Arno G. Motulsky, M.D. - US grants

This application relates to an interdisciplinary center in human and medical genetics and inherited diseases. The aim of the program is understanding of gene action in man with particular reference to ultimate prevention and treatment of genetic diseases. Particular emphasis in many projects is given to the interaction of heredity and environment in the pathogenesis of common disease. The Center brings together investigators whose interests range from basic to clinical approaches. Methods used in the various studies involve some aspects of DNA technology, enzyme and protein biochemistry, genetic tumor tracing techniques, cytogenetics, tissue culture, gene cloning, observation of natural history of disease, as well as family and population studies. Most investigations are done on human blood and tissue but yeast and mice are also used. Several core units serve as general resources while specific research projects include 1) cloning of human genes in yeast; 2) mechanisms of mammalian X chromosome inactivation; 3) mechanisms and detection of human hemoglobin mutations in vitro; 4) biochemical and genetic studies on a) traits of pharmacogenetic and ecogenetic significance (paraoxonase, transketolase, aryl hydrocarbon hydroxylase), and b) mekbrane defect(s) in hypertension; 5) tumor genetics in mice as models for oncogenesis in man; and 6) mechanisms and natural history of Turner syndrome.

This application requests support for the Center for Inherited Diseases - an interdisciplinary Center at the University of Washington dealing with various aspects of medical genetics. The Center brings together investigators interested in both basic and applied human genetics. Its principal aim is better understanding and ultimately better treatment and prevention of human hereditary diseases. Core units supply the necessary biochemical, cytogenetic, computer-statistical, and clinical skills and resources for optimal investigations. The Center carries out a variety of studies in human and medical genetics with particular reference to common diseases including the study of the molecular genetics of lipoproteins in susceptibility to coronary heart disease, identification of specific genes involved in membrane transport in hypertension, possible molecular collagen abnormalities in osteoporosis, and biochemical genetic study of genetic variation of paraoxonase in determining different susceptibility to insecticide poisoning. Attempts will be made to identify the gene and gene products of cystic fibrosis using new molecular techniques. The developmental switch from alpha-fetoprotein to albumin production will be investigated in order to identify specific regulatory genes affecting development. Homologous areas on the X and Y chromosome will be studied in order to better understand the mechanisms by which X and Y chromosomal action is regulated. The specific contribution of oncogenes to neoplasia will be explored in experimental skin tumor initiation and progression.

The study plans to relate the molecular composition of the red-green color vision gene complex as studied by an analysis of DNA from blood specimens to assessment of color vision by various noninvasive psychophysical measurements. Various red-green color vision defects are found in 8% of Caucasian male individuals. Such defects are caused by rearrangements and deletions of the red green pigment genes that are located very close to each other on the X chromosome. Considerable complexity in these molecular patterns has been found. Different molecular patterns can be associated with a given color vision anomaly and complex pigment gene patterns have been found in individuals with normal color vision. In this study the detailed molecular makeup of color vision genes will be determined in populations of differing ancestry (Caucasian, Afro-American, Japanese, and others) as well as in Old World monkeys. Particular attention will be given to the exact molecular definition of fusion genes that are composed of segments of both red and green pigment gene material and their effect on color vision phenotypes. Phenotypic studies will be done in humans to correlate the genetic-molecular findings with refined psychophysical measurement of vision anomalies and defects. A hypothesis will be tested that predicts a lower frequency of color vision defects in populations where individuals with normal color vision have fewer green pigment genes than are observed in the Caucasian population where color normal individuals with two or more green genes are common. On a practical plane, the in vitro study of color vision provides genetic markers for a variety of investigations and may lead to blood tests for the diagnosis of color vision defects. The elucidation of the molecular- genetic structure of this complex locus affecting sensory perception correlated to its phenotypic effects provides a model for future study of complex human genes on phenotypes affecting perception and behavior.

Description: The Pilot Projects Program is intended to support six exploratory research projects related to the theme, "Mechanisms Underlying Human Variability in Response to Environmental Exposures." The goals of the program are to: (1) stimulate CEEH investigators to initiate novel studies in the area of ecogenetics; (2) attract University of Washington scientists not currently working in ecogenetics and related fields to this area; (3) develop preliminary data to serve as a basis for future NIH research grants; and (4) encourage collaborative and inter-disciplinary work. Proposals will be solicited from CEEH and non- CEEH university investigators annually. Evaluation criteria will be weighted by scientific merit (50%), relevance to aims and goals of the CEEH (25%), collaborative and interdisciplinary involvement (12.5%), and use of CEEH facilities (12.5%). Proposals will be peer-reviewed by one referee from the University of Washington and one external evaluator, with final funding recommendations by the CEEH Executive external evaluator, with final funding recommendations by the CEEH Executive Committee. The Pilot Projects Program was expanded during the last year to include pilot grants in Ethical, Legal, and Social Issues of ecogenetics (ELSI). The latter category of proposals will be evaluated by appropriate experts, with final decision making to include input from 1-2 faculty members from the University of Washington Public Health Genetics Program (PHG).