Recall the discussion of genetic mosaicism in Down syndrome in
chapter 1 (p. 22). A recent review by Marijo Kent-First (3),
describes the broader significance of the phenomenon of mosaicism
to human embryology.
All females are genetic mosaics
To compensate for the presence of only one X-chromosome in male cells
(46,XY), compared to female cells (46,XX), one of the two active
X-chromosomes in every cell of the female blastocyst is randomly and
stably inactivated. Inactivation of the X-chromosome is correlated
with expression of the XIST locus and production of an RNA that
remains associated with the inactivated X-chromosome. In
addition, CpG islands at the 5' end of inactivated genes become
methylated unlike the CpG islands in genes of the active
X-chromosome. X-inactivation also leads to changes in chromosome
structure; the inactive X chromosome lacks histone H4 acetylation
and the chromosome condenses into a distinct Barr body.
X-inactivation is not maintained, however, within cells of the
female germ line. The inactive X-chromosome of each female germ
cell is reactivated at the oogonium stage. Both X-chromosomes then
remain active throughout meiosis and development of the definitive
oocyte. Thus, male zygotes inherit an active X-chromosome from the
oocyte (which remains active throughout the life-time of the
male), and a Y chromosome from the spermatozoon. On the other
hand, female zygotes inherit two active X-chromosomes, one from
the oocyte and one from the spermatozoon. Both X-chromosomes
remain active in all cells through early cleavage until random,
stable inactivation of one of them in each cell occurs again in
the late blastocyst.
The consequence of X-inactivation in cells of the female
blastocyst is that their clonal descendants differ with respect to
whether the paternal or maternal X-chromosome remains active and
thus, whether they express specific maternal or paternal genes.
The classical example of this phenomenon is the female calico cat
which inherits an X-linked yellow allele from one parent and an
X-linked non-yellow allele from the other. One or the other color
is expressed in patches which represent clones descending from
cells with the respective active X-chromosome.
X-chromosome mosaicism and inheritance of disease
If a female inherits an X-linked recessive mutation for
Duchenne's muscular dystrophy from one parent and its
wild-type allele from the other, she does not exhibit symptoms of
the disease because of the presence of other cells in her body
that contain an active X-chromosome expressing the wild-type
allele. Such an individual is called a "silent carrier". If one of
the X-chromosomes in a 46,XX female, however, carries a dominant
X-linked mutation for disease, its deleterious effects are not
fully compensated for by other cells expressing the wild-type
X-linked allele and so some symptoms of disease may be observed.
Examples include Goltz syndrome, which is distinguished by skin
atrophy and skeletal malformations and incontinentia pigmenti,
a disease characterized by spotty pigmentation. These mutations,
however, may cause severe symptoms in males including early
lethality, since all cells contain an X-chromosome expressing the
Many other examples of genetic chromosomal mosaicism occur in
humans. Nonetheless, the most common involve sex chromosomes
(XO/XX, XX/XY, XXX/XX, XY/XO). Indeed, a high proportion of Turner
syndrome individuals are mosaics.
Mosaicism poses problems for genetic screening
Recall that genetic screening of polar bodies may be carried out
with techniques such as spectral karyotyping, fluorescent in situ
hybridization (FISH) or PCR (p. 27). Since many cases of
post-fertilization mosaicism are thought to arise from abnormal
centrosomes or centrioles (which are inherited from the father),
these abnormalities cannot be revealed by analysis of the polar
body. Conversely, evidence of mosaicism in the chorionic villi at
later stages of development may be a poor indicator of chromosome
abnormalities in the fetus. Abnormal karyotypes appear more
frequently within the placenta (from the outer cell mass) than in
the amniocytes (from the inner cell mass), possibly because the
embryo selects against abnormal cell lineages allowing normal
cells to survive. Another problem occurs in the case of
microdeletions causing male-factor infertility occurring in only
some cells of a mosaic individual. These may simply be
undetectable against the background of the wild type gene present
in normal cells of the mosaic. A different problem arises from
mosaicism that results from spontaneous stochastic increases in
copy number of genes containing trinucleotide repeats which may occur
during meiosis or mitosis. These mutations may cause
myotonic dystrophy, epidermolysis bulbosa, fragile X
syndrome and Huntington's disease, but the time of onset or
severity of disease is not predictable, even with early detection
of these repeats.
Dr. Kent-First concludes by arguing that the cost:benefit
equation and patient welfare (especially) must be thoughtfully
weighed when considering genetic screening for detection of hidden
instances of mosaicism.
1. Bellabio A, Willard HF. 1992. Mammalian X-chromosome
inactivation and the XIST gene. Curr. Opin. Genet. Dev. 2:439.
2. Daniels R, Holding C, Kontongiani E, Monk M. 1996. Single cell
analysis of single genes. J. Assist. Reprod. Genet. 13:163.
3. Herzing LB, Romer JT, Horn JM, Ashworth A. 1997. Xist has
properties of the X-chromosome inactivation center. Nature.
4. Kent-First M. 1997. A lesson from mosaics: Don't leave the
genetics out of molecular genetics. J. NIH Res. 9:29.
5. Lyon M. 1993. Epigenetic inheritance in mammals. TIG.9:123.
6. Migeon, BR. 1994. X-chromosome inactivation: molecular
mechanisms and genetic consequences. TIG. 10:230.
7. Williams N. 1995. How males and females achieve X equality.
Back to Table of Contents