| Laboratory of Genetics |
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| Overview: The Laboratory of Genetics (LG) includes a Human Genetics Section, directed by David Schlessinger, a Genome Instability and Chromatin-Remodeling Section directed by Weidong Wang, the Developmental Genomics Section under the direction of Minoru S.H. Ko, an Image Informatics and Computational Biology Unit led by Ilya Goldberg, and a Gene Recovery and Analysis Unit headed by Ramaiah Nagaraja. |
| The interests of the Laboratory are based on the view that aging has genetic determinants as an integrated part of human development, with a profound dependence on the interplay of synthetic and degradative processes that are initiated in utero. Seven major types of study are in progress: |
| 1. Transitions between immortal and mortal cells, particularly at the level of large-scale regulatory phenomena at the level of chromatin. For example, the transition of immortal embryonic stem cells to mortal differentiating cells is a fundamental feature of the initiation of aging in metazoans. The genes specifically activated and repressed during such transitions are being studied in a mouse model, by differential assays of gene expression in oocytes, preimplantation embryos, placenta, and several types of stem cells (in the Developmental Genomics and Aging Section). |
| 2. Cohorts of genes involved in the development of selected "nonrenewable" systems. For example, to understand and ultimately try to compensate for loss of cells and tissues during aging, skin appendage development is being studied. Studies start from human or mouse hereditary defects that have been attributed to single genes, such as the ectodysplasin-A involved in X-linked ectodermal dysplasia. |
| 3. Mechanisms and treatment of heritable disorders of connective tissue. In addition to studies of lesions and their effects in skeletal dysplasias, systematic studies are determining gene cohorts involved in skeletal growth and development. The work is complemented by efforts to understand the potential roles of alternative and traditional medical practice in the care of persons with genetic conditions, with particular attention to the prevention or alleviation of chronic pain. |
| 4. Nuclear organelles that determine large-scale chromatin remodeling events. Such events are involved in chromosome dynamics related to large-scale control of gene expression and DNA repair. The Genome Instability and Chromatin-Remodeling Section is using a combination of approaches to isolate and characterize critical complexes, including the ones that are modified to cause the Werner, ATRX, and Bloom Syndromes, and Fanconi Anemia. |
| 5. Genes involved in embryonic events that prefigure aging-related phenomena. For example, the Human Genetics Unit is involved in studies of premature ovarian failure, in which the aging phenomenon of early menopause is determined by an increased rate of follicula atresia during fetal life, and skin appendage formation and regeneration. |
| 6. The genetics of aging-related complex conditions is being approached by interactive studies with the "founder" population in Sardinia. Initial phenotypes to be studied along with epidemiological factors include arterial stiffness, selected psychiatric/psychological traits. For this project investigators from the Laboratory of Cardiovascular Science (Edward Lakatta, Samer Najjar, and Angelo Scuteri), the Laboratory of Personality and Cognition (Paul Costa, Antonio Terracciano, and Alan Zonderman), and the Laboratory of Genetics (Alexei Sharov and Timur Nedorezov) are working with Antonio Cao and Giuseppe Pilia, human geneticists at the University of Cagliari, Sardinia, and Goncalo Abecasis, a statistical geneticist at the University of Michigan. |
| 7. The Image Informatics and Computational Biology Unit is helping to develop quantitative visual assays. The unit is principal developer and co-founder of the Open Microscopy Environment (OME) project. OME is a software package and a set of standards for the collection, maintenance, and analysis of biological images. Currently, the group is continuing to develop relevant tools, applying them to determine the spatial distribution of differentially expressed gene products in pre-implantation mouse embryos, and to screen for mutants in C. elegans. |
| The laboratory is also equipped with other state-of-the-art resources for genomic approaches in the Gene Recovery and Analysis Unit, including large-insert clones and recovery methods, automated sequencing, and chromatin analysis techniques. Among the specific projects of the Unit is the detailed mapping and sequencing of the mouse t-complex, a region important for embryonic development and developmental genetics, and to study long-range control of genes with regulatory elements at a great distance from the transcription section. |
| Among specific technological improvements that are being developed are techniques for the recovery of complete genes and YACs in circular, autonomously replicating clones (in the Gene Recovery Unit), and protocols to make and analyze high-quality cDNA libraries from very few cells from subregions of embryos (in the Developmental Genomics and Aging Section) and in collaborating with the Microarray Laboratory run by Kevin Becker (see Research Resources Branch) and Agilent Technologies to develop gene expression profiling with microarrays based on the cDNAs. The laboratory also benefits from joint efforts with other groups and resource providers both within NIA and at a number of extramural sites in the United States and abroad. |
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