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 and Assistant Professor of Biology at the 
Massachusetts Institute of Technology. He received his undergraduate degree in chemistry from Swarth- 
more 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 subse- 
quently joined the faculties of Whitehead and MIT. 
TO a large degree, human individuals vary 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 variability, it is impor- 
tant to distinguish between variation in a single 
gene, called Mendelian, and massive multigene 
variation, called chromosomal. 
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 ge- 
netic variability 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 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 have found that the entire sex-determining 
function can be traced to one tiny portion of the 
human Y chromosome. This sex-determining re- 
gion 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 characteris- 
tics. We found that almost all XX males had in- 
herited a small bit of the Y chromosome attached 
to one of their X chromosomes. Conversely, some 
XY females lacked the same segment of the Y that 
was present in XX males. On the basis of patterns 
of chromosomal deletions found in such patients, 
we constructed a map of the Y chromosome. It 
was then we came to recognize that the presence 
or absence 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 
outcome of sexual development. Laboratories 
around the world have scoured this small region 
searching for such sex-determining genes. We are 
now conducting a variety of experiments to char- 
acterize the functions of two genes in the region: 
ZFY, which we identified a few years ago, and 
SRY, a gene recently described by British 
scientists. 
Both ZFFand 5i?Fappear to encode DNA-bind- 
ing proteins that are likely to regulate the tran- 
scriptional activity of particular but unknown 
target genes. The evidence is strong that 5.^Fis a 
sex-determining gene. Much less clear is the role, 
if any, that ZFF plays in the process. We hope to 
learn more about the function of the ZFF gene by 
simultaneously analyzing a closely related gene, 
ZFX, that we identified on the X chromosome. 
Turner Syndrome 
As mentioned earlier, embryos normally have 
two sex chromosomes. However, about 1-2 per- 
cent of all human embryos have only one. The 
vast majority of such XO embryos are lost to spon- 
taneous miscarriage, but a few survive. The sur- 
viving XO embryos develop as females with a par- 
ticular set of physical features known as Turner 
syndrome, which includes short stature, webbing 
of the neck, puffiness of the hands and feet, and 
failure of secondary sexual development. It had 
been postulated that Turner syndrome might be 
the result of having a single copy of one or more 
genes common to the X and Y chromosomes. 
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