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THE X AND Y CHROMOSOMES IN MAMMALIAN DEVELOPMENT 
David C. Page, M.D., Assistant Investigator 
Dr. Page's laboratory has explored the structure 
and function of the mammalian genome and its role 
in embryonic development. Eff^orts during the past 
year were focused on the mammalian sex chromo- 
somes and were particularly directed toward com- 
prehensive mapping of the human Y chromosome, 
identification and characterization of genes and pro- 
teins involved in Turner syndrome, and investiga- 
tion of sex determination. 
Physical Mapping of the Human 
Y Chromosome 
Complete physical maps, consisting of overlap- 
ping recombinant DNA clones spanning an entire 
genome, constitute powerful tools for exploring the 
organization of an organism's genetic material and 
the information it encodes. With the advent of yeast 
artificial chromosome (YAC) vectors, it has become 
feasible to consider constructing such a physical 
map of the human genome. The Y chromosome is a 
particularly appropriate target for physical mapping 
at this time. First, genetic mapping is impossible 
except in the small pseudoautosomal region, the 
only part of the Y chromosome to undergo meiotic 
recombination. Second, the Y is among the smallest 
of human chromosomes, its euchromatic region 
having an estimated size of 30 Mbp. 
Dr. Page's laboratory constructed an essentially 
complete, low-resolution map of the Y chromosome 
by assembling 196 YAC clones, each containing a 
segment of the human Y chromosome, into a single 
overlapping array. This array encompasses >98% of 
the euchromatic ponion of the chromosome. First, a 
library of large-insert YAC clones was prepared us- 
ing genomic DNA from a human XYYYY male. The 
map was constructed by screening the library to 
identify the clones containing 160 STSs (sequence- 
tagged sites: short stretches of genomic sequence 
detected by polymerase chain reaction [PCR] as- 
says). In all, 207 Y-DNA loci were assigned to 127 
ordered intervals based on their presence or absence 
in the YACs, yielding ordered landmarks at an aver- 
age spacing of 220 kbp across the euchromatic re- 
gion. At present this is the highest resolution map of 
any mammalian chromosome. The map reveals that 
Y-chromosomal genes are scattered among a patch- 
work of X-homologous, Y-specific repetitive, and 
single-copy DNA sequences. This map of overlap- 
ping clones and ordered, densely spaced markers 
should facilitate complete definition of the gene 
content of the Y chromosome. In addition, the 
methods and strategy used to construct this map 
should be widely applicable to other human 
chromosomes. 
Identification of Y-linked genes has historically 
relied on analysis of naturally occurring deletions. 
Such deletion mapping of the Y chromosome is 
practical because individuals with deletions of por- 
tions of the chromosome are viable and occur at a 
reasonable frequency in the population. Such indi- 
viduals include XX males, some XY females, and 
persons in whom chromosome banding has revealed 
translocated, isodicentric, or ring Y chromosomes. 
Because the Y is a haploid chromosome, the pres- 
ence or absence of Y-specific sequences in the DNA 
of these individuals can be assessed directly. 
Having assembled a large battery of Y-DNA 
probes. Dr. Page and his colleagues characterized 
about 1 50 individuals with partial Y chromosomes. 
On the basis of these results, the euchromatic region 
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