TOPICS & REFERENCES

• Sex Determination and Sex Chromosomes

• X and Y Chromosomes. Sexual

Differentiation in Humans.
• The Y Chromosome and Male Development.
• Sex-determining region Y (SRY) .
• X-inactivation.
• Kleinfelter and Turner syndromes.
• Recessive and Dominant Inheritance of X-
Linked Disorders.
• PAGE 87-98
 X and Y Chromosomes.
 The different sex chromosome constitution
of normal human male and female cells has
been appreciated for more than 50 years.
Soon after cytogenetic analysis became
feasible, the fundamental basis of the XX/XY
system of sex determination became
apparent.
 The X and Y chromosomes have long
attracted interest because they differ between
the sexes, because they have their own
specific patterns of inheritance, and because
they are involved in primary sex
determination.
 They are structurally distinct and subject to
different forms of genetic regulation, yet they
pair in male meiosis.
 Sexual Differentiation in Humans
 During early development, every human embryo undergoes a period
when it is potentially hermaphroditic.
 By the fifth week of gestation, gonadal primordia (the tissues that will
form the gonad) arise as a pair of gonadal (genital) ridges associated
with each embryonic kidney. The embryo is potentially hermaphroditic
because at this stage its gonadal phenotype is sexually indifferent—
male or female reproductive structures cannot be distinguished, and the
gonadal ridge tissue can develop to form male or female gonads.
 As development progresses, primordial germ cells migrate to these
ridges, where an outer cortex and inner medulla form (cortex and
medulla are the outer and inner tissues of an organ, respectively). The
cortex is capable of developing into an ovary, while the medulla may
develop into a testis.
 In addition, two sets of undifferentiated ducts called the Wolffian and
Müllerian ducts exist in each embryo. Wolffian ducts dif- ferentiate
into other organs of the male reproductive tract, while Müllerian
ducts differentiate into structures of the female reproductive tract.
• Because gonadal ridges can form either ovaries or testes,
they are commonly referred to as bipotential gonads.
• What switch triggers gonadal ridge
development into testes or ovaries?
 The presence or absence of a Y chromosome is the key.
 Sexual Differentiation in Humans.
 The process of sex determination can be thought of as occurring
in distinct but interrelated steps
1. Establishment of chromosomal sex (i.e., XY or XX) at the
time of fertilization
2. Initiation of alternate pathways to differentiation of one or
the other gonadal sex, as determined normally by the
presence or absence of the testis-determining gene on the
Y chromosome
3. Continuation of sex-specific differentiation of internal and
external sexual organs
4. Especially after puberty, development of distinctive
secondary sexual characteristics to create the
corresponding phenotypic sex, as a male or female
 Whereas the sex chromosomes play a determining role in
specifying chromosomal and gonadal sex, a number of genes
located on both the sex chromosomes and the autosomes are
involved in sex determination and subsequent sexual
differentiation. In most instances, the role of these genes has
come to light as a result of patients with various conditions known
as disorders of sex development
 The Y Chromosome and Male Development
 The structure of the Y chromosome and its role in sex development has been determined at both the
molecular and genomic levels.
 In male meiosis, the X and Y chromosomes normally pair by segments at the ends of their short arms
and undergo recombination in that region. The pairing segment includes the pseudoautosomal
region of the X and Y chromosomes, so called because the X- and Y-linked copies of this region are
essentially identical to one another and undergo homologous recombination in meiosis I, like pairs of
autosomes.
 By comparison with autosomes and the X chromosome, the Y chromosome is relatively gene poor and
contains fewer than 100 genes (some of which belong to multigene families), specifying only
approximately two dozen distinct proteins. Notably, the functions of a high proportion of these genes
are restricted to gonadal and genital development.

