target gene through which the homeotic genes con- 
trol segment identity. 
Downstream Target Genes through Which 
Distal-less Exerts Its Activity 
To understand the role of Distal-less in organizing 
spatial pattern, it is important to identify the genes 
through which it acts. A number of prospective can- 
didate target genes have been identified by virtue of 
their patterns of expression in the embryo. These 
genes are under genetic control of Distal- less in 
the embryonic limb primordia. The question of 
whether they are direct targets for transcriptional 
regulation by Distal-less is being addressed, and 
their contribution to limb development assessed. 
Comparison of Pattern Formation 
in Wing and Leg 
Distal-less is expressed in the presumptive adult 
limb structures throughout their development, but 
is not expressed in the surrounding body wall pro- 
genitor cells. In the absence of Distal-less function, 
body wall structures develop normally, but limb 
structures are entirely absent. Distal-less function is 
not required in the dorsal appendages to support the 
development of wing (as opposed to body wail). A 
number of mutants have been described that lack 
wings, including apterous. Null mutants show a 
complete deletion of wing structures. The apterous 
gene has been cloned and characterized. It encodes 
a predicted transcription factor of the LIM family, 
which is expressed in the dorsal surfaces of the wing 
and the body wall. Therefore, although the pheno- 
typic consequences of removing apterous from the 
wing show some similarity to the effects of remov- 
ing Distal-less from the leg, the genes' functions are 
not directly comparable in molecular terms. 
Dr. Cohen is also Assistant Professor of Cell Biol- 
ogy and of Molecular Genetics at Baylor College of 
Medicine. 
Article 
Cohen, B., McGuffin, M.E., Pfeifle, C, Segal, D., 
and Cohen, S.M. 1992. apterous, a gene re- 
quired for imaginal disc development in Dro- 
sophila encodes a member of the LIM family 
of developmental regulatory proteins. Genes Dev 
6:715-729. 
MOLECULAR GENETICS OF HUMAN DISEASE 
Francis S. Collins, M.D., Ph.D., Investigator 
Almost all diseases have a genetic component, but 
for many the underlying biological defect has re- 
mained elusive. A powerful method for identifying 
such genes, known as positional cloning, has re- 
cently emerged. It utilizes the inheritance pattern of 
the disease within families to pinpoint the gene on a 
specific chromosome, followed by intensive search- 
ing of that region to identify a gene that produces 
abnormalities in affected individuals. The Collins 
laboratory is currently pursuing four disease genes 
whose molecular basis has been or will be uncov- 
ered by this strategy. 
Familial Early-Onset Breast Cancer (BRCAl) 
A positive family history increases an individual's 
risk for developing breast cancer, and in some re- 
markable families with many affected women the 
inheritance of this disease appears to be a pure auto- 
somal dominant. This early-onset breast cancer gene 
was mapped to chromosome 17 in 1990 by Dr. 
Mary-Claire King and her colleagues (University of 
California, Berkeley). The Collins laboratory, in col- 
laboration with Dr. King, has initiated a broad series 
of efforts to identify the gene and find the mutations 
within it that carry such a high risk of the develop- 
ment of cancer. In addition to breast cancer, it is 
clear that the same gene is involved in many cases of 
ovarian cancer. 
Over the past year, in close collaboration with Dr. 
Barbara Weber (Division of Hematology and Oncol- 
ogy, University of Michigan), a large number of af- 
fected families have been identified, DNA samples 
have been obtained, and linkage analysis has been 
carried out. Several of these families do indeed ap- 
pear to carry the chromosome 1 7 gene, and in one of 
them a crucial recombinant event has allowed 
narrowing of the responsible interval to about half 
its previous size. An intense effort is now under way 
to clone this entire region, using a variety of novel 
technologies, including chromosome microdissec- 
tion, radiation hybrids, fluorescent in situ hybridiza- 
tion, and yeast artificial chromosome (YAC) clon- 
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