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Program Nr: 1 from the 1999 ASHG Annual Meeting Development of a Strategy to Screen for Mutations and Drugs Affecting Gene Expre

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Program Nr: 1 from the 1999 ASHG Annual Meeting Development of a Strategy to Screen for Mutations and Drugs Affecting Gene Expre Program Nr: 1 from the 1999 ASHG Annual Meeting Development of a strategy to screen for mutations and drugs affecting gene expression and its application to genomic imprinting. A.L. Beaudet, T.-F. Tsai, K.-S. Chen, J. Weber, M. Justice. Dept Molecular & Human Gen, Baylor Col Medicine, Houston, TX. We wished to isolate mutations affecting genomic imprinting related to Prader Willi and Angelman syndrome. We used the mouse Snrpn promoter which lies within a CpG island that is methylated and silenced on the maternal chromosome as opposed to unmethylated and expressed on the paternal chromosome. In ES cells, we introduced the agouti cDNA as a knockin gene under the control of the Snrpn promoter. In nonagouti (a/a) mice, paternal inheritance of the fusion gene confers a tannish abdominal color; the abdomen is black if the fusion gene is absent or inherited maternally. Differential methylation and imprinted expression of the Snrpn promoter was preserved and switched normally, and administration of 5-azacytidine altered coat color. Two breeding strategies involving ENU mutagenesis of males were utilized: (1) males homozygous for the fusion gene and a/a were mutagenized and bred to a/a wild type females to yield 100 percent tannish offspring and (2) mutagenized wild type a/a males were bred to females a/a and homozygous for the fusion gene to yield 100 percent black offspring, such that mutations affecting genomic imprinting could be detected visually. No mutant animals were isolated in the first >100 offspring from breeding scheme 1 and one presumptive mutation or epigenetic event affecting imprinting and causing an unmethylated maternal allele was found in the first >150 animals from breeding scheme 2. These results demonstrate the feasibility of the general method to isolate regulatory mutations affecting transcription. Possible reporter cassettes include visible markers, easily quantitated secreted proteins, and histological markers. Bicistronic cassettes could be used to help discriminate effects not directly involving the fusion gene. This method is useful for studies of gene regulation and development, for drug screening in vivo or in tissue culture, for genetic improvement of animals, and for various medical applications. Copyright © 1999 The American Society of Human Genetics. All rights reserved. Program Nr: 2 from the 1999 ASHG Annual Meeting Strong Evidence for Linkage of High Density Lipoprotein Cholesterol (HDL-C) Concentrations to a Genetic Location on Chromosome 9p in Mexican Americans. R. Arya1, R. Duggirala1, L. Almasy2, M.P. Stern1, P. O' Connell3, J. Blangero2. 1) Division of Clinical Epidemiology, Department of Medicine, UTHSCSA, San Antonio, TX; 2) Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, TX; 3) Department of Pathology, UTHSCSA, San Antonio, TX. Although the genetic basis of coronary heart disease is not clear, numerous studies have examined the genetic architecture of quantitatively intervening phenotypes such as high density lipoprotein cholesterol (HDL-C). It is well understood that HDL-C has strong genetic determinants. However, little is known about the chromosomal regions harboring the major loci influencing HDL-C levels. Therefore, we employed a multipoint variance component linkage approach to identify loci that exert major influence on variation in HDL-C levels. This study, a part of the San Antonio Family Diabetes Study, was based on phenotypic data from 415 individuals distributed across 27 low income Mexican American pedigrees. Genotypic data for these individuals were available for more than 400 markers. We conducted multipoint variance component linkage analyses as implemented in the computer package SOLAR. All genetic analyses included age and gender as covariates. Prior to conducting multipoint analyses, the heritability of HDL-C was determined to be 55.0 ± 9.4%. We found significant evidence for linkage (LOD score = 3.6) of HDL-C levels to a genetic location in between markers D9S925 and D9S1121 on chromosome 9p. This locus explains 47.2 ± 13.0% (p = 0.0000235) of the total phenotypic variance in HDL-C. Interestingly, this region on chromosome 9p is not that far from the region on chromosome 9p which we previously reported to be linked to type 2 diabetes. This region has also been reported to be linked to fasting glucose levels in Caucasians. Also, six other chromosomal regions (i.e., chromosomes 2,3,7,8,11, and 20) across the genome exhibited LOD scores ranging from 1.2 to 1.7. In conclusion, we found significant evidence for linkage of HDL-C levels to a genetic location on chromosome 9p in Mexican Americans, which appears to have major influence on HDL-C variation. Copyright © 1999 The American Society of Human Genetics. All rights reserved. Program Nr: 3 from the 1999 ASHG Annual Meeting Is direct speech compatible with non-directive genetic counseling? Results of a sociolinguistic investigation. J. Benkendorf1, M. Prince1, C. Gordon2, M. Rose3, A. DeFina2. 