(short arm, centromere, and proximal long arm) of 
the Y chromosome was resolved into 43 ordered 
intervals, all defined by naturally occurring chromo- 
somal breakpoints and averaging <800 kbp in 
length. 
This deletion map provides a foundation for un- 
derstanding the Y chromosome's role in sex de- 
termination and Turner syndrome (see below), 
and it should speed ongoing efforts to identify Y- 
chromosomal genes involved in gonadoblastoma (a 
rare gonadal neoplasm), male fertility, and stature. 
The map is now being used to pursue a poorly un- 
derstood Y-linked gene encoding or regulating H-Y, 
a minor histocompatibility antigen. In collaboration 
with Dr. Elizabeth Simpson (Medical Research 
Council, London), the gene was localized to a small 
interval on the long arm of the chromosome by H-Y 
typing of individuals with partial Y chromosomes. 
(These studies of the human Y chromosome were 
supported by the National Institutes of Health.) 
Ribosomal Protein S4 and the Molecular 
Genetics of Turner Syndrome 
Turner syndrome is a complex human phenotype 
characterized by low viability in utero, short stat- 
ure, gonadal degeneration, and various somatic ana- 
tomic defects. Often associated with an XO karyo- 
type. Turner syndrome is one of the most common 
chromosomal disorders in humans. Evidence sug- 
gests that Turner syndrome is the result of haploidy 
for one or more genes common to the X and Y chro- 
mosomes. By deletion analysis, a 90-kbp portion of 
the Y chromosome was identified as the probable 
location of one or more Turner genes. 
One gene, RPS4Y, has been identified within this 
region. A closely related gene, RPS4X, is located on 
the X chromosome. RPS4Y and RPS4X diverged 
from a single common ancestral gene during evolu- 
tion, retain very similar intron/exon structures, and 
encode isoforms of ribosomal protein S4. Ribo- 
somes from human male tissues contain both the X- 
and Y-encoded protein isoforms, which appear to 
function interchangeably. RPS4X is the only gene 
on the long arm of the human X chromosome known 
to escape X inactivation. It is possible that the 
Turner phenotype results, in part, from reduced 
protein synthetic capacity in embryos with one 
rather than two RPS4 genes per cell. 
Although the mouse X chromosome carries a ho- 
mologue of human RPS4X, this mouse X gene is 
subject to X inactivation, and no homologue is 
found on the mouse Y chromosome. These findings 
may account for the less severe phenotype observed 
in XO mice as compared with XO humans. In collab- 
oration with Dr. Ruth Lehmann (HHMI, Massachu- 
setts Institute of Technology and the Whitehead In- 
stitute), Dr. Page and his colleagues have set out to 
examine the effects of RPS4 deficiency on embry- 
onic development in Drosophila. 
Molecular Genetics of Sex Determination 
in Humans 
By examination of Y-DNA sequences in human XX 
males and XY females, Dr. Page's laboratory found 
that whether a human embryo develops as a male or 
female is determined by the presence or absence of a 
280-kbp region (interval lA) constituting <0.5% of 
the Y chromosome. The vast majority of XX individ- 
uals with descended testes and normal male exter- 
nal genitalia carry the entirety of interval 1 A of the Y 
chromosome, while 1 1 unrelated XY females in the 
Page laboratory's studies entirely lack interval lA. 
Colleagues in other laboratories have identified a 
gene, SRY, that is located in interval lA and plays a 
pivotal role in sex determination. Detailed studies 
of a critical subset of human XX males, XY fe- 
males, and XY hermaphrodites confirm the sex- 
determining role of SRY and suggest that a sec- 
ond gene in interval lA might also function in sex 
determination. 
Most human XX males carry terminal portions of 
the short arm of the Y chromosome, while some XY 
females have deletions of terminal portions of the 
short arm of the Y. Genetic studies suggest that XX 
males and XY females with Y deletions are the re- 
sults of reciprocal processes, all involving anoma- 
lous exchanges between the X and Y short arms. 
Some such events involve grossly unequal ex- 
changes between misaligned X and Y chromosomes. 
Progress has been made in cloning and sequencing 
of the Y chromosomal breakpoints — the X-Y inter- 
change junctions — from several XX males and XY 
females. 
The sex-determining region of the Y chromo- 
some, including SRY, is deleted in some human XY 
females. However, most human XY females carry Y 
chromosomes that, as judged by Southern blotting, 
appear to be grossly intact. Seventy- four such unex- 
plained human XY females or hermaphrodites were 
identified, and SRY point mutations were found in 
six cases. The remaining 68 unexplained XY fe- 
males and hermaphrodites may prove to carry muta- 
tions in other sex-determining genes. (These studies 
of sex determination were supported by the Na- 
tional Institutes of Health.) 
Dr. Page is also Associate Member of the White- 
head Institute for Biomedical Research and Asso- 
ciate Professor of Biology at the Massachusetts In- 
stitute of Technology. 
GENETICS 247 
