes a context within the nucleus to distinguish the active from the inactive X chromosome. The experiments described in this application have three specific aims (1) to determine the nature of the X inactivation center and the role of XIST in initiating X inactivation, by examining the effect(s) of expressing the XIST gene in mouse embryonic stem cells and/or in transgenic mice, by determining the effect(s) of a recently discovered mutation in XIST on the initiation of X inactivation, and by characterizing additional such mutations in families with multiple cases of non-random X inactivation; (2) to determine a developmental context for the establishment of X inactivation, by studying the expression of genes subject to and escaping from X inactivation in mice early in development at the time X inactivation occurs. This is in order to determine whether escape from inactivation is a failure of initiation, establishment, or maintenance of X inactivation; and (3) to examine the chromosomal basis for X inactivation, by studying the distribution of genes on the human and mouse X-chromosomes that are subject to or escape from X inactivation and by using transgenic mice to specifically test the hypothesis that X inactivation is determined at the level of chromosomal domains rather than on an individual gene basis. The proposed experiments should provide a definitive genetic and molecular test of the hypothesis that the XIST gene is, in fact, part of the X inactivation pathway, as well as provide insights into the chromosomal, developmental, and molecular mechanisms by which cis-limited control of X-linked gene expression is achieved.
Keywords: early embryonic stage, gene expression, gene induction /repression, genetic transcription, molecular genetics, regulatory gene, sex chromosome, DNA methylation, DNA replication, allele, cytogenetics, developmental genetics, gene mutation, genetic regulatory element, nucleic acid sequence, RNase protection assay, embryonic stem cell, fluorescent in situ hybridization, human genetic material tag, laboratory mouse, molecular cloning, northern blotting, polymerase chain reaction, transfection, transgenic animal
Project start date: 1991-01-01
Project end date: 2000-11-30
5R01GM045441-09 (1999): $299975
5R01GM045441-08 (1998): $290386
5R01GM045441-07 (1997): $281167
An Integrated Curriculum For Genome Sciences And Policy(RMI)
Huntington F Willard, Director
Molecular Genetics And Microbiologyduke University
2200 W. Main St.
durham, Nc 27705
Grant 5K07GM073003-05 from National Institute Of General Medical Sciences IRG: ZGM1
Abstract: With the availability of the full sequence of the human and other genomes, there are enormous opportunities and expectations for utilizing the sequence to benefit the public welfare. At the same time, however, the rapidly increasing pace of genome discovery and the prospect of widespread use of genomic information has raised awareness of a number of potentially troubling issues for society at large, in areas as diverse as individual rights, genetic discrimination, the nature of humanity, intellectual property law, the meaning of normal variation, large-scale data storage and analysis, and national health and science policy. Effective consideration of both the genome sciences and their implications for individuals and society requires a set of individuals who are not only highly trained in biomedical research, but also broadly knowledgeable in public policy and the social sciences and capable of participating in the design and implementation of research at the intersections of these disciplines. The Duke University Institute for Genome Sciences and Policy (IGSP) was established with the explicit understanding that such advances for society require not just leading science, but science embedded in a thorough and thoughtful discussion of these societal and policy issues. While this campus-wide initiative is well underway, its focus to date has been on the development of infrastructure to support interdisciplinary research in the genome sciences and on recruitment of new faculty in many schools across campus. The current proposal will foster a similar dedication to the training mission of the IGSP and will lead to the development of an Integrated Curriculum in Genome Sciences and Policy at the undergraduate, graduate and postgraduate levels. This integrated curriculum will build on the Pl´s commitment to and history of effectiveness in education at all levels and on Duke University´s substantial commitment to the IGSP and its long tradition of supporting and enhancing interdisciplinary scholarship
Keywords: curriculum, educational resource design /development, genome education evaluation /planning, health science research NIH Roadmap Initiative tag
