The Mammalian Sex Chromosomes 
unequal exchange within this region of homol- 
ogy between the X and Y chromosomes. 
Another area of substantial interest in the labo- 
ratory relates to deletions in X chromosome- 
encoded genes. Duchenne muscular dystrophy is 
a human genetic disorder resulting from abnor- 
rnalities in an X-encoded gene called dystrophin. 
The majority of patients with Duchenne dys- 
trophy have deletions of part or all of the dystro- 
phin gene. 
Patients with X-linked ichthyosis, a heritable 
skin disorder, have deficient activity of the en- 
zyme steroid sulfatase (STS). This gene is en- 
coded in 150 kilobases of X chromosomal DNA, 
and in 90 percent of patients with this relatively 
frequent cutaneous disorder, the entire gene is 
deleted. Our studies have established that such 
deletions result from recurrent de novo events on 
the X chromosome. These involve the unequal 
exchange of DNA catalyzed by a low-copy- 
number repetitive element that flanks the STS 
gene. 
Thus recombination between similar but non- 
identical elements appears to be responsible for 
the genesis of these common deletional events. 
We are currently trying to determine whether this 
process occurs with a high degree of frequency 
elsewhere within the genome. 
The phenomenon of X chromosome inactiva- 
tion is another area of interest in our laboratory. 
Since all normal female mammals have two X 
chromosomes and males have only a single X, 
there is a fundamental dosage inequity. This is 
normalized for most genes by functional inactiva- 
tion of one of the X's in female somatic cells very 
early in embryogenesis. Previously, we have 
shown that X chromosome inactivation is inte- 
grally related to DNA methylation. Currently we 
are investigating a model of X chromosome inac- 
tivation in vitro involving the use of differentiat- 
ing teratocarcinoma cells. We hope to identify 
proteins and other gene products that are impor- 
tant in counting the number of X chromosomes 
present and in initiating the X inactivation 
process. 
There is also a small group of genes that appear 
to escape the process of X inactivation even when 
they are situated on otherwise inactive X chro- 
mosomes. Our previous studies have shown that 
these genes escape inactivation in a position-in- 
dependent fashion. We are currently studying the 
regulatory signals involved in X inactivation and 
those unique features that render some genes re- 
sistant to this phenomenon. We have cloned and 
characterized the promoter of the STS gene as an 
example of this class of genes and have found 
what appears to be a novel promoter structure. 
We are trying to identify other genes that 
escape X inactivation so that we can compare reg- 
ulatory regions between them and identify DNA 
sequences that are critical for initiating and prop- 
agating X inactivation signals along the chromo- 
some. The studies described should provide a 
better understanding of the evolution of the sex 
chromosomes and insight into the pathogenesis 
of the many human disorders that are due to mu- 
tations or structural and numerical abnormalities 
of these chromosomes. 
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