Download Genes on the X and Y chromosomes controlling sex

28 Berry CM, Thompson JD, Hatcher R. The radio receptor assay for hCG in ectopic pregnancy.
Obstet Gynecol 1979;54:43-6.
29 Schwartz RO, De Pietro DL. Beta-hCG as a diagnostic aid for suspected ectopic pregnancy. Obstet
Gynecol 1980;56:197-9.
30 Phipps JJ, Naftalin NJ. Ectopic pregnancy diagnosed by measurement of hCG but not laparotomy.
Lancet 1986;i:552.
31 Pittaway DE, Reish RL, Wentz AD. Doubling times of hCG increase in early viable pregnancies.
AmJ Obstet Gynecol 1985;152:299-303.
32 Kadar N, De Vore G, Romero R. Discriminatory hCG zone: its use in the sonographic evaluation
for ectopic pregnancy. Obstet Gynecol 1981;58:156-61.
33 Stenman UH, Alfthan H, Myllyness L, Seppala M. Ultrarapid and sensitive time resolved
fluoroimmunometric assay for hCG. Lancet 1983;ii:647-9.
34 Milwidsky A, Segar S, Menasbe M, Adori A, Palti A. Corpus luteum in ectopic pregnancy. Ints7
Fertil 1984;29:244-7.
35 Radwanska E, Frankenberg J, Allen El. Plasma progesterone levels in normal and abnormal early
human pregnancy. Fertil Steril 1978;30:398-402.
36 Mathews CP, Goulson PB, Wild RA. Serum progesterone levels as an aid to the diagnosis of ectopic
pregnancy. Obstet Gynecol 1986;68:390-4.
37 Romero R, Copel NA, Kadar N, Jeauty P, Decherney A, Hobbins JC. Value of culdocentesis in the
diagnosis of ectopic pregnancy. Obstet Gynecol 1985;65:519-22.
38 Weckstein LN, Boucher AR, Tucker H, Gibson D, Rettenmaier MA. Accurate diagnosis of early
ectopic pregnancy. Obstet Gynecol 1985;65:393-7.
39 Reece EA, Petrie RH, Sirmans MF, Finster M, Todd WD. Combined intrauterine and
extrauterine gestations: review. Am 7 Obstet Gynecol 1983;146:323-30.
40 Spirt BA, O'Hara KR, Gordon L. Pseudo-gestational sac in ectopic pregnancy: sonographic and
pathologic correlation. 7ournal of Clinical Ultrasound 1981;9:338-43.
41 Robinson HP, de Crespigny LC. Ectopic pregnancy. Clin Obstet Gynecol 1983;1O:407-12.
42 Webster HD Jr, Barclay DL, Fischer CK. Ectopic pregnancy: a seventeen year review. AmJ7 Obstet
Gynecol 1965;92:23-34.
43 Mahony BS, Filly RA, Nyberg DA, Callen PW. Sonographic evaluation of ectopic pregnancy.
J Ultrasound Med 1985;4:221-9.
44 Gleicher N, Giglia RV, Deppe G, Elrad H, Friberg J. Direct diagnosis of unruptured ectopic
pregnancy by real-time ultrasonography. Obstet Gynecol 1983;61:425-8.
45 Kim DS, Chung SR, Park MI, Yim YP. Comparative review of diagnostic accuracy in tubal
pregnancy: a 14 year survey of 1040 cases. Obstet Gynecol 1987;70:547-54.
46 Gonzalez FA, Waxman M. Ectopic pregnancy. Diagnostic Gynecology and Obstetrics 1981;3:101-9.
Genes on the X and Y chromosomes controlling sex
Genetic sex is a matter of quantity
The way in which differentiated tissues arise from pluripotent
cells in the embryo remains mysterious. Gene regulation is the
key, of course, and much is being learnt about, for example,
the control of transcription by DNA binding proteins.' The
sex difference is an example of differentiation that might be
expected to yield answers if only because many species,
including man, have heteromorphic sex chromosomes that
segregate to offspring in a predictable fashion. But the
segregation is not quite predictable: in our own species there
are exceptions to the X-Y sex determining system, and these
interesting exceptions are now providing answers to questions
about the initiation of mammalian sex differentiation.
To understand the importance of these findings we must go
back to the late 1950s, when it was confirmed that males had a
46, XY and females a 46, XX karyotype. In both mouse and
man XO was found to be female and XXY to be male,
indicating the dominant role of the Y chromosome in the
differentiation of the testis.23 This was a surprise to some
because in Drosophila melanogaster and some other invertebrates sex was known to be determined by the ratio of X
chromosomes to autosomes-thus XOs were male and XXYs
female.4
Study of correlations between karyotypes and phenotypes
in chromosomal variants of Klinefelter's and Turner's
syndromes soon showed that the testis determining factors,
as they were called, were located in the short arm of the
Y chromosome5; those without this segment in at least
some cells were invariably female. Somatic cell mosaics
with XX/XXY and XO/XY sex chromosome complements
and XX/XY chimaeras were sometimes intersexes, with both
testes and ovaries showing varying degrees of dysgenesis.
