semble these markers into a high-resolution human 
genetic linkage map, with a predicted minimum 
sex-averaged resolution of 2.5 cM. 
Candidate Genes and Mechanosensory 
Transduction 
It is unlikely that localization of genes for hearing 
loss by homozygosity mapping and related ap- 
proaches will suffice for positional cloning of the 
targeted genes, but the integration of candidate 
genes into the genetic map should facilitate their 
recovery. As the signal transduction pathways re- 
quired for the development of the inner ear begin to 
be understood and the components of the auditory 
sensory transduction system are defined at a molecu- 
lar level, the list of potential candidate genes will 
grow. 
In collaboration with Dr. David Corey (HHMl, 
Massachusetts General Hospital), Dr. Duyk and his 
colleagues have begun the process of identifying the 
molecular components of the hearing apparatus by 
combining molecular biological and biophysical 
approaches. Their starting point has been the con- 
struction of cDNA libraries from microdissected in- 
ner ear material highly enriched for hair cells. Using 
these resources. Dr. Charles Sole and Vida Meyers 
have identified members of the myosin gene family 
that are expressed in hair cells as candidates for an 
essential component of the auditory mechanosen- 
sory process, the adaptation motor. Dr. Hong Chen 
has used interaction cloning strategies to identify 
additional candidate components of the sensory ap- 
paratus. In collaboration with Ici Thalmann (Wash- 
ington University, St. Louis), he has also cloned an 
organ of Corti-specific gene, based on partial amino 
acid sequence. The continued study of these compo- 
nents and others will lead to the understanding of 
the molecular basis of hearing. 
As components of the sensory transduction path- 
way are identified, human and murine homologues 
will be recovered and mapped to specific chromo- 
somes, and closely linked DNA polymorphic 
markers will be developed and integrated into the 
high-resolution genetic map. This information will 
represent important resources in the hunt for genes 
underlying hereditary hearing loss. 
Dr. Duyk is also Assistant Professor of Genetics 
at Harvard Medical School and a member of the 
Eaton-Peabody Laboratory at the Massachusetts 
Eye and Ear Infirmary. 
Articles 
Cogen, P.H., Daneshvar, L., Metzger, A.K., Duyk, 
G., Edwards, M.S.B., and Sheffield, V.C. 1992. In- 
volvement of multiple chromosome 17p loci in 
medulloblastoma tumorigenesis. Am f Hum 
Genet 50:584-589. 
Duyk, G., Gastier, J., and Mueller, R.F. 1992. Traces 
of her workings: recent progress in hereditary 
hearing loss. Nature Genet 2:5-8. 
Metzger, A.K., Sheffield, V.C, Duyk, G., Daneshvar, 
L., Edwards, M.S.B., and Cogen, P.H. 1992. Iden- 
tification of a germ-line mutation in the p53 gene 
in a patient with an intracranial ependymoma. 
Proc Natl Acad Sci USA 88:7825-7829. 
Ostrander, E.A., Jong, P.M., Rine, J., and Duyk, G. 
1992. Construction of small-insert genomic DNA 
libraries highly enriched for microsatellite repeat 
sequences. Proc Natl Acad Sci USA 89:3419- 
3423. 
TUMOR SUPPRESSOR GENES 
Andrew P. Feinberg, M.D., M.P.H., Associate Investigator 
Twenty years ago, Knudson proposed that some 
cancers arise by two genetic "hits," the first trans- 
mitted as a dominant trait for hereditary predisposi- 
tion to cancer and the second arising in somatic 
cells. These two hits, if allelic, would represent a 
recessive, or suppressor, tumor gene. Two of Knud- 
son's paradigms were retinoblastoma and Wilms' tu- 
mor (WT), since they sometimes arise as multiple 
tumors in very young children. Presumably a germ- 
Hne mutation affecting all of their cells represents 
the first "hit." While the retinoblastoma gene ele- 
gantly fits Knudson's model. Dr. Feinberg's labora- 
tory has found that WT is far more complex, in- 
volves multiple genes, and may also involve the 
unconventional pathogenetic mechanism of genetic 
imprinting. 
Wilms' Tumor Genes on llpl3 
Some children with the WAGR (Wilms' tumor, an- 
iridia, genitourinary dysplasia, and mental retarda- 
tion) syndrome show overlapping deletions involv- 
ing Hp 13, and sporadically occurring WTs were 
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