The Mammalian Sex Chromosomes 
Larry J. Shapiro, M.D. — Investigator 
Dr. Shapiro is also Professor of Pediatrics and Biological Chemistry at the University of California, Los 
Angeles. He received his M.D. degree from Washington University, St. Louis, where he also completed clin- 
ical training in pediatrics. He received postdoctoral research training at the NIH. Dr. Shapiro has received 
many honors for his research and is currently President of the Society for Pediatric Research. 
SEX determination is a developmental process 
of substantial fundamental and practical inter- 
est. In a number of vertebrates, sex is determined 
by environmental factors. For example, some 
reptiles and amphibians have a temperature- 
dependent sex-determining mechanism. In 
various fishes, sex is determined through social 
cues and interactions. In a number of nonverte- 
brate species, the somatic sexual phenotype and 
the actual gonadal sex can be dissociated. In 
mammals, however, the presence or absence of a 
Y chromosome is the absolute determinant of sex- 
ual differentiation. The presence of one or more 
Y-encoded genes is necessary and sufficient to ini- 
tiate differentiation of the embryonic gonad into 
a testis. FoIIow^ing this commitment, a variety of 
secondary events result in the elaboration of hor- 
mones that produce the full male phenotype. 
It is generally believed that mammalian X and 
Y chromosomes have evolved from a common an- 
cestral homologous chromosome pair. However, 
a gene or genes must exist on the Y chromosome 
that does not have a functional counterpart on the 
X to effect testicular differentiation. To ensure 
this state of affairs, there must have been a sup- 
pression of genetic recombination between the 
ancestral X and Y chromosomes during evolu- 
tion. Such suppression likely occurred through 
the introduction of gross rearrangements in ei- 
ther the X or Y chromosome to make possible the 
subsequent divergence of DNA sequences. 
In modern-day sex chromosomes, however, 
several areas of persistent X-Y homology can be 
identified. The first of these is a region approxi- 
mately 3 megabases long in which absolute se- 
quence identity between the X and Y chromo- 
some distal short arms has been demonstrated. 
This region facilitates pairing and appropriate 
segregation of the X and Y chromosomes during 
male meiosis. The frequent meiotic recombina- 
tion occurring between the X and Y within this 
segment ensures the homogenization of DNA se- 
quences in this region. 
We have documented the role of this segment 
of the X and the Y chromosomes in sex chromo- 
some pairing through studies of a patient who 
had a small deletion of the needed pairing se- 
quences from his X chromosome. As a result of 
this abnormality, his sex chromosomes were un- 
able to align with each other during meiosis. It is 
possible that more subtle abnormalities of this 
pairing region result in some cases of male steril- 
ity or predispose to improper sex chromosome 
segregation and consequent X or Y aneuploidy. 
We and others have identified other regions of 
X-Y chromosome similarity wherein sequences 
are not absolutely identical. Through the map- 
ping and sequencing of these regions and compar- 
ative studies in a number of primate species, we 
have developed a model for the recent evolution 
and divergence of the X and Y chromosomes. This 
model suggests that at least one pericentric inver- 
sion of the Y chromosome has occurred, probably 
within the past 40 to 60 million years of primate 
evolution. As a consequence, some DNA se- 
quences are represented on the long arm of the Y 
chromosome that have homologues on the short 
arm of the X. 
Many of the sequences on the Y chromosome 
appear to have undergone degeneration and to 
have accumulated mutations that render them 
molecular fossils with no apparent function. 
However, we have recently studied the structure 
and expression of the human amelogenin genes, 
which are located in the same general area. The 
amelogenin X and Y genes are approximately 90 
percent similar in their DNA sequences, but are 
predicted to encode proteins of varying amino 
acid composition. Through studies of RNA pro- 
duction in developing tooth buds, we have 
shown that both the X and Y genes are functional 
and can be expressed in males, leading to the pro- 
duction of two different amelogenin proteins. 
Thus not all of the sequences involved in the Y 
chromosome pericentric inversion have under- 
gone degeneration. 
Another practical aspect of the X-Y homology 
is that it can occasionally be the site of aberrant 
recombinational events producing X/Y translo- 
cations. We have studied a number of these pa- 
tients in some detail and have shown that this 
cytogenetic abnormality is in fact the result of 
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