Project start date: 2004-09-22
Project end date: 2009-07-31
5K07GM073003-05 (2008): $124226
An Integrated Curriculum For Genome Sciences And Policy
Huntington F Willard, Director
Molecular Genetics And Microbiologyduke University
2200 W. Main St.
durham, Nc 27705
Grant 5K07GM073003-04 from National Institute Of General Medical Sciences IRG: ZGM1
Abstract: With the availability of the full sequence of the human and other genomes, there are enormous opportunities and expectations for utilizing the sequence to benefit the public welfare. At the same time, however, the rapidly increasing pace of genome discovery and the prospect of widespread use of genomic information has raised awareness of a number of potentially troubling issues for society at large, in areas as diverse as individual rights, genetic discrimination, the nature of humanity, intellectual property law, the meaning of normal variation, large-scale data storage and analysis, and national health and science policy. Effective consideration of both the genome sciences and their implications for individuals and society requires a set of individuals who are not only highly trained in biomedical research, but also broadly knowledgeable in public policy and the social sciences and capable of participating in the design and implementation of research at the intersections of these disciplines. The Duke University Institute for Genome Sciences and Policy (IGSP) was established with the explicit understanding that such advances for society require not just leading science, but science embedded in a thorough and thoughtful discussion of these societal and policy issues. While this campus-wide initiative is well underway, its focus to date has been on the development of infrastructure to support interdisciplinary research in the genome sciences and on recruitment of new faculty in many schools across campus. The current proposal will foster a similar dedication to the training mission of the IGSP and will lead to the development of an Integrated Curriculum in Genome Sciences and Policy at the undergraduate, graduate and postgraduate levels. This integrated curriculum will build on the Pl´s commitment to and history of effectiveness in education at all levels and on Duke University´s substantial commitment to the IGSP and its long tradition of supporting and enhancing interdisciplinary scholarship
Keywords: curriculum, educational resource design /development, genome education evaluation /planning, health science research NIH Roadmap Initiative tag
Project start date: 2004-09-22
Project end date: 2009-07-31
5K07GM073003-04 (2007): $124226
5K07GM073003-03 (2006): $124226
An Integrated Curriculum:Genome Sciences And Policy(RMI)
Huntington F Willard, Director
Duke University 2200 W. Main St. Durham, Nc 27705
Grant 5K07GM073003-02 from National Institute Of General Medical Sciences IRG: ZGM1
Abstract: With the availability of the full sequence of the human and other genomes, there are enormous opportunities and expectations for utilizing the sequence to benefit the public welfare. At the same time, however, the rapidly increasing pace of genome discovery and the prospect of widespread use of genomic information has raised awareness of a number of potentially troubling issues for society at large, in areas as diverse as individual rights, genetic discrimination, the nature of humanity, intellectual property law, the meaning of normal variation, large-scale data storage and analysis, and national health and science policy. Effective consideration of both the genome sciences and their implications for individuals and society requires a set of individuals who are not only highly trained in biomedical research, but also broadly knowledgeable in public policy and the social sciences and capable of participating in the design and implementation of research at the intersections of these disciplines. The Duke University Institute for Genome Sciences and Policy (IGSP) was established with the explicit understanding that such advances for society require not just leading science, but science embedded in a thorough and thoughtful discussion of these societal and policy issues. While this campus-wide initiative is well underway, its focus to date has been on the development of infrastructure to support interdisciplinary research in the genome sciences and on recruitment of new faculty in many schools across campus. The current proposal will foster a similar dedication to the training mission of the IGSP and will lead to the development of an Integrated Curriculum in Genome Sciences and Policy at the undergraduate, graduate and postgraduate levels. This integrated curriculum will build on the Pl s commitment to and history of effectiveness in education at all levels and on Duke University s substantial commitment to the IGSP and its long tradition of supporting and enhancing interdisciplinary scholarship.
