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J Appl Physiol
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Genome and Hormones: Gender Differences in Physiology
Invited Review: Sex-based differences in gene expression
HARRY OSTRER
Human Genetics Program, Department of Pediatrics, New York
University School of Medicine, New York, New York 10016
Y-linked genes; X-linked genes; sex determination; sex-limited gene
expression
were rediscovered, they
were applied rapidly to the study of human traits (8, 9,
35, 56). Within a short time, it became apparent that a
number of traits, although seemingly genetic, represented deviations from Mendel’s rules. The first deviation from Mendelism, sex-linked inheritance, sought
to explain why men and women were phenotypically
different and why some traits were manifested more
commonly in one sex. E. B. Wilson and Nettie Stevens
observed differences in the chromosomal constitution
of males and females in certain species. This led to the
chromosomal theory of sex determination and sexbased differences (63). Sex-linked inheritance was
found to be applicable in humans for hemophilia and
color blindness and subsequently for other traits (4).
With the advent of molecular genetics in the latter
20th century and more recently the sequencing of the
whole human genome, many X-linked and Y-linked
genes have been identified that can account for some of
the phenotypic variability.
Genetic studies of sex-based differences were complemented by work in developmental biology and endocrinology. The pioneer in this field was Alfred Jost, who
conducted a series of experiments that provided the
framework for how the reproductive apparatus of males
WHEN MENDEL’S LAWS OF HEREDITY
Address for reprint requests and other correspondence: H. Ostrer,
Human Genetics Program, Dept. of Pediatrics, NYU School of Medicine, 550 First Ave., MSB 136, New York, NY 10016 (E-mail:
[email protected]).
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develop in response to hormonal signals transmitted by
the testes and how the absence of such signals leads to
the development of the reproductive tract of females (23).
In the 1950s, the fields of genetics and developmental
biology coalesced and led to the identification of individuals with genetic sex reversal, that is, people with a
phenotype of one sex and a chromosomal constitution of
the other. The study of such individuals, whether as
sporadic or familial cases, was invaluable for gaining
insight into the genetic pathways involved in sex determination (41). The study of such individuals could also
prove to be invaluable for understanding how hormones,
sex-linked genes, and sex-specific developmental pathways could account for other phenotypic differences between males and females. Here, I review the molecular
genetics of sex chromosomes and differences in gene
expression between males and females, some of which
are known to affect sexual differentiation, with the goal of
creating a conceptual framework for how the genetic
basis of phenotypic differences between males and females might be approached.
MOLECULAR GENETICS OF SEX CHROMOSOMES
Several features emerged from the original work
with sex-linked transmission (36). Males have an XY
chromosomal constitution, whereas females have an
XX chromosomal constitution. As a result, the sex of
the individual demonstrates a paternal origin effect.
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Ostrer, Harry Invited Review: Sex-based differences in gene expression. J Appl Physiol 91: 2384–2388, 2001.—Certain diseases are more
prevalent among women than men. The reasons for this increased
prevalence are unknown, but there could be a genetic basis. Increased
expression of X-linked genes in females, protective effects of Y-linked
genes in males, or sex-limited gene expression that is developmentally or
hormonally regulated could all account for these differences. Analysis of
individuals with and without genetic sex reversal provides a means for
distinguishing between genetic and hormonal causes. This can be complemented by genetic linkage and gene expression profiling to aid in the
identification of candidate genes.
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INVITED REVIEW
J Appl Physiol • VOL
somes (54). With the use of deletion mapping techniques, functional significance has been ascribed to
some of these genes, including those for stature, suppression of gonadoblastoma, and prevention of the
Turner syndrome phenotype (39, 40, 57). Differences in
histocompatibility can also be ascribed to Y-linked
genes. The SMCY gene encodes the HY antigen, which
is ubiquitously expressed in male tissues, as early as
two-cell embryos (1). HY is a minor histocompatibility
antigen that can promote immunologically mediated
rejection of male tissues transplanted into female mice
(14). SMCY has an X-linked ortholog from which it
differs by the presence of an HY epitope (defined by the
octamer peptide TENSGKDI) that presumably accounts for the antigenic difference between males and
females (51). The UTY gene also encodes a male-specific histocompatibility antigen that is recognized by
female T cells in a major histocompatibility complexrestricted manner (61).
Other genes with X-Y homologs may serve similar
functions but may differ from each other in subtle
ways. The RPS4Y and RPS4X genes encode ribosomal
binding proteins that differ at 19 of 263 amino acids.
Both genes are widely transcribed in human tissues,
which suggests that the ribosomes of men and women
are structurally, if not functionally, distinct (12).
Molecular genetics of the human X chromosome.