The most extreme examples of sex reversal were males
with Klinefelter's syndrome and an apparently XX female
karyotype6 and females with gonadal dysgenesis and an
apparently XY male karyotype.7 The "XX males" and "XY
females" were predicted to have gained or lost the testis
determining segment as a result of accidental recombination
between the differential segments ofthe X and Y chromosomes
during male meiosis.8
The first clue in favour of such abnormal X-Y interchange
was the observation that several XX males had lost the father's
Xg blood group allele in the process.8 Later it was shown that
one X chromosome was a little longer than the other9 and that
the tip of the short arm of the Y could sometimes be seen at the
end of one of the X chromosomes.'0 Conclusive proof came
from DNA probing, which showed that many XX males not
only had specific sequences from the short arm of the Y" in
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the distal end of the short arm of the X'2 but also had lost X
sequences.'3 Conversely, a smaller proportion of XY females
could be shown to have lost short arm sequences of the Y
chromosome. 14 It became clear that XX males and XY females
held the key to sex differentiation. The goal was to clone the
gene for testis determination from the DNA of XX males with
X-Y interchange.
It is now almost certain that this goal has been achieved.
Page et al reported last December the details of a likely
candidate for the testis determining gene.'5 This was cloned
from an XX male and was found to be missing from a female
who had a reciprocal translocation between the short arm of
the Y chromosome and chromosome 22 that was associated
with the loss of a tiny segment (160 kilobases) of the short
arm of the Y chromosome. The gene codes for a protein that
contains a series of zinc fingers, a motif characteristic of
proteins that bind DNA, which are thought to participate
in regulating transcription. Its action on the pathway to
differentiation of the testis is unknown, but it might well be
the primary sex determining signal.
A key observation in the important paper by Page et al is
that in addition to the Y linked gene there is apparently a copy
of the testis determining gene carried by the short arm of the
X chromosome. This copy is distinguishable by restriction
mapping and is located more proximally, where it might be
expected to be subject to X inactivation. Given that the X
homologue codes for the same protein as the Y homologue,
female somatic cells (whether XX, XO, or XXX, and so on)
have only one active copy of the gene compared with male
cells (whether XY, XXY, XXXY, or XYY), which have at
least two. XX males usually have two doses because the Y
homologue is transferred to part of the X chromosome that
escapes inactivation.
The implication of these findings is that our species now
falls into line with other species, including Drosophila
melanogaster, in which the primary sex determining system
depends on active gene dosage. In fact all mammalian species
tested are consistent with the dosage system, and even in birds
(which have nothing comparable with X inactivation) it seems
likely that the ZZ male has a double dose of the testis
determining gene compared with the ZW female. It follows
that the description testis determining gene is misleading as
the same gene leads to ovarian differentiation if present in a
single dose. As suggested by German, it would be better to
refer to the X and Y homologues as gonad differentiating
genes and the loci as GDX and GDY, respectively.'6
Several groups of patients remain in whom unusual gonadal
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differentiation requires a more complex explanation. Failure
of testis differentiation in XY females may result not only
from deletion of the GDY locus because of X-Y interchange.
Deletion of the GDX locus would have the same effect and
may even be responsible for familial cases inherited in an X
linked recessive manner, provided that XX carriers of GDX
deletions were fertile. Alternatively, other gene mutations
affecting later stages in the pathway to testis differentiation
may be involved.
The defect in XX true hermaphroditism and in XX males
without the GDY locus is even more intriguing. XX true
hermaphrodites have both ovarian and testicular tissue
(usually ovotestes) associated with ambiguity of the external
and internal genitalia.' The phenotype is identical to spontaneous human XX/XY chimaeras and to artificial XX/XY
aggregation chimaeras in mice, but neither the GDY locus nor
any other Y specific sequence can be detected.'" Similarly, in
XX males without the GDY locus other Y specific sequences
are almost invariably absent. These patients are phenotypically
rather different from X-Y interchange males-principally
because they often have hypospadias-and they probably
belong to the same range of abnormal gonadal differentiation
as XX hermaphrodites.
It might be that in both these XX cases the dosage of gonad
differentiating factors is disturbed by an inversion or other
mutation on the short arm of one X chromosome such that
one GDX locus escapes from X inactivation. Random X
inactivation of the two X chromosomes will then lead to
somatic cell mosaicism for cells with two active doses of GDX
and cells with only one active dose. This is identical to XX/XY
chimaerism, in which some cells are testis determining and
others are ovary determining. Again familial cases with
siblings affected either by XX true herniaphroditism or XX
Klinefelter's syndrome (or both)'7 may all be explained by the
X chromosome with the activated GDX locus sometimes
being transmitted as an X linked dominant trait (with variable
penetrance) by unaffected fertile XX mothers or XY fathers.
The techniques of molecular genetics are powerful, and we
may confidently expect tests of these hypotheses in experimental animals. For example, the sex reversal of female
embryos by adding additional copies of the GDX gene during
early development would provide confirmation. But the
important message at the moment is that a DNA binding
protein will probably shortly be characterised whose primary
function is to determine quantitatively the direction a group
of cells will take along the pathway to tissue differentiation.