Keywords: curriculum, educational resource design /development, genome, education evaluation /planning, health science research
Project start date: 2004-09-22
Project end date: 2009-07-31
5K07GM073003-02 (2005): $124226
Sponsored Links Excellgen http://Excellgen.com
Integrated Curriculum For Genome Sciences/Policy (RMI)
Huntington F Willard, Director
Duke University 2200 W. Main St. Durham, Nc 27705
Grant 1K07GM073003-01 from National Institute Of General Medical Sciences IRG: ZGM1
Abstract: With the availability of the full sequence of the human and other genomes, there are enormous opportunities and expectations for utilizing the sequence to benefit the public welfare. At the same time, however, the rapidly increasing pace of genome discovery and the prospect of widespread use of genomic information has raised awareness of a number of potentially troubling issues for society at large, in areas as diverse as individual rights, genetic discrimination, the nature of humanity, intellectual property law, the meaning of normal variation, large-scale data storage and analysis, and national health and science policy. Effective consideration of both the genome sciences and their implications for individuals and society requires a set of individuals who are not only highly trained in biomedical research, but also broadly knowledgeable in public policy and the social sciences and capable of participating in the design and implementation of research at the intersections of these disciplines. The Duke University Institute for Genome Sciences and Policy (IGSP) was established with the explicit understanding that such advances for society require not just leading science, but science embedded in a thorough and thoughtful discussion of these societal and policy issues. While this campus-wide initiative is well underway, its focus to date has been on the development of infrastructure to support interdisciplinary research in the genome sciences and on recruitment of new faculty in many schools across campus. The current proposal will foster a similar dedication to the training mission of the IGSP and will lead to the development of an Integrated Curriculum in Genome Sciences and Policy at the undergraduate, graduate and postgraduate levels. This integrated curriculum will build on the Pl s commitment to and history of effectiveness in education at all levels and on Duke University s substantial commitment to the IGSP and its long tradition of supporting and enhancing interdisciplinary scholarship.
Keywords: curriculum, educational resource design /development, genome, education evaluation /planning, health science research
Project start date: 2004-09-22
Project end date: 2009-07-31
1K07GM073003-01 (2004): $123062
Huntington F Willard, Director
Geneticscase Western Reserve University
10900 Euclid Ave
cleveland, Oh 44106
Grant 2T32GM008613-06 from National Institute Of General Medical Sciences IRG: BRT
Abstract: This application seeks renewed support of the Genetics Graduate Training Program at CWRU, the goal of which is to train students to be outstanding independent scholars and investigators using genetics as a major tool to study biological and biomedical problems. The defining element in the philosophy of the program is the broad range of organisms, biological systems, and approaches being pursued in the training laboratories. Whether a student´s research focus is in human, molecular, or developmental genetics; whether in Drosophila, C. elegans, yeast, mouse, or human; whether using cloned DNA, cultured cells, model organisms or human families, each student is expected to develop a broad understanding of and appreciation for the range of approaches and topics being pursued in other organisms or specialties. Training towards this goal is achieved through five primary mechanisms advanced coursework, a weekly journal club, an invited speaker seminar program, student research presentations, and original research. The CWRU Genetics Graduate Training Program offers a unique range of opportunities for students. Training laboratories are located in several departments, including Genetics, Molecular Biology, Neuroscience, Pediatrics, Medicine and Anesthesiology. The program offers extensive new facilities and research programs in human genetics, molecular genetics, genomics, gene expression, developmental genetics, chromosome structure and function, genome mapping and organization, quantitative genetics and the molecular and genetic basis of human disease, thereby providing an opportunity for integrated training in all aspects of genetics in organisms ranging from yeast to C. elegans and Drosophila to mouse and humans. The training program is administered by the Department of Genetics, which includes both basic science and clinical faculty. Students are admitted either through the multi-program Biomedical Sciences Training Program at CWRU or by direct application to the Genetics Program. All first-year students perform a series of diverse research rotations and select a laboratory with a research mentor (trainer) in the Genetics program at the end of the first year. The program is administered by a Steering Committee consisting of the Director and faculty trainers, each with responsibilities for specific aspects of the program. This integrated training program in molecular, developmental, and human genetics reflects our commitment to the diversity of genetics as a unifying theme across all of biology and medicine
Project start date: 1996-07-01
