The X and Y Chromosomes in Mammalian 
Development 
David C. Page, M.D. — Assistant Investigator 
Dr. Page is also Associate Member of the Whitehead Institute for Biomedical Research, Associate Professor 
of Biology at the Massachusetts Institute of Technology, and Assistant Professor at the Harvard 
University-MIT Division of Health Sciences and Technology. He received his undergraduate degree in 
chemistry from Sivarthmore College and a medical degree from Harvard Medical School and the 
Harvard-MIT Health Sciences and Technology Program. After training with Raymond White, at the 
University of Massachusetts, and David Botstein, at MIT, Dr. Page became one of the first Fellows 
of the Whitehead Institute. He subsequently joined the faculties of Whitehead and MIT. 
TO a large degree, human individuals differ in 
physical characteristics because of the im- 
pact of genetic variation on the course of embry- 
onic development. The human genome is orga- 
nized into 23 pairs of chromosomes, each 
believed to carry, on average, about 5,000 genes. 
When considering genetic differences among in- 
dividuals, it is important to distinguish between 
variation in a single gene, called Mendelian, and 
massive multigene variation, as found in chromo- 
somal disorders. 
As discussed elsewhere in this volume, single- 
gene defects are responsible for certain condi- 
tions such as color blindness, cystic fibrosis, and 
muscular dystrophy. Other conditions, such as 
Down syndrome, appear to be the result of 
"wholesale" abnormalities affecting an entire 
chromosome. As reductionists and molecular bi- 
ologists, we proceed on the assumption that the 
developmental consequences of chromosomal ab- 
normalities will ultimately be understood in 
terms of individual genes and their particular 
functions. 
My colleagues and I are seeking to understand 
how massive variability in one chromosome pair 
— the sex chromosomes — dramatically affects 
the course of development. Embryos normally in- 
herit one sex chromosome from each parent. The 
mother contributes an X chromosome, and the 
father contributes either an X or a Y. Thus normal 
embryos have one of two sex chromosome consti- 
tutions, XX or XY. 
Sex Determination 
In both humans and mice the presence or ab- 
sence of the Y chromosome determines whether 
an embryo develops as a male or as a female. XX 
embryos become females, XY embryos males. For 
years scientists wondered whether the Y chromo- 
some carried few or many sex-determining genes 
and how those were distributed along the 
chromosome. 
We found that the entire sex-determining func- 
tion can be traced to one tiny portion of the hu- 
man Y chromosome. This sex-determining region 
was identified by studying DNA from "XX males" 
and "XY females." XX males have small testes 
and are sterile. XY females are also sterile and do 
not develop secondary sexual characteristics. We 
found that almost all XX males had inherited a 
small bit of the Y chromosome attached to one of 
their X chromosomes. Conversely, some XY fe- 
males lacked the same segment of the Y that was 
present in XX males. On the basis of the chromo- 
somal deletions found in such patients, we con- 
structed a map of the Y chromosome. It was then 
we came to recognize that the presence or ab- 
sence of one small region, about 0.4 percent of 
the chromosome, correlated well with gender. 
Detailed analysis of XX males suggests that one 
or more genes within this relatively small seg- 
ment of the Y chromosome determine the out- 
come of sexual development. Laboratories 
around the world have scoured this relatively 
small segment of the Y chromosome searching for 
such sex-determining genes. We are now con- 
ducting a variety of experiments to characterize 
the functions of two genes in the region: ZFY, 
which we identified in 1987, and SRY, a. gene 
described by British scientists in 1990. 
Both ZFY and SRY appear to encode DNA- 
binding proteins that are likely to regulate the 
transcriptional activity of particular but un- 
known target genes. Experiments clearly demon- 
strate that SRY is a sex-determining gene. Much 
less clear is the role, if any, that ZFY plays in the 
process. We hope to understand better the func- 
tion of the ZFF gene by simultaneously analyzing 
a closely related gene, ZFX, that we identified on 
the X chromosome. 
In some human XY females, we have identified 
mutations near or within the SRY gene. By con- 
trast, other XY females, some human and some 
mouse, appear to have intact Y chromosomes but 
may have mutations elsewhere, perhaps in auto- 
somal genes that play important roles in sex deter- 
mination. Identification of such autosomal sex- 
determining genes is a future goal. Our studies of 
sex determination arc supported by a grant from 
the National Institutes of Health. 
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