as db: ifoc and glutl. These data strongly suggest that 
the db mouse and the fa/fa rat have defects in the 
same gene. 
This information is important for several reasons. 
First, since mutation in the db gene can cause obe- 
sity in two species, these data suggest that the gene 
might enter into body weight control in other mam- 
mals, including humans. This possibility can be 
tested by analyzing cosegregation of RFLPs for ifa 
and glutl with an obese phenotype in human pedi- 
grees. Suitable pedigrees from several places, in- 
cluding the Pima Indians and the Maracaibo Indians 
of Venezuela, are being collected. Second, these ef- 
forts have likely yielded another mutant allele of db. 
This will be helpful for the cloning of the db gene. 
The molecular nature of the fa/ fa mutation will ulti- 
mately provide more information about its struc- 
ture-function relationship. Finally, it will be quite 
useful in the long term to have a rat model for the db 
mutation, as most physiologic and neuroanatomic 
studies are more easily done on rats than on mice. 
Molecular Mapping of the tubby 
and fat Mutations 
Experiments have been initiated to clone the fat 
and tubby mutations, fat and tub are recessive, and 
both result in an obese phenotype that is somewhat 
less severe than that of ob and db mice. Mutant mice 
generally weigh ~60 grams. While little is known 
about the biologic features of these mutant animals, 
the implementation of the same techniques being 
used to clone ob and db can be applied to clone the 
fat and tub genes. Separate genetic crosses have 
been established between the fat and tub mice and 
Mus castaneus. These studies have confirmed the 
map positions of fat on chromosome 8 and tub on 
chromosome 7, laying the groundwork for the physi- 
cal mapping of these mutations. 
In summary, the new techniques of molecular ge- 
netics are being applied to the study of obesity and 
type II diabetes. These studies make use of mutant 
mice, with the goal of isolating the human homo- 
logues of the mutant mouse gene. The availability of 
cloned obesity genes will make possible molecular 
studies of the regulation of body weight in health 
and disease. 
Dr. Friedman is also Associate Professor and 
Head of the Laboratory of Molecular Genetics at 
the Rockefeller University. 
Articles 
Abbott, C, Blank, R., Eppig, J., Fiedoreck, F.T., 
Friedman, J. M., Huppi, K., Jackson, I., Mock, B., 
Stoye, J., and Wiseman, R. 1992. Mouse chromo- 
some 4 report. Mamm Genome 3:S55-S64. 
Bahary, N., Pachter, J.E., Felman, R., Leibel, R.L., 
Albright, K.A., Cram, S., and Friedman, J.M. 
1992. Molecular mapping of mouse chromo- 
somes 4 and 6: use of a flow-sorted Robertsonian 
chromosome. Genomics 13:761-769. 
Dietrich, W., Katz, H., Lincoln, S B., Shin, H.-S., 
Friedman, J.M., Dracopoli, N.C., and Lander, 
E.S. 1992. A genetic map of the mouse suitable for 
typing intraspecific crosses. Genetics 131:423- 
447. 
Friedman, J.M., and Leibel, R.L. 1992. Tackling a 
weighty problem. Ce// 69:217-220. 
Friedman, J.M., Vitale, M., Maimon, J., Israel, 
M.A., Horowtiz, M.E., and Schneider, B.S. 1992. 
Expression of the cholecystokinin gene in pediat- 
ric tumors. Proc Natl Acad Sci USA 89:5819- 
5823. 
Greenfield, A.J., Brown, S.D.M., Friedman, J.M., 
and Bahary, N. 1992. Mapping of clone D45m^6i> 
to the distal end of mouse chromosome 4. Mouse 
Genome 90:94. 
MOLECULAR GENETICS OF THE MAJOR fflSTOCOMPATIBILITY COMPLEX 
Jan Geliebter, Ph.D, Assistant Investigator 
Dr. Geliebter and his colleagues are studying the 
molecular mechanisms by which multigene families 
evolve as a unit, a process referred to as concerted 
evolution. The laboratory is focusing on the role of 
recombination in the concerted evolution of the mu- 
rine major histocompatibility complex (MHC), as 
well as the function of its protein products. 
Histocompatibility molecules are the proteins 
found on the cells of mammals that are responsible 
for graft rejection. The biological function of these 
molecules is to bind foreign antigens and present 
them to the immune system. Mice and humans have 
three to six different histocompatibility molecules, 
each of which can bind a limited number of anti- 
gens. To bind a large number of antigens and ensure 
the survival of the species, it is beneficial that many 
varieties of the histocompatibility molecules be 
present in the population. 
GENETICS 193 
