The molecular basis of metamorphosis in Dro- 
sophila is being studied by the laboratory of Assis- 
tant Investigator Carl S. Thummel, Ph.D. (Univer- 
sity of Utah) by isolation and characterization of 
regulatory genes induced by the steroid hormone 
ecdysone. Current work is focused on one such 
gene, E74. The E74 gene has a complex structure 
consisting of three overlapping transcripts. An 
ecdysone-responsive promoter directs the synthesis 
" of a 60 kb primary transcript that is spliced to form 
the 6 kb E74A mRNA. The unusual length of this 
transcription unit delays the appearance of 
cytoplasmic E74A mRNA until one hour after the 
addition of ecdysone. This transcript contains an 
unusually long 5 -untranslated leader region, pro- 
viding the potential for translocational regulation. 
Preliminary evidence suggests that this leader may 
function to delay further the expression of the 
E74A protein. Internal promoters direct the pro- 
duction of two E74B mRNAs. The E74A and E74B 
transcripts encode related proteins that have 
unique amino-terminal domains but share a com- 
mon carboxyl-terminal domain. This common do- 
main is highly basic and is 50% identical to the pro- 
tein encoded by the ets-2 proto-oncogene. The 
protein encoded by the E74A mRNA binds to a sin- 
gle site in the middle of the E74 gene. Biochemical 
studies to characterize the E74 proteins are cur- 
rently under way. 
The human X and Y chromosomes have received 
considerable attention from geneticists. The Y chro- 
mosome appears to be critically involved in sex 
determination, and the X chromosome contains 
a number of genes that are important in vari- 
ous human genetic disorders, such as hemophilia, 
glucose-6-phosphate dehydrogenase deficiency, 
Duchenne muscular dystrophy, X-linked ichthyo- 
sis, and retinitis pigmentosa. In addition, an inter- 
esting type of regulation has been found to involve 
the X chromosome. Although females have two 
X chromosomes and males only one, the amounts 
of most X-encoded gene products are the same 
in both sexes. This is because one of the two X 
chromosomes in female cells is switched off very 
early in embryogenesis. The laboratory of Investiga- 
tor Larry J. Shapiro, M.D. (University of California at 
Los Angeles) is interested in the mechanisms that 
produce this X chromosome inactivation as well as 
the processes responsible for the generation of mu- 
tations in X-linked diseases. Their research should 
help to clarify the structural organization of the sex 
chromosomes and their evolutionary history, as 
well as provide us with an understanding of the 
genetic basis of a number of human hereditary dis- 
orders. 
Associate Investigator Yun-Fai Chris Lau, Ph.D. 
(University of California at San Francisco) and his 
colleagues have characterized two putative testis- 
determining genes, the zinc finger Y (ZFY) on the Y 
chromosome and the male-enhanced antigen 
(MEA) genes on chromosome 6. The cDNAs for the 
ZFY gene and a homologous gene {ZFX) on the X 
chromosome have been isolated and sequenced. 
Expression studies have demonstrated that the ZFY 
and ZFX genes are differentially transcribed as dis- 
crete-sized mRNAs in adult gonadal and somatic 
tissues, suggesting the possibility of separate 
functions for these genes. The expression of the 
mouse Zfy gene is linked to spermatogenesis in 
adult males. Zfy transcripts were also detected 
in fetal mouse testes during gonadogenesis. These 
observations support the hypothesis that the 
ZFY gene is analogous to the TDF gene in humans 
and that the Zfy-1 gene is the Tdy gene of the 
mouse. In addition, testis-specific expression of the 
ZFY gene in adult males also suggests that it may 
play a role in regulating male germ cell develop- 
ment. Studies on transgenic mice that have the en- 
tire human MEA and linked genes indicate that the 
human genes are expressed at as high levels in 
adult testis as are the endogenous mouse genes 
and are subjected to the same tissue-specific regula- 
tion. Together with the previous finding of the ex- 
pression of the mouse Mea and Gene A in fetal go- 
nads, these data are consistent with the view that 
the MEA/Mea and related genes are important for 
mammalian spermatogenesis and/or testis differen- 
tiation. 
A primary map of DNA markers for the entire 
human genome is almost complete. Once an un- 
known gene has been localized to a specific chro- 
mosomal region by family linkage studies with 
markers on the primary map, more closely linked 
markers can be developed for the region, to flank 
the locus in question and define the segment that 
needs to be searched for the gene. That level of 
characterization has been reached in the laboratory 
of Investigator Raymond L. White, Ph.D. (University 
of Utah) for two genes, those responsible for ade- 
nomatous polyposis coli and for von Reckling- 
hausen (type 1) neurofibromatosis. Efforts to iso- 
late and clone these genes and to characterize their 
functions are under way. 
New mutations are a frequent cause of inherited 
disease. This is particularly true of some severe dis- 
eases and those that are due to mutations on the X 
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