1. X-CHROMOSOME INACTIVATION:
MOLECULAR MECHANISM AND
GENETIC CONSEQUENCES
By: Ambaye, S. & Mujahed, H

2. INTODUCTION
 What makes a child a boy or a girl ?
 X-Chromosome and Y-chromosome
are different.
 Males and Females should
have the same amount
X-chromsome genes
product.

3. INTODUCTION
 Dosage Compensation
A mechanism to equalize the dosage of X-
chromosome gene products by means of
inactivating one of female X-chromosomes in
mammels.
 In Drosophila dosage Compensation
accompleished by two fold transcriptional
upregulation male X chromosome.

4.  The existence of XCI was first suggested by Mary
Lyon in 1961.
 For this reason this suggestion was known as the
`Lyon hypothesis,'

5. MOLECULAR MECHANISMS OF X INACTIVATION
 X-chromosome contains X Inactivation Center (XIC)
which located in long arm.
 XIC contains an unusual gene called inactive X
(Xi)-specific transcripts (XIST).
 XIST expresses a noncoding functional 17 (kb)
RNA molecule.
 XIST expressed only when more than one X-
chromosome found in same cell.

6. MOLECULAR MECHANISMS OF X INACTIVATION
(Migeon, 1994)

7. MOLECULAR MECHANISMS OF X INACTIVATION
XIST
(Brown, C. J. et al. 1991)

8. MOLECULAR MECHANISMS OF X INACTIVATION
 XIST transcripts remains in the nucleus.
 While Xist is being transcribed, blocking factors
prevent the association with X chromosome.

9. MOLECULAR MECHANISMS OF X INACTIVATION
 Blocking factores are released, Xist RNA is
stablized and upregulated.

10. MOLECULAR MECHANISMS OF X INACTIVATION
 Before inactivation the X chromosome coated with
stabilized Xist RNA.

11. MOLECULAR MECHANISMS OF X INACTIVATION
 Genes on the X chromosome are silenced following
Xist RNA coating using an unknown mechanism.

12. MOLECULAR MECHANISMS OF X INACTIVATION
 Chromatin modifications, including histone
deacetylation and methylation of promoters of X-
linked.
(Avner, P., & Heard, 2001)

13. GENETIC IMPRINTING AND X INACTIVATION
 X-chromosome inactivation ocurres by two ways:
Random and imprented.
Differes in:
 Developmental timing.
 Mechanism.

14. GENETIC IMPRINTING
 Paternal X-chromosome is preferentially silenced
in the placenta.
 Extensive methylation of CpG islands on paternal
X-chromosome.
 Suggested to take a place during spermatogenesis.

15. GENETIC IMPRINTING
Summary of
Fthl17 gene
family
expression in
preimplantation
stage embryos.
Kobayashi S et al. Nucl. Acids Res. 2010;nar.gkq113
© The Author(s) 2010. Published by Oxford University Press.

16. RANDOM X INACTIVATION
 One of the two X-chromosomes is randomly
inactivated in the early female embryo
developmental stage.
 Cells ensure that one
of the Xs still active.

17. RANDOM X INACTIVATION

18. CONSEQUENCES OF X CHROMOSOME
INACTIVATION
 The result is that the effective dosages of products
of X-linked genes are equal in males and females.
 The X chromosome is large and with many genes,
whereas the Y chromosome
is much smaller and carries
orthologs of only a few of the
X-linked genes.

19. CONSEQUENCES OF X CHROMOSOME
INACTIVATION
 Inactivation in females results in cellular mosaicsim,
one population of cells expresses the maternal
allele; the other expresses the paternal one.

20. CONSEQUENCES OF X CHROMOSOME
INACTIVATION
 Females benefit from the presence of heterozygous
populations of cells.
 In case of X-linked mutations that are detrimental
and even lethal, sons may not be affected of the
mutant gene they express.
 Also growth competition between the mosaic
populations can result in elimination of cells that
express the mutant allele.

21. CONSEQUENCES OF X CHROMOSOME
INACTIVATION
 X inactivation can create problems when cells with
the mutation have a growth advantage (e.g: cancer
cells).
 Elimination of normal cells occurs as the result of
chromosomal abnormalities that arise by chance.
 As a consequence, females may manifest diseases
usually found only in males

22. “It has been six weeks now. Six weeks of tireless,
frenzied activity since that sperm jostled its way
into that egg. So little time spent in this warm,
dark, womby home, and so much achieved”
David Bainbridge, The X In Sex

23. REFERENSES
Avner, P. and Heard, E. (2001). X-chromosome inactivation: counting, choice
and initiation. Nat Rev Genet 2, 59-67.
Brown, C. J., Ballabio, A., Rupert, J. L., Lafreniere, R. G., Grompe, M.,
Tonlorenzi, R. and Willard, H. F. (1991). A gene from the region of the
human X inactivation centre is expressed exclusively from the inactive X
chromosome. Nature 349, 38-44.
Migeon, B. R. (1994). X-chromosome inactivation: molecular mechanisms and
genetic consequences. Trends Genet 10, 230-235.
Yang, C., Chapman, A. G., Kelsey, A. D., Minks, J., Cotton, A. M. and Brown,
C. J. (2011). X-chromosome inactivation: molecular mechanisms from the
human perspective. Hum Genet.