A Gene Involved in Multigenic Inheritance of Obesity

  For the most part, obesity is a complex trait that is heritable, but is under the influence of multiple, interacting genes and environmental factors. Mice that carry certain radiation-induced mutations near the pink-eyed dilution (p) locus get much fatter (20.1% body fat) than their normal littermates (13.3% body fat). Comparison of deletions that do and do not cause obesity allowed Dabney Johnson and her collaborators in the Mammalian Genetics Section of ORNL's Life Sciences Division to identify the segment of chromosome commonly deleted only in the fat animals.

  Previous studies had shown that one major factor contributing to obesity in mice is linked to microsatellite markers (see below) D7Mit82, D7Mit84, and D7Mit62, all three of which lie within a genome interval included in those p region deletions associated with obesity. Madhu Dhar, a postdoctoral fellow in Johnson's laboratory, has constructed a microsatellite map of this interval to facilitate the positional cloning of this "fat" gene.

  Microsatellites are randomly distributed (CA)n repeat sequences found in the mouse genome, where n = 9-30. There are at least 10⁵ copies of these sequences in the mouse genome, and they are easily amplified by the polymerase chain reaction (PCR) from unique-sequence primers that flank each repeat. Given the abundance and apparently random distribution of these sequences, a microsatellite marker can be mapped every 30 kb on average in the genome. Once the map is established, traits such as obesity can be localized relative to a set of microsatellite markers.

  The ability to locate these molecular landmarks at very short intervals greatly increases the chance of finding any one of the approximately 80,000 genes (coding sequences). Johnson's group has already selected, using the three relevant microsatellite markers, both yeast artificial chromosomes (YACs) and bacterial artificial chromosomes (BACs) that contain fragments of mouse DNA from the common "fat" region. Her group will now isolate from these YACs and BACS the DNA that actually encodes a gene product (RNA and/or protein), and search among those for a product involved in fat metabolism or storage.

@nbsp The five "fat" genes that have been cloned recently account for only a small percentage of mouse and human obesity. Our isolation of these "fat" genes involved in polygenic obesity will allow the medical community to handle a much larger proportion of the overweight human population.

Contact: Dabney K. Johnson
Phone: 423-574-0953
E-mail: johnsondk@bioax1.bio.ornl.gov