Download Genetics of sex determination in man and mouse

Development 102, 251-258 (1988)
Printed in Great Britain © The Company of Biologists Limited 1988
Review Article
251
Genetics of sex determination in man and mouse
P. N. GOODFELLOW1 and S. M. DARLING2
xHuman Molecular Genetics Laboratory, Imperial Cancer Research Fund, Lincoln's Inn Fields, London WC2A 3PX, UK
Mount Sinai Hospital Research Institute, 600 University Avenue, Toronto, Ontario M5C 1X5, Canada
2
The cytological evidence has revealed a visible mechanical basis for the production of males and females in
equal numbers and irrespective of external conditions
(Wilson, 1909).
Introduction
In mammals, the sex of an individual is the result of
an orderly cascade process initiated by genetic controls and propagated by endocrine mechanisms. This
process results in the production of males and females
which differ in reproductive function, anatomy,
physiology and behaviour. Males and females also
differ in sex chromosome constitution: males have a
single X chromosome and a Y chromosome; females
have two X chromosomes. Using DrosophUa species
as a model, it was assumed that sex in mammals
would depend on X-chromosome dosage; however,
with improved techniques for karyotyping, investigation of individuals with abnormal sex chromosome
constitutions refuted this hypothesis. Individuals with
a single X chromosome develop as females (Ford et
al. 1959; Welshons & Russell, 1959); individuals with
a normal Y chromosome develop as males, independent of the presence of supernumerary X chromosomes (Jacobs & Strong, 1959; Cattanach, 1961). It
was concluded that sex in mammals is determined
chromosomally by the presence or absence of the Y
chromosome. In 1930, Fisher proposed two alternative mechanisms for Y-chromosome control of sex:
either all the genes encoding male traits are Y-linked
or the Y chromosome encodes a control gene which
regulates the expression of genes elsewhere in the
genome. All the evidence is consistent with the
second alternative and the current working hypothesis is that a Y-encoded gene induces the development of testes. Subsequent hormone production by
the testes induces the male phenotype (Jost et al.
Key words: sex determination, X chromosome, Y chromosome, TDF, Tdy, genetic map.
1973). As the male phenotype derives from the
presence of the testis, the Y-encoded gene has been
named testis-determining factor (TDF) in man and
testis-determininggene-Ychromosome (Tdy) in mouse.
In the absence of the Y chromosome, ovary-controlling genes induce the production of ovaries (Eicher &
Washburn, 1986) and, in the absence of male hormones, the female phenotype develops (Jost et al.
1973).
Key regulatory genes that are responsible for
choosing between different developmental genetic
programmes have been described in several animals
(e.g. DrosophUa species, Akam, 1987). Identification
of these regulatory genes in mammals has proved
to be more problematic. However, the genes responsible for the choice between male and female
phenotypes must be developmental regulatory genes.
Isolation of these genes will not only answer fundamental questions about the phenomenon of sex but
may also provide a general model for the genetic
control of mammalian development. In this review,
we will explore the genetic mechanisms that underlie
the formation of the two sexes in mouse and man.
This review covers much of the same ground as the
recent Supplement to Development and readers desiring a more detailed treatment should consult that
issue.
Sex determination and sex differentiation
The pivotal event in determining the sex of an
individual is the specialization of the gonads. Once
formed, the gonads control the subsequent sexual
phenotype (Jost et al. 1973). For the purposes of this
review, we will define sex determination as the
process that results in either testis or ovary formation.
The process subsequent to gonad formation we will
define as sex differentiation. Obviously as our knowledge improves it may be possible to define more
precisely the sex determination step prior to the
formation of the specialized gonads.
252
P. N. Goodfellow and S. M. Darling
The process of sex differentiation is well understood at the anatomical and physiological levels. In
males, the development of the testis as an organ is
associated with cellular development of male germ
cells, Sertoli cells and Leydig cells. The Leydig cells
produce testosterone, and high levels of this hormone
induces Wolffian duct development leading to the
formation of the epididymis, vas deferens and seminal vesicles. Testosterone also induces the bipotential
primordia of the external genitalia to develop into
penis shaft, scrotum and glans penis. The Sertoli cells
produce anti-Mullerian hormone (AMH, also known
as Miillerian-inhibiting factor, substance or hormone;
MIF, MIS, MIH) which causes regression of the
Miillerian ducts (Josso et al. 1977).