M A FERGUSON-SMITH
Professor of Pathology,
University of Cambridge,
Cambridge CB2 IQP
1 Evans RM, Hollenberg SM. Zinc fingers: gilt by association. Cell 1988;52: 1-3.
2 Welshons WJ, Russell LB. The Y chromosome as the bearer of male determining factors in the
mouse. Proc Natl Acad Sci U,SA 1959;45:560-6.
3 Jacobs PA, Strong JA. A case of human intersexuality having a possible XXY sex determining
mechanism. Nature 1959;183:302-3.
4 Baker BS, Belote JM. Sex determination and dosage compensation in Drosophila melanogaster.
Ann Rev Genet 1983;17:345-93.
5 Jacobs PA, Ross A. Structural abnormalities of the Y chromosome in man. Nature 1966;210:352-4.
6 de la Chapelle A, Hortling H, Niemi M, Wennstrom J. XX sex chromosomes in a human male: first
case. Acta Med Scand [Suppl] 1964;412:25-38.
7 Ferguson-Smith MA. Karyotype-phenotype correlations in gonadal dysgenesis and their bearing
on the pathogenesis of malformations. J Med Genet 1965;2:93-156.
8 Ferguson-Smith MA. X-Y chromosomal interchange in the aetiology of true hermaphroditism and
of XX Klinefelter's syndrome. Lancet 1966;ii:475-6.
9 Madan K. Chromosome measurements on an XXp+ male. Hum Genet 1976;32:141-2.
10 Magenis RE, Webb MJ, McKean RS, et al. Translocation (X; Y) (p22.23:pl 1.2) in XX males:
etiology of male phenotype. Hum Genet 1982;62:271-6.
11 Guellaen G, Casanova M, Bishop C, Geldwerth D, Andre E, Fellous M, Weissenbach J. Human
XX males with Y single-copy DNA fragments. Nature 1984;307:172-3.
12 Magenis RE, Casanova M, Fellous M, Olson S, Sheehy R. Further cytologic evidence for Xp-Yp
translocation in XX males using in situ hybridisation with Y-derived probe. Hum Genet
1987;75:228-33.
13 Petit C, de la Chapelle A, Levilliers J, Castillo S, Noel B, Weissenbach J. An abnormal terminal
X-Y interchange accounts for most but not all cases of human XX maleness. Cell 1987;49:595602.
14 Disteche CM, Casanova M, Saal H, et al. Small deletions of the short arm of the Y chromosome in
46XY females. Proc Natl Acad Sci USA 1986;83:7841-4.
15 Page DC, Mosher R, Simpson EM, et al. The sex determining region of the human Y chromosome
encodes a finger protein. Cell 1987;51: 1091-104.
16 German J. Gonadal dimorphism explained as a dosage effect of a locus on the sex chromosomes, the
gonad-differentiation locus (GDL). AmJ3 Hum Genet 1988;42:414-21.
17 Skordis NA, Stetka DG, MacGillivray MH, Greenfield SP. Familial 46, XX males coexisting with
familial 46, XX true hermaphrodites in same pedigree. J7 Pediatr 1987;110:244-8.
Sickness absence: the doctor's role
Mostly concerned with serious illness
Sickness absence, or more accurately absence from work
attributed to incapacity, is expensive for the country and for
employers. Its cost must be measured not only in social
security payments but also in the loss of productivity and the
inefficiencies of employing extra staff or organising overtime
to cover for missing staff. Government statistics do not record
sickness absence as such, but in the United Kingdom before
1983 some 375 million days of sickness and invalidity benefit
were paid annually because of certified incapacity for work.'
This figure includes payments to the unemployed sick who
would not necessarily be in work if they were fit and excludes
married women who opt out of the state insurance scheme,
special occupational groups such as non-industrial civil
servants, and absences lasting less than four days (which did
not qualify for benefit). More recent data also exclude
payments under the statutory sick pay scheme and are
therefore less relevant.
The epidemiology of sickness absence is complicated by the
variety of indices used to measure it. Two important features
do, however, emerge clearly. Firstly, the demographic
pattern of short term absences differs from that of longer
absences. As might be expected, long term absence tends to
636
be a problem of older employees; short absences occur more
often in the young, especially in women.2 Thus any analysis
should examine not only the total time lost from work but also
the numbers and lengths of spells which make up the total.
Secondly, ill health is only one of many factors that determine
whether an employee takes sick leave. Other influences
include working conditions, the size and structure of the
employing organisation, the arrangements for sick pay, and
personal characteristics such as age, sex, personality, and
family responsibilities.3 There are appreciable regional differences in the rates of sickness absence, with the highest
frequencies in the north and west. This variation is apparent
even within geographically homogeneous industries such as
the Post Office3 and may result from cultural differences as
well as from differences in morbidity.
One implication of these observations is that the control of
short term sickness is primarily a problem for the manager.
Employees who go off sick do not divide neatly into the
genuinely ill who are deserving of sympathy and the
malingerers who can be uncovered by careful medical
examination. When patients suffer from chronic disorders
such as asthma or colitis they may be expected to need more
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