Project end date: 2006-06-30
2T32GM008613-06 (2001): $261424
5T32GM008613-05 (2000): $224960
5T32GM008613-04 (1999): $224112
5T32GM008613-03 (1998): $198711
TRAINING IN THE GENOME SCIENCES AND THE HEMOGLOBINOPATHIES
Huntington F Willard, Director
Duke University, 2200 W. Main St., Suite 820, Durham, Nc 27705
Grant 5T90HG004008-05 from Fogarty International Center
Abstract: The overall goal of the Duke University - University of North Carolina at Chapel Hill (UNC) Training Program in the Genome Sciences and the Hemoglobinopathies is to train a cohort of both domestic and foreign postdoctoral fellows to be outstanding investigators of the basis for and treatment of the hemoglobinopathies, using genomics and related large-scale and high-throughput approaches in the genome sciences. Whether each trainee´s chosen area of focus is in genomics, proteomics or computational biology and whether one´s future research is basic, translational or clinical, each fellow will be expected to gain a broad and comprehensive understanding of the genome sciences as applied to ongoing research projects in the hemoglobinopathies. Training towards this goal will be achieved through advanced coursework; extensive rotations in genomics, proteomics, and computational laboratories; a weekly colloquium involving researchers in the genome sciences; research in laboratories with active programs in hemoglobinopathy research; and co-mentoring by training faculty with expertise both in the genome sciences and in the hemoglobinopathies in order to develop a full appreciation for the multidisciplinary nature of this training program. The training program will be directed jointly by the Director of the Duke Institute for Genome Sciences & Policy and by the Director of the Duke-UNC Comprehensive Sickle Cell Center. Outstanding fellows will be identified from among a strong pool of applicants to existing postdoctoral training opportunities at both Duke and UNC in hematology, transfusion medicine, medical genomics, vascular disease and the genome sciences; from applicants to individual mentors at Duke and UNC; and from applicants identified by an international advisory group consisting of colleagues and collaborators in Tanzania and Thailand. Research opportunities will be provided by a group of more than 25 Duke and UNC faculty members with expertise in the genome sciences and in the hemoglobinopathies. We will develop a group of domestic and foreign colleagues who are dedicated to advance our understanding and treatment of the hemoglobinopathies. This network of investigators will form the basis for an ongoing series of international collaborations to reduce the pain and burden of these disorders
Keywords: Area; Clinical; Collaborations; Computational Biology; Disease; Disorder; Faculty; Future; Genome; Genomics; Goals; Hematology; Hemoglobinopathies; Hemoglobinopathies / Iron Metabolism; Individual; Institutes; International; Investigators; Laboratories; Medical; Medicine; Mentors; Nature; North Carolina; Pain; Painful; Postdoc; Postdoctoral Fellow; Programs (PT); Programs [Publication Type]; Proteomics; R01 Mechanism; R01 Program; RPG; Research; Research Associate; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Researchers; Rotation; Science; Science Policy; Science of Medicine; Series; Sickle Cell; TRNSF; Tanzania; Thailand; Training; Training Programs; Transfusion; United Republic of Tanzania; Universities; Vascular Diseases; Vascular Disorder; base; blood vessel disorder; cohort; disease/disorder; drepanocyte; member; multidisciplinary; post-doc; post-doctoral; post-doctoral training; postdoctoral training; programs; sickle RBC; sickle erythrocyte; sickle red blood cell
Project start date: 2006-05-01
Project end date: 2011-04-30
Budget start date: 1-MAY-2010
Budget end date: 30-APR-2011
PFA/PA: RFA-HG-05-002
5T90HG004008-05 (2010): $199108
5T90HG004008-02 (2007): $125966
1T90HG004008-01 (2006): $188420
HIGH-PERFORMANCE COMPUTING SYSTEM FOR BIOINFORMATICS
Huntington F Willard, Director
Duke University, 2200 W. Main St., Durham, Nc 27705
Grant 1S10RR025590-01 from National Center For Research Resources
Abstract: The explosive growth of computational biology has made it difficult for research organizations to keep pace with users´ demands for ever-increasing computational power. The complications that biologists face come from two developments. First, new technologies generate huge amounts of data. Of course this makes it possible for biological investigations to broaden their scope to whole genome, cellular, and even organism levels, but at a cost of overtaxing existing methods and resources for data analysis. Second, algorithms and methods of analysis have become more computationally intensive, in part as a response to the opportunities that data richness has brought about and in part to manage the unfortunate signal-to-noise ratio that seem implicit in genomic datasets. Also, the emergence of "systems biology" has led to growing complication in computational work, since systems biology seeks eventually to model biological phenomena in silico. In effect, one of the major -- and indeed the most flexible -- instruments for genome scientists and systems biologists is the high performance computer, because it is an essential tool for making sense of the prodigious amounts of data already coming from high-throughput sequencers, gene expression microarray equipment, mass spectrometers, and the like. On high-performance cluster computers, many researchers are making use of