The formation of ovaries in females is associated
with the development of the female phenotype: the
production of oviducts, uterus and cervix from the
Miillerian duct; regression of the Wolffian duct and
differentiation of the external genital primordia to
produce female genitals.
Surgical removal of the gonads from a fetus results
in the subsequent formation of female internal and
external genitalia, implying that the fetal ovaries are
not directly required for differentiation of the female
phenotype (Jost et al. 1973).
The description of sex differentiation outlined
above has been deduced largely from experiments
designed to change the hormonal status of the fetus
and the conclusions have been confirmed by analysis
of individuals in whom gonadal and phenotypic sex
have been dissociated by genetic mutation. A particularly illustrative mutation is testicular feminization
(Tfm) which has been described in mouse, rat and
man (Ohno, 1979). In the afflicted individual, testis
formation and secretion of androgens and AMF is
normal; however, the external phenotypic appearance is female with normal female external genitalia.
The defect is due to a deficiency of androgen receptors in the target tissues (Attardi & Ohno, 1974;
Migeon etal. 1981). Thus, differentiation proceeds as
if testosterone is absent, with regression of the
Wolffian duct and normal development of female
external genitalia. The AMH secreted by the testes
causes Miillerian duct regression so that internal
female genitalia fail to develop. Similarly, several
other mutations interfering with androgen metabolism cause dissociation between male sex determination and subsequent differentiation (Polani,
I981a,b; Lyon etal. 1981). The detailed knowledge of
the morphology and endocrinology of sexual differentiation makes this an ideal model system for
studying control of organ formation at the cellular
and molecular level.
Compared with sex differentiation, information
about the biochemical basis of sex determination is
rudimentary. Nevertheless, genetic analysis of individuals with abnormal sex determination and the
application of techniques of molecular biology have
provided a starting point for understanding sex determination in mammals.
The biology of the Y chromosome
The mammalian Y chromosome is composed of two
separate regions with distinct functions; both regions
are essential for the Y chromosome's role in sex
determination (Darlington, 1937). The first region is
shared with the X chromosome and is responsible for
pairing between the morphologically dissimilar X and
Y chromosomes in male meiosis. It is assumed that
pairing is essential for the correct meiotic segregation
of sex chromosomes which forms the basis for
chromosomal determination of sex. Maintenance of
sequence homology is achieved by recombination
within the shared region (Bengtsson & Goodfellow,
1987). Sequences and genes that exchange between
the sex chromosomes fail to show classical 'sex
linkage' and this type of inheritance has been termed
pseudoautosomal (Burgoyne, 1982). The region
shared by the sex chromosomes is frequently referred
to as the pseudoautosomal region (PAR). In man, the
PAR is at the ends of the X- and Y-chromosome short
arms (Pearson & Bobrow, 1970; Chen & Falek,
1971); in mouse, the PAR is assumed to be at the end
of the apparently single arm of the X and Y chromosomes. The second region on the Y chromosome
encodes genes that must not recombine with the X
chromosome. The paradigms for this behaviour are
TDF and Tdy; if these sex-determining genes were to
become X-linked the chromosomal basis of sex determination in man and mouse would break down.
Genetic definition of TDF in man
Several individuals have been found who have visible
deletions- and translocations of the Y chromosome
(Buhler, 1980; Davis, 1981; Goodfellow et at. 1985a).
Correlation of sexual phenotype with these Ychromosome structural abnormalities suggested that
TDF was located in the region around the centromere. These studies were hampered by the small size
of the Y chromosome which made it difficult to define
the limits of deletions and translocations. A second
problem was the frequent occurrence of mosaicism
and chimaerism which can result in a different karyotype in the tissue tested, usually blood or skin,
compared with the gonad.
More precise definition of the chromosomal
location of TDF has been made possible by the
construction of detailed maps of the human Y
Genetics of sex determination
chromosome. Although the Y chromosome is about
one third the size of the X chromosome, it is
remarkable in being almost completely devoid of
genes. Whereas over 100 genes have been mapped to
the X chromosome, only four or five genes are known
to be encoded by the Y chromosome and one of these
is pseudoautosomal (Goodfellow et al. 1985b). This
paucity of genetic markers inhibited the construction
of genetic maps until the introduction of molecular
techniques allowed the isolation of DNA sequences,
which provided an unlimited supply of markers
(reviewed in Goodfellow etal. 1985a).