X-linked traits are characterized by absence of maleto-male transmission; they may be transmitted from
fathers to daughters or from mothers to daughters and
sons. If one copy of the mutant gene is required for
expression in females, then the trait is dominant. If
two copies are required, then the trait is recessive. The
presence of the hemizygous state in males makes it
easier to map the genes for X-linked recessive conditions than the genes for autosomal disorders. To date,
over 1,200 X-linked conditions have been described
(34). Some conditions are distinctive in their phenotypic features, whereas others, such as mental retardation, are nonspecific (35). The pattern of inheritance
can infer the X-linked nature of these conditions. Precise mapping to specific regions of the X chromosome
can be performed by linkage to specific markers.
X-linked dominant conditions, such as incontinentia
pigmenti, Rett syndrome, microphthalmia with linear
skin defects, and Aicardi syndrome, may not show Mendelian transmission because they are expressed only in
females and usually as sporadic cases. The paucity of
male cases for these conditions is presumed to result from
lethality during gestation (2, 17, 28, 29, 42).
Most X-linked genes have dosage compensation between males and females by X chromosome inactivation, a process also known as “lyonization.” This process of random inactivation of one of the two X
chromosomes starts in early embryos (30). The inactivation originates at a site on the long arm of the X
chromosome (termed the “X chromosome inactivation
center”) and spreads over the chromosome (49). The inactivation is stable and is transmitted to the progeny
cells. X chromosome inactivation skips over some regions
of the X chromosome affecting some genes but not others;
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X-linked traits do not show a pattern of male-to-male
transmission. Rather, in sons, X-linked traits demonstrate a maternal origin effect. To compensate for differences in gene dosage between males and female, a
mechanism of X chromosome inactivation developed
(see Molecular genetics of the human X chromosome
below).
Sex chromosomes differ from autosomes in their organization. The sex chromosomes have two regions, a
pseudoautosomal segment shared between X and Y
chromosomes and a sex-limited region. The pseudoautosomal regions of the X and Y chromosomes pair at the
tips of their short and long arms and undergo recombination during meiosis in spermatocyte precursors
(22). The term pseudoautosomal is used because alleles
that are inherited within the region are not transmitted exclusively to males or females and thus behave as
if they were inherited on autosomes (52). Sex-based
differences in gene expression may occur from the
sex-limited regions of the X or Y chromosomes. Genes
within the sex-limited regions of the X and Y chromosomes are linked to the sexual phenotype of the individual. Genes in the sex-limited region of the Y chromosome have a male-only pattern of transmission.
Molecular genetics of the human Y chromosome.
Some of the genes in the sex-limited region of the Y
chromosome have functions that could occur only in
males, such as testis determination or spermatogenesis (27). Testis determination is mediated by the SRY
gene (for “sex-determining region Y”) (16, 53). This
gene is conserved on the Y chromosomes of most mammals and functions as a developmental switch. Once
expressed in the gonadal ridge of humans, it remains
on through the period of testicular differentiation and
leads the enhanced expression of SF1 and other sexdetermining genes in humans (18). Sry has been shown
to function as a transcriptional activator in mice (10).
Its mechanism of action in humans is unknown, although it has been proposed to function as a repressor
of a repressor (33). The SRY gene has been shown to be
expressed in early male embryos and in the central
nervous system of humans and mice (32). This observation has led to the suggestion that expression of SRY
could account for hormone-independent, somatic differences between males and females.
Genes that promote spermatogenesis have been
shown to exist in three different regions of the Y
chromosome because deletion of one or more of these
regions is found in individuals with oligo/azospermia
(20, 25, 31, 60). Deletions of these regions remove one
or more of the candidate genes (DAZ, RBMY, USP9Y,
and DBY). Of these, DAZ is a favored candidate because DAZ protein appears to be expressed in the right
place at the right time. This protein is present in both
the nuclei and cytoplasm of fetal gonocytes and in
spermatogonial nuclei; during male meiosis, it relocates to the cytoplasm (46).
A number of other genes have been identified on the
Y chromosome. Some of these are present as single
genes on the Y, whereas others have multiple copies on
the Y or homologous copies on the X and Y chromo-
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SEXUALLY DIMORPHIC GENE EXPRESSION
FROM AUTOSOMES
In addition to SRY, the autosomal genes WT1, SOX9,
SF1, WNT4, DMRT1 and FGF9 play a role in gonadal
development. Temporal and spatial differences have
been observed for all of these genes in developing
human testes and ovaries, thereby demonstrating a
dimorphic genetic pathway for gonadal determination
and development (4, 18, 19, 44, 59). Several bits of
evidence suggest that the effects of SRY in causing
J Appl Physiol • VOL
male sexual differentiation may channel through
SOX9. The expression of SOX9 in the gonads of 46,XY
human embryos follows a pattern similar to that of
SRY (18). The expression commences with testicular
induction and increases over the next several days
with maximal detection observed over the sex cords,
most likely in Sertoli cells. A 46,XX male patient was
observed with a chromosomal duplication encompassing the SOX9 gene. This finding suggested that enhanced expression of SOX9, even in the absence of
SRY, is sufficient to cause testis determination (21). In
XX Odsex mice, derepression of Sox9 expression in XX
gonads leads to male development (5). Ordinarily, this
derepression might be mediated by Sry.