basic "job-level parallelism" by which a single user may run multiple jobs (or independent sub-parts of jobs) on many hundreds of computers at once. Often, this is in the form of computational "parameter space studies" where the same application is run on tens, hundreds and thousands of different sets of inputs. Simulating the evolution of regulatory regions, for example, requires multiple runs in which the size and number of short regulatory motifs are tuned. The prediction of gene regulatory networks requires multiple simulations in which different cell types and different tissue regions are modified. Simulations of gene expression dynamics in populations of cells must also be run multiple times in order to account for "cellular noise" and get a comprehensive picture of the phenomena. This need for repeated computations makes cluster computing an attractive approach for these problems. Our proposal requests 94 power-efficient compute servers and about 8 terabytes (usable) high-speed data storage with matched disaster recovery storage. This equipment will be put into operation using Sun Grid Engine, a software application that coordinates computational resources so that individual machines function as one clustered computational instrument. Bioinformatic software tools, as well as custom-made applications, are available for researchers to use on the equipment. Next-generation instruments have made acquiring genomic data inexpensive and ever more efficient, and new technologies promise to add greatly to the resolution and richness of data used for biomedical research and for translational medicine. This torrent of data needs equally powerful and flexible tools for analysis and information creation, in effect matching high-throughput data producers with high performance computational tools for analysis. We propose the creation of a well integrated computational system that matches in compute power the prodigious data flows from instruments producing genomic data
Keywords: Accounting; Algorithms; Analysis, Data; Bio-Informatics; Bioinformatics; Biologic Phenomena; Biological; Biological Phenomena; Biomedical Research; Body Tissues; Cell Communication and Signaling; Cell Signaling; Cells; Complication; Computational Biology; Computer Programs; Computer Simulation; Computer Software Tools; Computer Systems; Computer software; Computerized Models; Computers; Custom; Data; Data Analyses; Data Set; Data Storage and Retrieval; Dataset; Development; Disasters; Equipment; Evolution; Face; Gene Expression; Generalized Growth; Genes, Regulator; Genome; Genomics; Growth; High Performance Computing; Individual; Intracellular Communication and Signaling; Investigation; Investigators; Jobs; Mathematical Model Simulation; Mathematical Models and Simulations; Methods; Modeling; Models, Computer; Noise; Nucleic Acid Regulatory Sequences; Occupations; Operation; Operative Procedures; Operative Surgical Procedures; Organism; Performance; Performance Computing, High; Population; Professional Postions; RFP; Recovery; Regulator Genes; Regulator Regions, Nucleic Acid; Regulatory Regions; Regulatory Regions, Nucleic Acid (Genetics); Regulatory Sequences, Nucleic Acid; Request for Proposals; Research; Research Personnel; Research Resources; Researchers; Resolution; Resources; Running; Scientist; Signal Transduction; Signal Transduction Systems; Signaling; Simulate; Simulation, Computer based; Software; Software Tools; Speed; Speed (motion); Surgical; Surgical Interventions; Surgical Procedure; System; System, LOINC Axis 4; Systems Biology; The Sun; Time; Tissue Growth; Tissues; Tools, Software; Transcriptional Regulatory Elements; Work; biological signal transduction; cell type; cluster computing; computational grid; computational modeling; computational models; computational simulation; computational tools; computer based models; computer program/software; computerized modeling; computerized simulation; computerized tools; computing resources; cost; data grid; data retrieval; data storage; datagrid; distributed computing; e-science; escience; facial; federated computing; federated data; federated database; flexibility; genetic regulatory element; grid computing; in silico; instrument; living system; mass spectrometer; new technology; next generation; ontogeny; public health relevance; regulatory gene; response; simulation; surgery; tool; trans acting element; translational medicine; virtual simulation
Project start date: 2009-06-01
Project end date: 2010-05-31
Budget start date: 1-JUN-2009
Budget end date: 31-MAY-2010
PFA/PA: PAR-08-036
1S10RR025590-01 (2009): $461402
Sponsored Links Excellgen http://Excellgen.com
MAPPING CENTROMERIC REGIONS OF HUMAN CHROMOSOMES
Huntington F Willard, Director
Geneticscase Western Reserve University
10900 Euclid Ave
cleveland, Oh 44106
Grant 5R01HG000107-08 from National Human Genome Research Institute IRG: GNM