Three types of genetic map have been constructed
and all three have contributed to the definition of
TDF. The first map is a meiotic map of the PAR. In
each male meiosis, a single obligate recombination
occurs within the PAR and the telomeric sequence
DXYS14 (Cooke et al. 1985) shows 50 % recombination between the sex chromosomes (Rouyer et al.
1986). MIC2, a pseudoautosomal gene, recombines
between the X and Y chromosomes with a frequency
of 2% (Goodfellow et al. 1986). Between these
extremes other markers show intermediate recombination rates. Recombination in the PAR of man has
several features of unique biological interest.
(1) The PAR has been estimated to be less than
5xl0 6 bp in size (Mondello et al. 1987; Rouyer et al.
1986); this means that the 50 % recombination in this
region seen in male meiosis, occurs at a rate ten times
higher than the genome average.
(2) Double recombinants have not been found in the
PAR (Rouyer et al. 1986; Goodfellow et al. 1986).
One explanation is that interference is a function of
physical size and not of recombination fraction.
(3) Recombination in female meiosis in the PAR is
only 4 - 5 % , approximately tenfold lower than in
male meiosis (Rouyer et al. 1986; Goodfellow et al.
1986).
The second type of map is a deletion map based on
the sequences present in the genomes of XX males.
About 1 in 20000 new-born males has a female
karyotype with two X chromosomes (de la Chapelle,
1981). The majority of XX males have a normal
phenotype, with the exception of the testes which are
small; all XX males are sterile. In 1960, FergusonSmith and colleagues suggested that XX males might
be caused by the inheritance of undetected Ychromosome sequences (Ferguson-Smith etal. 1960);
this hypothesis was expanded by the proposal that an
abnormal meiotic exchange between the X and Y
chromosomes could lead to the formation of XX
males (Ferguson-Smith, 1966). This suggestion has
proved to be correct. About 80 % of XX males have
inherited Y-derived sequences (Guellaen et al. 1984;
Page, 1986; Pritchard, 1987) and these sequences are
found at the tip of the X-chromosome short arm,
253
consistent with an XX interchange model (Andersson
et al. 1986; Buckle et al. 1987). The amount of Yderived sequences transferred in different XX males
is variable and this has allowed the construction of a
deletion map of the Y chromosome (Vergnaud et al.
1986; Page, 1986). From this map, TDF has been
placed in the distal region of the Y-specific part of the
short arm, adjacent to the pseudoautosomal region.
This implies that the pseudoautosomal gene MIC2 is a
flanking marker for TDF, as is DXYS5, the mostdistal Y-specific marker described by Vergnaud et al.
(1986).
The region between MIC2 and DXYS5 on the Y
chromosome contains all of the genetic information
required for male sex determination. Indirect estimates and preliminary physical mapping by longrange restriction enzyme analysis both suggest that
this region is not bigger than a few million basepairs
(G. Rappold, personal communication). Any theory
for the mode of action of TDF that requires multiple
copies of the gene (Ohno, 1967; Chandra, 1985) must
be constrained by these observations.
The third map is a physical map utilizing long-range
restriction mapping and pulsed field gel electrophoresis. Using DNA probes for MIC2 and DNA probes
for several Y-specific sequences, we have constructed
a map which spans the boundary between the PAR
and the Y-specific regions of the Y chromosome
(Pritchard et al. 1987). From this map, we have
identified sequence motifs, known as HTF islands
(Bird, 1986), which are frequently associated with the
promoter regions of genes; one HTF island is Yspecific and lies close to the PAR boundary. This
HTF island may define TDF. However, it should be
stressed that not all genes are marked by the association with an HTF island (Bird, 1986) and TDF may
fall into this class.