1) Ob/Gyn, Georgetown Univ Med Center, Washington, DC; 2) Linguistics, Georgetown Univ; 3) Linguistics, Stanford Univ, Palo Alto, CA. To date, genetic counseling research has focused on such aspects of non-directive counseling as the giving or withholding of information, and responses to client requests for advice. We investigated the yet unexplored area of how language choices, the "talk" of genetic counseling, facilitate or hinder the counseling process. Under an IRB-approved protocol with informed consent, we audiotaped 40 prenatal genetic counseling sessions. Transcripts of each session detailing all utterances, overlaps and pauses were prepared for discourse analysis, a sociolinguistic tool that includes studying conversational style, speaker-listener symmetry, directness and other interactional patterns. We found that the genetic counseling process requires flexibility in the use of direct and indirect speech. Analysis of our data demonstrates that: 1) indirect speech, marked by the use of hints, hedges and politeness strategies facilitates rapport and mitigates the tension between a client-centered relationship and a counselor-driven agenda; 2) direct speech, or speaking literally, is the most effective strategy for providing information and education; and 3) confusion exists between the use of direct speech and the intent to provide non-directive counseling, especially when facilitating client decision making. In response to client questions indirect phrases i.e., "some people" or "most people" maintained counselor neutrality; however, this well-intended indirectness, used to preserve client autonomy, obstructed direct explorations of client needs. Explanations (indirect), rather than "yes," "no" answers (direct) were often similar barriers. We will present suggestions, based on our data, for promoting the compatibility of direct speech with a non-directive genetic counseling model. This study provides new insights into how "talk" affects the work of genetic counseling and indicates the need for on-going research and professional development in this area. (This work was supported by the Jane Engelberg Memorial Fellowship, an annual grant from the Engelberg Foundation to the NSGC, Inc.). Copyright © 1999 The American Society of Human Genetics. All rights reserved. Program Nr: 4 from the 1999 ASHG Annual Meeting Genome wide analysis of DNA replication and replication origins in higher eukaryotes. J. Herrick1, P. Stanislawski1, O. Hyrien2, A. Bensimon1. 1) DNA Biophysics Lab, Pasteur Institute, Paris, 75425 France; 2) Ecole Normale Superieure, Genetique Moleculaire, 46 rue dUlm, 75130 Paris cedex 05, France. A new method for the study of DNA replication in higher eukaryotes is presented. The method is based on a process called molecular combing and allows for the genome wide analysis of the spatial and temporal organization of replication units and replication origins in a sample of genomic DNA. Molecular combing is a process whereby molecules of DNA are stretched and aligned on a glass surface by the force exerted by a receeding air/water interface. Since the stretching occurs in the immediate vicinity of the meniscus, all molecules are identically stretched in a size and sequence independent manner. The application of fluorescence in situ hybridization to combed DNA results in a high resolution optical mapping that is simple, controled and reproducible. The ability to comb large numbers of genomes on a single coverslip (up to several hundred haploid genomes) allows for a statistically significant number of measurements, which in turn results in a mapping resolution of 1 to 4 kb for any given genetic locus. We have applied the method to the study of DNA replication in the Xenopus laevis in vitro replication system. It was found that 1) origins of replication are activated asynchronously throughout the genome and 2) that origin density increases as DNA replication advances. These results represent the first genome wide study of DNA replication in this species and demonstrate that molecular combing is an attractive tool for genomic studies of DNA replication in higher eukaryotes. Copyright © 1999 The American Society of Human Genetics. All rights reserved. Program Nr: 5 from the 1999 ASHG Annual Meeting Inversion of the circadian rhythm of melatonin in Smith-Magenis syndrome. H. De Leersnyder1, J.-C. von Kleist- Retzow1, A. Munnich1, B. Claustrat2, S. Lyonnet1, M. Vekemans1, M.-C. De Blois1. 1) Department of Genetics, Hôpital Necker, Paris, France; 2) Nuclear Medecine Centre, Hôpital Neurologique,
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