Abstract: The centromeric regions of human chromosomes are dominated by a class of tandemly repeated DNA, alpha satellite, which consists of an extensive group of related, highly diverged repeats, based on a monomer repeat length of ~171 basepairs. Long tandem arrays of alpha satellite, estimated to be hundreds to thousands of kilobasepairs long, are located at the centromeric region of each chromosome. In some cases, centromeric regions are characterized by multiple, independent alpha satellite subsets or by subsets of different classes of satellite DNA (beta or classical), in addition to alpha satellite. Because conventional strategies for mapping human chromosomes cannot easily accommodate long, megabase stretches of repetitive DNA, a directed approach is required for high-resolution physical and genetic mapping of the centromeric region of each human chromosome, for full integration into the complete chromosome maps being generated in other laboratories. The current proposal is an extension of our centromere mapping project, which has been ongoing for the past two years. We propose (i) to isolate representative DNA probes for the alpha, beta, and classical satellite classes located at or near the centromere of all 24 types of human chromosome and to develop specific sequence tagged sites (STS´s) for these centromeric loci; (ii) to develop high-frequency polymorphisms for each centromeric locus and to genotype the 40 CEPH families to contribute to centromere-based genetic linkage maps of each chromosome; (iii) to measure the size and amount of variation of centromeric DNA for each chromosome in a representative collection of individuals to provide a physical estimate to close the "centromere gap" in conventional maps of each chromosome; and (iv) to characterize in detail the complete arrays of four centromeres selected as models (chromosomes 4,7,17, and X), using one- and two-dimensional long-range pulsed-field mapping and short- and long-range cloning in lambda phage and in yeast artificial chromosomes, and strategies designed to identify and clone the junctions between the edges of the centromere array and the chromosome arms. The proposed studies address directly several of the Five-Year Goals of the Human Genome Project to complete a fully connected human genetic map by providing a polymorphic marker, identified by an STS, at the centromere of each chromosome; to contribute to a fully assembled STS physical map of each human chromosome by providing a well-characterized STS at the centromere of each chromosome and by generating the pulsed-field restriction mapping data needed to fully integrate the centromere into complete chromosome maps; and to generate overlapping sets of closely spaced, ordered markers that span the centromeres of selected chromosomes, with continuity over several million basepairs
Keywords: DNA, centromere, chromosome, genetic mapping, genetic marker, linkage mapping, sequence tagged site gene duplication, genetic polymorphism, genotype, human population genetics bacteriophage lambda, gel electrophoresis, genetic library, genetic manipulation, human genetic material tag, human tissue, in situ hybridization, molecular cloning, nucleic acid probe, nucleic acid sequence, polymerase chain reaction, pulsed field gel electrophoresis, yeast artificial chromosome
Project start date: 1989-07-01
Project end date: 1996-08-31
5R01HG000107-08 (1994): $413452
5R01HG000107-07 (1993): $406031
7R01HG000107-06 (1992): $385244
MOLECULAR GENETICS OF HUMAN X CHROMOSOME INACTIVATION
Huntington F Willard, Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 5R01GM045441-05 from National Institute Of General Medical Sciences IRG: MGN
Abstract: Early in embryonic development, one of the two X chromosomes in mammalian females becomes heterochromatic, late replicating, and largely genetically inactive as a means of dosage compensation for X-linked genes. Once established, this inactivation is irreversible and clonally stable in somatic cells. While the basic features of X inactivation have been well established for some time, the molecular basis for the initiation and promulgation of this chromosome-based cis-regulatory signal remains unknown. The proposed research will address a number of key questions regarding fundamental aspects of the X inactivation process. How does the process initiate early in embryogenesis? Are one or more X inactivation centers required for initiation? If a specific locus is required for initiation of X inactivation, is it also required for the maintenance of inactivation through successive cell divisions? What proportion of genes are subject to inactivation and what proportion "escape" inactivation? Are inactivated and non-inactivated genes clustered in specific regions of the chromosome or is X inactivation controlled on a locus basis? How is it determined which genes respond to and which genes are refractory to the X inactivation signal? Our analysis of human X chromosome inactivation will focus initially on the genetic basis for the initiation and maintenance of X inactivation and on the nature of genes that escape inactivation. The specific aims of the proposed research are (i) to examine the transcriptional basis for inactivation of X-linked genes in a series of human/mouse somatic cell hybrids retaining either "active" X or "inactive" X chromosomes; (ii) to identify and characterize new genes that escape the inactivation process by isolating human cDNA clones expressed from "inactive" human X chromosomes; (iii) to test the hypothesis that there is a single region on the X responsible for X inactivation by examining structurally abnormal inactive X chromosomes in somatic cell hybrids to define the putative X inactivation center; (iv) to evaluate whether the continued presence of such a locus is required for the stable maintenance of the inactive X; (v) to isolate the X inactivation center in yeast artificial chromosomes; and (vi) to establish a system to examine human X chromosome and/or yeast artificial chromosomes carrying large fragments of DNA including candidate sequences for the human X inactivation center.