Alternative candidate genes for the defined HTF
island might include genes associated with Turner's
syndrome. This syndrome is found in females with a
single X chromosome and consists of streak gonads,
due to premature loss of oocytes, and a variety of
physical stigmata, including short stature (Turner,
1938). Sex-reversed females with an XY karyotype
occur with a frequency of about 1 in 100 000 new-born
females (Polani, 1981a). These females also have
streak gonads and occasionally have other components of Turner's syndrome. The X-Y interchange
model can be invoked to explain the generation of
XY females since the reciprocal product of an abnormal X-Y recombination event would consist of a Y
chromosome deleted for Y sequences including TDF
and containing X-chromosomal sequences. Deletion
of Y-specific sequences has been found in several XY
females (Disteche etal. 1986; Mulleref al. 1986; Page,
1986). Two explanations are possible for the variable
254
P. N. Goodfellow and S. M. Darling
expression of the nongonadal components of Turner's
syndrome in XY females. The Y chromosome and/or
pseudoautosomal region could encode genes the
deletion of which results in Turner's syndrome
(Rosenfeld et al. 1979); in this case, the HTF island
we have identified may indicate the presence of these
genes. Alternatively, the variable amount of X sequences transferred to the deleted Y chromosome
may encode the Turner's syndrome genes.
Genetic definition of Tdy in mouse
Analysis of sex-reversed syndromes in mice has led to
the localization of Tdy. In 1971, Cattanach et al.
described a dominant mutation that causes sex reversal of female mice (Cattanach et al. 1971). Males
carrying this mutation, called sex reversed (Sxr),
produce four different types of offpsring when mated
to normal females; normal XX females, normal XY
males, Xtr-carrier XY males and sterile Sxr XX
individuals with a male phenotype (XX Sxr males).
Sxr was postulated to be either a constitutive mutation of an autosomal sex-determining gene that is
normally under Y control, or the transposition of a
strongly sex-determining Y region to an autosome.
Evidence to support either of these hypotheses was
lacking since attempts to map Sxr cytologically and by
linkage studies had failed (Cattanach et al. 1971;
Cattanach, 1975; Winsor et al. 1978; Chandley &
Fletcher, 1980; Evans et al. 1980). Discovery of the
chromosomal localization of Sxr came from an unexpected source. Singh et al. (1980) isolated a femalespecific satellite DNA sequence from the banded
krait snake (Bkm, banded fcrait minor satellite). In
these snakes, females are the heterogametic sex and
males the homogametic sex. Using the Bkm DNA
probe in Southern blot analysis of mouse DNAs, a
hybridizing fragment was observed that was specific
to male DNA. XX Sxr male DNA when analysed
with the same probe showed the male-specific pattern. In addition, Singh & Jones (1982) were able to
demonstrate by in situ hybridization to mouse
chromosomes that there is a concentration of Bkmrelated sequences on the normal mouse Y chromosome at its centromere. XX Sxr males had a concentration of Bkm-related sequences localized at the
distal end of a large chromosome which they identified as probably being the X chromosome. Singh &
Jones (1982) went on to propose that the Sxr mutation
results from this transposition of a fragment of the Y
chromosome containing Tdy and a concentration of
Bkm-related sequences onto another chromosome,
most probably the X. Burgoyne (1982), Eicher (1982)
and Hansmann (1982) have proposed a model to
explain the location and transmission of Sxr. The
consensus suggestion is that an extra copy of the Y-
linked Tdy is present on the distal tip of the Y
chromosome in the XY Sxr carrier male. The distal
tip area of the Y chromosome is proposed to be the
pseudoautosomal region and both the gene STS
(Keitges et al. 1985) and a viral integration site
(Habers et al. 1986) are known to be inherited
pseudoautosomally in mice. During male meiosis, the
duplicated Sxr fragment is transferred onto the X
chromosome by an obligate pseudoautosomal recombination event, inheritance of this X chromosome
results in XX Sxr males. Cytological confirmation of
the presence of the Sxr fragment at the distal end of
the Y chromosome in XY Sxr carriers and at the distal
end of one X chromosome in XX Sxr males was
shown by Evans et al. (1982).
It has been suggested that Bkm sequences may be
directly related to sex determination either by encoding a gene product (Jones, 1983; Epplen et al.