Dimorphic gene expression may occur for other developmental pathways that could influence disease
susceptibility. In addition to control from a regulatory
sex chromosome-linked gene, such as SRY, genes under the control of sex steroids demonstrate dimorphic
gene expression because of differences in the production of these hormones by men and women (48). Such
differences have been observed for CYP11A1 in the
brain, steroid sulfatase in trophoblasts, and estrogen
receptor in the liver, among others. CYP11A1, the gene
for the first enzyme in steroid biosynthesis (P450SCC,
cholesterol side-chain cleavage enzyme), is expressed
in the temporal and frontal lobe cortex of the brain and
is significantly higher in women than in men (62).
Steroid sulfatase is an enzyme that catalyzes the hydrolysis of the sulfate ester bonds of sulfated steroids,
such as cholesterol, dehydroepiandrosterone, and estrone sulfate. Human cytotrophoblasts in primary culture show a gender-specific regulation of steroid sulfatase activity, with an increase of twofold to threefold in
female, but not in male, cells (58). The estrogen receptor is a complex genomic unit in mice that exhibits
alternative splicing that is regulated in a tissue-specific manner. Five variants have been described that
are generated by alternative splicing that differ in
their 5⬘ untranslated regions. All encode a 66-kDa
estrogen receptor protein, which the previously identified mRNA C variant generates. The expression of the
H isoform mRNA is restricted to liver, although female
mice produce around a fivefold higher level of this
transcript than male mice (26). Most likely, many other
sex-specific differences will be found.
Many different factors have been described that affect genes whose expression is influenced by steroid
hormones (reviewed in Ref. 45). Some of these factors
operate in trans, whereas others operate in cis. The
trans elements include the availability of the hormones, their receptors, the receptor transcriptional
coregulatory proteins, and basal transcription factors
in the responsive tissue. The cis elements are the
binding sites for the hormone receptors. For the estrogen receptor, specificity is conferred by the sequence of
the DNA response element (24). By contrast, for the
androgen receptor, specificity is conveyed by binding
cooperatively to multiple androgen responsive elements in native promoters (15).
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thus the degree of inactivation at a given locus is variable, ranging from complete to none at all (50). Some of
the loci that escape X chromosome inactivation have
homologous genes in either the pseudoautosomal or sexlimited regions of the Y chromosome (27).
Skewing may occur in which one X chromosome may
be preferentially inactivated in a majority of cells. This
skewing of X chromosome inactivation may be a heritable trait, may occur by chance alone, or may be the
result of selection (7, 37, 43, 55). The stochastic nature
of X chromosome inactivation has been highlighted by
differences in the patterns of X chromosome inactivation among the tissues of an individual and by discordance in the patterns of X chromosome inactivation
between monozygotic twins (13, 47). When this occurs
for an X chromosome that contains a mutant gene, only
one twin in the pair may have a population of cells in
which inactivation of the X chromosome bearing a
mutant gene predominated and thus is affected with
the condition. This appears as discordance of the Xlinked phenotype between the twins. Variability in X
chromosome inactivation may likewise account for discordance in X-linked phenotypes among singleton sisters who harbor the same mutant allele.
On the other hand, heritable, skewed X chromosome
inactivation may account for concordance of X-linked
phenotypes among female relatives. Skewed inactivation in some cell types occurs because the expression of
a mutant allele (or failure to express the normal allele)
prevents cells from maturing along a developmental
pathway. The B cells of females heterozygous for the
X-linked agammaglobulinemia express only the X
chromosome that encodes the normal allele (3, 7).
Those precursor cells in which the chromosome with
the normal gene is inactivated fail to mature along the
B cell pathway. Individuals with balanced X-autosomal
translocations tend to have selective inactivation of the
normal (or untranslocated) X chromosome (64). Inactivation of the translocated X chromosome is lethal at a
cellular level because the inactivation spreads to the
autosomal segment and monosomy for the autosomal
regions is selected against by the suboptimal dosage of
autosomal genes. Skewed inactivation may also arise
from mutations in the minimal promoter of the XIST
gene; normally, X chromosome inactivation correlates
with expression of the XIST gene on the chromosome
being inactivated. Transmission of this mutant causes
extreme skewing of X chromosome inactivation to be a
heritable trait (43).
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CONCLUSION
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