Keywords: DNA replication, genetic transcription, human population genetics, molecular genetics, sex chromosome, cell transformation, chromosome aberration, chromosome walking, complementary DNA, cytogenetics, early embryonic stage, fusion gene, gene expression, genetic mapping, germ cell neoplasm, heterochromatin, hybrid cell, linkage mapping, nucleic acid sequence, point mutation, reproductive development, restriction mapping, transfection, human genetic material tag, laboratory mouse, molecular cloning, northern blotting, nucleic acid hybridization, polymerase chain reaction, restriction fragment length polymorphism, yeast artificial chromosome
Project start date: 1991-01-01
Project end date: 1995-07-31
5R01GM045441-05 (1994): $220194
5R01GM045441-04 (1993): $211725
5R01GM045441-02 (1992): $224600
ANALYSIS OF HUMAN CENTROMERES USING NOVEL ARTIFICIAL CHROMOSOME VECTORS
Huntington F Willard, Director
Duke University, 2200 W. Main St., Durham, Nc 27705
Grant 5R01GM077649-04 from National Institute Of General Medical Sciences
Abstract: Centromeres are critical components of eukaryotic chromosomes, with a key role in ensuring proper segregation in mitosis and meiosis. While the location of the centromere is precisely determined and maintained in most organisms, the basis for centromere specification in many eukaryotic genomes, including the human genome, is obscure and likely involves both epigenetic and sequence-based events. Centromeres represent an evolutionary paradox despite their essential function in chromosome segregation and the highly conserved nature of many proteins involved in the process of cell division, the underlying genomic sequences are highly variable, both within and between species. In the human genome, centromeres are characterized by large arrays of a tandemly repeated DNA sequence, a satellite. While genetic, genomic and functional studies have demonstrated that a satellite sequences are involved in centromere function in human cells, the sequences are highly heterogeneous and share few features in common with satellite DMAs of non-primate species. Thus, notwithstanding a clear role for epigenetic regulation in specifying centromeric chromatin, our poor understanding of the role of genomic sequences in centromere specification remains a significant gap in current knowledge. The experiments described here have two specific aims (i) to improve and validate novel human artificial chromosome technology to generate structurally definable, unit-sized human artificial chromosomes that maintain the size and structure of the input vector sequences and can be recovered from human cells for detailed analysis; and (ii) to use human artificial chromosomes to systematically evaluate the role of genomic sequences and their organization in centromere specification in cultured cells, by altering specific sequences within the human a satellite repeat unit, by designing and testing novel multimeric a satellite array configurations, and by substituting in whole or in part other mammalian centromeric satellite sequences from both other primate and the mouse genomes. These experiments will allow us to explore the nature of the genomic code that specifies centromere identity and function despite lack of rigid sequence conservation, as well as provide insights into the genomic and epigenetic mechanisms that contribute to centromere function in human chromosomes