1982) or by binding an autosomal repressor of the
male phenotype (Chandra, 1985). This type of hypothesis is very difficult to refute, however; the
distribution of Bkm sequences throughout the mouse
genome (Kiel-Metzger & Erickson, 1984) and the
absence of a marked concentration of Bkm sequences
on the Y chromosome in other species (Kiel-Metzger
et al. 1985; and unpublished observations) are not
entirely consistent with the hypothesis.
Cytological investigation suggests that Sxr is about
5 x 106 bp in size and this must define the limits of Tdy.
Recently, Sxr', a derivative of Sxr, has been found
which has lost genetic information required for both
H-Y antigen expression (McLaren et al. 1984) and
early spermatogenesis (Burgoyne et al. 1986). The
precise size of Sxr' is not known. The failure of Sxr'
to express H-Y antigen and similar failure of human
XX males to express H-Y antigens (Simpson et al.
1987) argues strongly that the H-Y antigen is not
directly involved in sex determination.
Autosomal and X-linked genes involved in sex
determination
It is part of the paradigm we are following that TDF
and Tdy interact with other genes to induce the
production of testes. Mutations in the 'responder'
genes could therefore result in abnormal sex determination. Evidence for 'responder ' gene mutations has
been obtained in man, mouse and several other
species. However, it should be stressed that a loss-offunction mutation in a 'responder' gene would have
the same phenotype as a gain-of-function mutation
making the production of ovaries dominant to the
production of testes.
20 % of XX males have no detectable Y-derived
sequences. Three explanations for these males can be
proposed (de la Chapelle, 1987).
Genetics of sex determination
(1) Mosaicism such that the gonads have a different
genetic constitution to the tested tissues.
(2) Inheritance of Y-derived sequences for which
DNA probes are not available.
(3) Mutation in 'responded genes.
Several XX males have been described in which no
Y-derived sequences have been found and the proximal pseudoautosomal region, inherited from the
father, has been derived from the X chromosome
(Petit et al. 1987). These males cannot have been
derived by an X-Y interchange and one explanation
is a loss of function mutation in a responder gene(s).
Similarly, clustering of XX males in families may
imply mutation in non-Y-linked genes (de la Chapelle, 1987). However, a proportion of these familial
XX males are known to be due to X-Y interchange
(Page etal. 1985).
There are several examples in the mouse of autosomal loci disrupting normal male development in
XY individuals. When transferring the Y chromosome from Mus domesticus poschiavinus, to the
genome of the C57BL/6J inbred strain, Eicher et al.
(1982) noticed there was a breakdown of the normal
testis-determination mechanism resulting in partial or
complete sex reversal of XY individuals. Similar XY
females have been noted when crossing Y chromosomes from other Mus domesticus strains onto the
C57BL/6J background (reviewed in Eicher & Washburn, 1986).
These findings have led Eicher and her colleagues
to postulate that the C57BL/6J strain contains an
autosomal sequence which does not interact correctly
with the Tdy locus or its product encoded by the Y
chromosome from M. domesticus. This implies that
Tdy is different on the two Y chromosomes and that
C57BL/6J carries an allele different from that of M.
domesticus at an autosomal locus involved in testis
determination. This locus, designated Tda-1, probably resides on either chromosome 2 or 4 (Eicher &
Washburn, 1986).
Another autosomal sex determination locus known
as T-associated sex reversal (Tas) is on chromosome
17 located within the hairpin-tail deletion (Washburn
& Eicher, 1983). The Tas mutation causes sex reversal
in XY mice on the C57BL/6J background but not
when crossed onto a C3H/HEJ background. Again
ovaries and ovotestes are found in the XY individuals. Washburn & Eicher (1983) and Eicher &
Washburn (1986) have proposed that the Tas locus
could function as the ovary-determining gene.
Ovarian development would be initiated by the
normal allele in the XX mouse but this allele would
be inactive in XY individuals when Tdy initiates testis
formation. If Tas is active in XY individuals before or
simultaneously with Tdy then ovaries or ovotestes
would develop. Alternatively, Tas could be defined
255
by loss-of-function mutations which fail to respond to
Tdy. In both cases, Tdy function would be dominant
to Tas function in normal sex determination.
The Polled mutation in goats is an autosomal
recessive and produces the male phenotype in karyotypically XX individuals (Hamerton et al. 1969). This
puzzling mutation could be a weak constitutive mutant in a responder gene.