SRY is the Major Testis-Determining Gene

• The earliest cytogenetic studies established the maledetermining function of the Y chromosome. In the
ensuing three decades, chromosomal and genomic analysis of individuals with different submicroscopic
abnormalities of the Y chromosome and well-studied disorders of sex development allowed identification of
the primary testisdetermining region on Yp.
• Whereas the X and Y chromosomes normally exchange in meiosis I within the Xp/Yp pseudoautosomal
region, in rare instances, genetic recombination occurs outside of the pseudoautosomal region. This leads to
two rare but highly informative abnormalities—males with a 46,XX karyotype and females with a 46,XY
karyotype—that involve an inconsistency between chromosomal sex and gonadal sex
• The SRY gene (sex-determining region on the Y) lies near the pseudoautosomal boundary on the Y chromo-
some. It is present in many males with an otherwise normal 46,XX karyotype and is deleted or mutated in a
proportion of females with an otherwise normal 46,XY karyotype, thus strongly implicating SRY
• in normal male sex determination. SRY is expressed only briefly early in development in cells of the germinal
ridge just before differentiation of the testis. SRY encodes a DNA-binding protein that is likely to be a
transcription factor, which up-regulates a key autosomal gene, SOX9, in the ambipotent gonad, leading
ultimately to testes differentiation. Thus, by all available genetic and developmental criteria, SRY is equivalent
to the TDF gene on the Y chromosome. If SRY is absent or not functioning properly, then the female sex
differentiation pathway ensues.
• Although there is clear evidence demonstrating the critical role of SRY in normal male sexual development,
the presence or absence of SRY/TDF does not explain all cases of abnormal sex determination.
 X Chromosome Inactivation
• Chromosomal and molecular mechanisms of X chromosome inactivation - the
most extensive example of random monoallelic expression in the genome and
a mechanism of dosage com- pensation that results in the epigenetic silencing
of most genes on one of the two X chromosomes in females.
• In normal female cells, the choice of which X chromosome is to be inactivated
is a random one that is then maintained in each clonal lineage. Thus females
are mosaic with respect to Xlinked gene expression; some cells express alleles
on the paternally inherited X but not the maternally inherited X, whereas
other cells do the opposite. This mosaic pattern of gene expression
distinguishes most X-linked genes from imprinted genes, whose expression, as
we just noted, is determined strictly by parental origin.
• The inactive X chromosome was first identified cytologically by the presence
of a heterochromatic mass (called the Barr body) in interphase cells,
• Although X inactivation is clearly a chromosomal phenomenon, not all genes
on the X chromosome show monoallelic expression in female cells.
 The X Inactivation Center and the XIST Gene. X inactivation occurs very early
in female embryonic development, and determination of which X will be
designated the inactive X in any given cell in the embryo is a random choice
under the control of a complex locus called the X inactivation center (XIC).
This region contains an unusual ncRNA gene, XIST, that appears to be a key
master regulatory locus for X inactivation. XIST (an acronym for inactive X [Xi]–
specific transcripts) has the novel feature that it is expressed only from the
allele on the inactive X; it is transcriptionally silent on the active X in both
male and female cells. Although the exact mode of action of XIST is unknown,
X inactivation cannot occur in its absence. The product of XIST is a long ncRNA
that stays in the nucleus in close association with the inactive X chromosome.
 Barr Bodies
Barr and Bertram observed a darkly
staining body in the interphase nerve cells
of female cats that was absent in similar
cells of males.
In humans, this body can be easily
demonstrated in female cells derived from
the buccal mucosa (cheek cells) or in
fibroblasts (undifferentiated connective
tissue cells), but not in similar male cells.
This highly condensed structure, about 1
mm in diameter, lies against the nuclear
envelope of interphase cells, and it stains
positively for a number of different DNA-
binding dyes.
This chromosome structure, called a sex
chromatin body, or simply a Barr body, is
an inactivated X chromosome.
 X Chromosome Inactivation
• The principle of X inactivation is that in somatic cells in normal
females (but not in normal males), one X chromosome is
inactivated early in development, thus equalizing the expression of
X-linked genes in the two sexes. In normal female development,
because the choice of which X chromosome is to be inactivated is
a random one that is then maintained clonally, females are mosaic
with respect to X-linked gene expression.
• There are many epigenetic features that distinguish the active and
inactive X chromosomes in somatic cells. These features can be
useful diagnostically for identifying the inactive X chromosome(s)
in clinical material. In patients with extra X chromosomes (whether
male or female), any X chromosome in excess of one is
inactivated.Thus all diploid somatic cells in both males and
females have a single active X chromosome, regardless of the
total number of X or Y chromosomes present.
• The X chromosome contains approximately 1000 genes, but not
all of these are subject to inactivation. Notably, the genes that
continue to be expressed, at least to some degree, from the
inactive X are not distributed randomly along the X chromosome;
many more genes “escape” inactivation on distal Xp (as many as
50%) than on Xq (just a few percent).
Kleinfelter and Turner syndromes