Available in PDF
In this issue...
In the News
Genomes to Life
OASCR and GTL
DOE Microbial Cell Project
Human Genome Draft
Genome Perspective
Honor for DeLisi
New NIH Institute
Structural Genomics
Imaging Structures
Synchrotron Use
Proteome Organisation
Breast Cancer Research
Gene Expressions Used
Nuclear Medicine
Nuclear Medicine Labs
Toxicogenomics Center
Kettering Prize
Zeta Phi Beta Conference
Microbial Genomes
Sloan-DOE Fellowships
Ribosomes Illuminated
In Memoriam: Walter Goad
Comparative Genomics
Model
Organism Studies
Sushi Delicacy
Arabidopsis Sequence
AAAS Prize
Microbial Conference
Flyer; "Microbe Month"
VISTA Software
Mouse
ORNL Mouse Program
MicroCAT Scanner Used
Draft Sequence Achieved
NCBI Mouse Resources
Human-Mouse Comparisons
MGI Allele Searching
Web, Publications, Resources
Next-Generation Computing
HGMIS Resources
NSF QSB Report
Structural Biology Basics
Minorities and the HGP
HGP Educational Kit
Testing, Counseling Resources
Biotech, ELSI Websites
Biotech Encyclopedia
ASM Report
Nature Yearbook
Next Wave Publication
High-School Curriculum
Education CD-ROMs
Exploring DNA in the Classroom
Funding
US Genome Research Funding
UK Scholarships, PostDocs
Meeting Calendars & Acronyms
Genome and Biotechnology Meetings
Training Courses and Workshops
Acronyms
HGN archives
and subscriptions
Human Genome Project Information home
|
ORNL Mouse Program Provides Powerful Tools for Studying Human Genes
Connecting Sequence and Function
Sequencing genomes was the easy part. Some major challenges facing the new era of post-sequencing biology include finding all genes and deducing their functions, elucidating the connections between mutations and disease, and untangling the complex networks of interactions controlling all these processes in living systems. Model organisms such as the mouse, whose genes and DNA regulatory regions are remarkably similar to those of humans, provide powerful tools for illuminating our own genetic material.
Researchers in the Mouse Genetics and Genomics (MGG) section at Oak Ridge National Laboratory (ORNL) are using mouse genetics and mutagenesis strategies to annotate biologically important features of the DNA sequence and to provide functional information for parts of the genome that are expressed or that regulate gene expression. A complementary effort exploits genome data for a better understanding of normal and abnormal biological processes defined by genetic and phenotypic analyses of mouse mutations.
Mouse Mutations
MGG is screening about 10% of the mouse genome for chemically induced recessive mutations affecting a wide variety of physiological, neurological, behavioral, morphological, developmental, reproductive, cancer, aging, and other genetic phenotypes. This activity expands on previous studies that identified over 50 mutations associated with visible or lethal phenotypes in 1% of this genome. The group is integrating microarray and proteomics technologies into these and other mutagenesis crosses for a molecular-based set of assays to complement whole-organism phenotypic screening. Point-mutation maps describing single-base changes of the target mutagenized regions are being merged with DNA sequence maps to correlate mutant phenotypes with specific genes.
Human Disease Models
Two allelic mutations were recently discovered that serve as models for human acute and chronic tyrosinemia (Aponte et al., Proc. Nat. Acad. Sci. USA 98, 641 45, 2001). The group also has identified a significant candidate gene for an obesity-associated quantitative trait locus that may have an imprinted or maternal-effect component (Dhar et al., Physiol. Genomics 4, 93 100, 2000).
MGG is evaluating specific candidate genes for induced mutations leading to (1) abnormal hematopoiesis (production of red blood cells), iron transport, and skeletal development; (2) abnormal brain function, resulting in epilepsy; (3) defective kidney function, resulting in juvenile death; (4) perinatal death, possibly due to skull or brain abnormalities; (5) early embryonic death due to a failure of yolk-sac hematopoiesis; (6) defective skin function, leading to alopecia and increased risk of skin cancer; and (7) modification of the agouti signaling pathway involved in pigmentation, obesity, diabetes, and cancer.
Screening Libraries
High-throughput mutation scanning is central to these gene-discovery efforts, so MGG is producing a large bank of 3000 to 5000 inbred C57BL/6JRn mice. They will carry point mutations induced in their sires by N-ethyl-N-nitrosourea and cryopreserving both tissues and gametes. DNA or RNA from these mice can be used to screen for point mutations in any gene. The mutations are identified by high-throughput heteroduplex analysis followed by DNA sequencing of PCR products from this large bank. Stocks of mice carrying the specific gene mutation can be reconstituted from the frozen gametes. An allelic series of mouse mutations for any preselected gene then can be used to test specific hypotheses about the structure- function relationships of the gene product in the context of a specific genetic network or environmental response. Initial targets for this type of analysis will include DNA-repair and other types of radiation- and stress-response genes; intracellular-transport genes; regulatory regions of selected genes, including imprinted ones; signaling molecules; and cancer-susceptibility genes.
User Facility
The Mouse Genetics Research Facility is a DOE Biological and Environmental Research User Facility, offering expertise in mouse genetics and mutagenesis, molecular biology, and functional genomics. Mutant mouse stocks, mutagenesis and phenotyping protocols, and genomic expression and phenotype data are available to the functional genomics and wider biological research communities through database, cryopreservation, and mouse-distribution efforts at ORNL. The Mutant Mouse Database provides searchable, one-stop shopping for new and archived mutant-mouse stocks created over the program's 50-year existence. [ Dabney Johnson, ORNL]
The electronic form of the newsletter may be cited in the following style:
Human Genome Program, U.S. Department of Energy, Human Genome News (v11n3-4).
|