The wood lemming (Myopus schisticolor) has a very
complex sex-determining system (Schempp et al.
1985). In addition to the usual X and Y chromosomes, a modified X chromosome, X*, is also found.
X* can be karyotypically distinguished from the
normal X chromosome by G banding. Remarkably,
X*Y animals are fertile females, implying that a
'responder' gene on the X chromosome is needed for
testis formation and that this gene is mutated to a
nonresponsive form on the X* chromosome.
Although the results are reminiscent of rare human
pedigrees in which sex reversal of XY individuals
appears to be inherited as an X-linked trait (Simpson
et al. 1981), the gross chromosomal differences between X and X* makes it unwise to draw a simple
conclusion about sex determination based on the
wood lemmings.
Mode of action of testis-determining genes
The biochemical products of TDF and Tdy have not
been defined; nevertheless, it is possible to pose the
question of where these genes are expressed.
The gonads of both sexes are derived from two
distinct tissues: somatic mesenchymal tissues which
form the matrix of the gonad and primordial germ
cells which migrate into and colonize the matrix. The
germ cells eventually form the gametes. Two mutations in the mouse, Steel and White spotting, cause
the number of germ cells colonizing the genital ridges
to be reduced to a very low number without affecting
formation of the gonad in either sex (McLaren, 1985).
In addition, XY germ cells can undergo oogenesis
and XO germ cells can reach the early stages of
spermatogenesis (the presence of a second X chromosome inhibits spermatogenesis in both XX and XXY
animals). These results suggest that germ cells are
irrelevant for sex determination and that germ cells
themselves respond to environmental signals
(McLaren, 1985).
Recent experiments suggest that the Sertoli cell
may be the site of action of the testis-determining
genes. In XX-XY chimaeric mice, where both XX
and XY cells are found in a gonad, it is uncommon to
find an ovotestis with separate ovarian and testicular
regions (McLaren, 1985). Testicular development in
chimaeras is usually found in the adults that have
25-30 % or more XY cells and ovarian development
256
P. N. Goodfellow and S. M. Darling
in those with 15-20 % or less XY cells. Ovotestes are
associated with the intermediate range. These results
could be explained by the XY cells producing a
diffusible inducing factor causing both somatic and
germ cells to undergo testicular differentiation. Burgoyne et al. (1986) have proposed an alternative
interpretation. In a series of transplantation experiments, juxtaposition of male and female fetal gonads
failed to induce male development in the female
gonads, although profound oocyte loss was noted. To
explain the apparently contradictory results from
chimaeras and transplantation, it was suggested that a
diffusible substance produced by the male gonads
inhibits the development of ovaries. A good candidate
for this factor is AMH which has recently been found
to induce atrophy of oocytes (Vigier et al. 1987). As
Sertoli cells produce AMH and are present at the
earliest stages of testis formation, it was proposed
that these cells are the site of action of Tdy. This
hypothesis was tested by reinvestigating the gonads of
XX-XY chimaeras (P. Burgoyne, personal communication). It was found that Sertoli cells always
had an XY chromosomal constitution, but the germ
cells and Leydig cells in fetal testes could be either
XX or XY. Sertoli cells never had an XX chromosomal contribution. This result suggests that a cell
must have a Y chromosome to be a Sertoli cell in a
developing gonad. The simplest but not the only
explanation is that Tdy acts in a cell autonomous
manner to produce Sertoli cells.
Conclusions
The Y chromosome is intimately associated with male
sex determination in mammals. Although the biochemical basis of sex determination is not clear the
precise chromosomal localization of TDFand Tdy can
be used as the starting point for cloning these genes
by reverse genetic methods (see Development 101
Supplement). Once these have been cloned and
probes are available, it should be possible to provide
answers to questions about the mechanisms of sex
determination and this may provide a model for the
genetic regulation of other developmental processes.
Armed with molecular probes, it will also be possible
to test the clear predictions derived from the cellular
investigations of sex determination.
We thank our friends who read this manuscript at short
notice and we are grateful for the tolerance of C. C. Wylie
as editor of Development. We would also like to thank P.
Burgoyne and G. Rappold for permission to quote unpublished observations and C. Middlemiss for editorial assistance.
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