Keywords: Artificial Chromosomes; Assay; Base Sequence; Bioassay; Biologic Assays; Biological Assay; Cell Communication and Signaling; Cell Division Process; Cell Signaling; Cells; Centromere; Chromatin; Chromosome Segregation; Chromosomes; Chromosomes, Artificial; Chromosomes, Artificial, Human; Chromosomes, Human; Classification; Code; Coding System; Cultured Cells; DNA Sequence; Ensure; Epigenetic; Epigenetic Change; Epigenetic Mechanism; Epigenetic Process; Event; Genetic; Genome; Genome, Human; Genomics; Human; Human Chromosomes; Human Genome; Human, General; Intracellular Communication and Signaling; Knowledge; Location; M Phase; M phase (cell cycle); Mammals, Primates; Man (Taxonomy); Man, Modern; Maps; Meiosis; Mitosis; Mitosis Stage; Nature; Nucleotide Sequence; Organism; Patients; Plants; Plants, General; Primates; Proteins; Racial Segregation; Regulation; Role; Signal Transduction; Signal Transduction Systems; Signaling; Specific qualifier value; Specified; Structure; Systematics; Technology; Testing; base; biological signal transduction; design; designing; experiment; experimental research; experimental study; functional genomics; gene product; genome, mammalian; genome, mouse; improved; insight; living system; mammalian genome; meiotic; mouse genome; novel; nucleic acid sequence; research study; segregation; social role; vector
Project start date: 2006-04-01
Project end date: 2011-03-31
Budget start date: 1-APR-2009
Budget end date: 31-MAR-2011
5R01GM077649-04 (2009): $287804
5R01GM077649-02 (2007): $287574
1R01GM077649-01 (2006): $295213
Training In The Genome Sciences And The Hemoglobinopathies
Huntington F Willard, Director
Molecular Genetics And Microbiologyduke University
Grant 5R90HG004150-04 from National Human Genome Research Institute IRG: GNOM
Project start date: 2006-05-01
Project end date: 2011-04-30
Sponsored Links Excellgen http://Excellgen.com
5R90HG004150-02 (2007): $152670
Core Analytical Resources Facility
Huntington F Willard, Director
Duke University 2200 W. Main St. Durham, Nc 27705
Grant 5P50HG003391-049002 from National Human Genome Research Institute IRG: ZHG1
Keywords: bioinformatics, biomedical facility, computational biology, health related legal, molecular biology information system, biotechnology
Training In The Genome Sciences And The Hemoglobinopathies
Huntington F Willard, Director
Duke University 2200 W. Main St. Durham, Nc 27705
Grant 1R90HG004150-01 from National Human Genome Research Institute IRG: GNOM
Keywords: genome, hemoglobinopathy, training, clinical research
Project start date: 2006-05-01
Project end date: 2011-04-30
1R90HG004150-01 (2006): $89664
Core Analytical Resources Facility
Huntington F Willard, Director
Duke University 2200 W. Main St. Durham, Nc 27705
Grant 5P50HG003391-039002 from National Human Genome Research Institute IRG: ZHG1
Keywords: bioinformatics, biomedical facility, computational biology, health related legal, molecular biology information system, biotechnology
Huntington F Willard, Director
Geneticscase Western Reserve University
10900 Euclid Ave
cleveland, Oh 44106
Grant 5T32GM008613-02 from National Institute Of General Medical Sciences IRG: ZGM1
Project start date: 1996-07-01
Project end date: 2001-06-30
5T32GM008613-02 (1997): $196533
CENTROMERE AND TELOMERE MAPPING AND FUNCTION
Huntington F Willard, Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 1R13HG001560-01 from National Human Genome Research Institute IRG: GNOM
Project start date: 1996-09-30
Project end date: 1997-09-29
1R13HG001560-01 (1996): $12800
Huntington F Willard, Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 1T32GM008613-01 from National Institute Of General Medical Sciences IRG: ZGM1
Project start date: 1996-07-01
Project end date: 2001-06-30
1T32GM008613-01 (1996): $91839
MOLECULAR GENETICS OF HUMAN X CHROMOSOME INACTIVATION
Huntington F Willard, Director
Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106
Grant 2R01GM045441-06 from National Institute Of General Medical Sciences IRG: MGN
Project start date: 1991-01-01
Project end date: 1999-11-30
2R01GM045441-06 (1996): $270523