PROGRAM IN GENETICS 
The Institute's Program in Genetics remains the 
largest of its five program areas, and it intersects 
extensively with each of the other four. Work 
carried out ranges from basic studies at the molecu- 
lar and cellular levels, through developmental path- 
ways, to clinically based studies of human genetic 
disorders and potential new therapeutic ap- 
proaches. Investigators within this program are lo- 
cated at Emory University, the University of Michi- 
gan, Johns Hopkins University, Indiana University at 
Bloomington and at Indianapolis, Harvard Medical 
School, Children's Hospital at Boston, the University 
of Colorado at Boulder, the Massachusetts Institute 
of Technology, the University of Chicago, Duke Uni- 
versity, Baylor College of Medicine, the University 
of Iowa College of Medicine at Iowa City, Yale Uni- 
versity, Rockefeller University, Stanford University, 
the California Institute of Technology, the Univer- 
sity of Pennsylvania, Princeton University, the Uni- 
versity of Utah, the University of Washington in Seat- 
tle, Fred Hutchinson Cancer Research Center in 
Seattle, Washington University in St. Louis, Brandeis 
University in Waltham, and the University of Califor- 
nia at Berkeley and at San Francisco. 
The molecular basis of human genetic disease is 
the theme of the research of Investigator Francis S. 
Collins, M.D., Ph.D. (University of Michigan) and 
his colleagues. Use of the positional cloning ap- 
proach has made it possible to identify genes respon- 
sible for inherited disease, even when there is little 
or no information available about the basic biologi- 
cal defect. This strategy was successful in yielding 
the genes for cystic fibrosis and neurofibromatosis 
over the past three years, and details of the basic 
biological defects in those two diseases are now be- 
coming much clearer. The positional cloning ap- 
proach is being intensively utilized to search for 
genes for familial breast cancer on chromosome 
number 1 7 and for Huntington's disease on chromo- 
some 4. In both of these searches the relevant inter- 
val has been narrowed to a manageable stretch of 
genomic DNA, and the identification of the responsi- 
ble genes is close at hand. 
The adenomatous polyp represents an early stage 
in the development of colon cancer in the general 
population as well as in families where inheritance 
of a mutation causing numerous polyps leads to a 
high incidence of colon carcinoma. The recently 
cloned gene (APC) responsible for the inherited 
condition is therefore of broad interest, and ongoing 
experiments by Investigator Raymond L. White, 
Ph.D. (University of Utah) and his colleagues are 
yielding information about its normal function and 
the consequences of various mutations. The tech- 
niques of genetic and physical mapping that led to 
the successful isolation of APC, and the experience 
gained in that endeavor, will speed the eventual 
identification of other genes that play roles in hu- 
man genetic disease. 
The laboratory of Assistant Investigator David C. 
Page, M.D. (Massachusetts Institute of Technology) 
has investigated the structure and function of the 
mammalian genome and its role in embryonic devel- 
opment. Efforts were focused largely on the human 
and mouse X and Y chromosomes and were directed 
at understanding genes involved in Turner syndrome 
and in sex determination. Comprehensive genetic 
maps of the human Y chromosome were generated; 
the methods developed should be applicable to the 
mapping of all human chromosomes. A pair of genes 
located on the human X and Y chromosomes was 
implicated in Turner syndrome, one of the most 
common chromosomal disorders. Mutations were 
identified that cause XX embryos to develop as males 
or cause XY embryos to develop as females. 
Investigation of genetic diseases of the human X 
chromosome is the major interest of the laboratory 
of Associate Investigator Stephen T. Warren, Ph.D. 
(Emory University) . Work continues to unravel the 
unusual mutation responsible for the fragile X syn- 
drome, the most frequently encountered form of 
human mental retardation. This novel mutation is 
the extraordinary expansion in patients of a 3-base 
pair repeat within the FMR-1 gene from a normal 
average of 29 repeats to beyond 1,000 repeats. Car- 
riers display intermediate levels of expansion that 
are remarkably unstable when transmitted from par- 
ent to child. The actual length of the repeat in car- 
riers influences the chance of having an affected 
child and resolves the unusual genetics of fragile X 
syndrome, termed the Sherman paradox. Progress 
has also been made in the investigation of Emery- 
Dreifuss muscular dystrophy (EDMD). An excellent 
candidate gene has been found that maps quite close 
to the EDMD mutation and encodes a protein similar 
to dystrophin, a protein involved in other X-linked 
muscular dystrophies. 
Investigator C. Thomas Caskey, M.D. (Baylor Col- 
lege of Medicine) and his colleagues are studying 
the mechanisms of genetic disease and seek to im- 
prove procedures for diagnosis and therapy. Their 
research over the past year has identified the gene 
defect for myotonic dystrophy and revealed the 
mechanism for mutation in humans, termed triplet 
GENETICS 135 
