The X chromosome expresses thousands of genes essential for cell activity whereas the Y chromosome expresses much fewer genes.

The imbalance of X linked genes between the sexes (2 for females; 1 for males) has to be corrected to ensure that the level of expression of genes carried on the X chromosome is the same in both sexes.

The mechanism by which this imbalance is delt with is referred to as dosage compensation.

Failure to correct the imbalance leads to abnormalities and arrested development.

Different animals deal with dosage compensation in different ways.

Mammals such as mice and humans achieve dosage compensation by inactivating one of the X chromosomes in females just after the blastocyst stage and around the time of implantation.

Once X inactivation is initiated in female embryos it is maintained in all somatic cells throughout life.

This increased transcription along the male X chromosome in Drosophila is due to massive binding of specific transcriptional factors in the control regions of their X linked genes.

In the hermaphrodites, there is a decrease in transcription from both the X chromosomes to achieve dosage compensation with the male.

The mechanism for upregulation in Drosophila is controlled by an inhibitory gene (sex lethal) which is turned off in males allowing for more than full expression from the one X chromosome.

In C. elegans, a gene referred to as dpy-27 becomes associated only with the X chromosome (lead by sdi--3 protein) in XX animals and causes condensation of the chromatin which reduces transcription of the two X chromosomes.

In mammals, X chromosome inactivation occurs in females and is also characterized by chromatin condensation (heterochromatin).

• Although the X chromosome is replicated at each cell division, it remains transcriptionally inactive.
• The inactivation process is random and can occur either on the paternal or maternal X chromosome in female cells.
• This pattern is preserved through many cell divisions in the individual's lifetime.
• However, this holds true only for somatic cells since in female germ cells the X chromosome is reactivated shortly before the cells enter meiosis so that mature oocytes have two active X chromosomes.
• In certain males that have inherited an extra X chromosome (i.e., XXY males), one of the X chromosomes is inactivated as in XX females.
• In all cases of X inactivation, the condensed chromosome is replicated and is present as a Barr body on the nuclear envelope which can be seen in all female cells.

The transcript is referred to as Xist and is made from a gene in the XIC.

• This transcript remains in the nucleus and appears to coat the inactive X chromosome preventing transcription from the genes along the chromosome.
• The control of Xist expression appears to be due to DNA methylation on the inactive X chromosome since the gene control region is unmethylated on the inactive X chromosome and methylated on the active X chromosome which does not express Xist.

• The inactive X chromosome has very little acetylation of its histone H4 subunit in the nucleosome.

Acetylation of histones is correlated with gene activity.

• In addition, most of the control regions of genes along the inactive X chromosome are methylated which locks them in an inactive state preventing transcription from these genes.

• This methylation pattern is erased in the germ cells and begins anew with the development of each organism.
• Likewise, the Xist gene expression changes during gametogenesis.

• During spermatogenesis, the Xist promoter becomes hypomethylated while the same sites are not affected during oogenesis.
• This process of differential gene expression depending upon parental or maternal origin is referred to as genomic imprinting.

• The process of imprinting as occurs in the Xist gene is an exception to the Mendelian rule.
• Because certain developmentally important genes are active only if they come from the sperm and others are active only if they come from the egg (imprinting), the maternal and paternal pronuclei are both necessary for the completion of mammalian development.

• At the end of that process the fertilized egg must be capable of controlling the development of the embryo.
• The genomes of the germ cells therefore have to revert to a state from which all of the cells of the organism can be derived so there must be no permanent alterations in their genomes.
• However, certain genes in eggs and sperm are programmed to be switched either on or off during development.

Evidence of this comes from the different contributions of the maternal and paternal genomes to the development of the embryo.

Mouse eggs can be manipulated by nuclear transplantation to have either two paternal genomes or two maternal genomes and can be reimplanted into the mouse for further development.

• The embryos that result are androgenetic and gynogenetic embryos respectively.
• Although both kinds of embryo have diploid chromosomes, their development is abnormal.
• The embryos with two paternal genomes have well-developed extra-embryonic tissues but the embryo is abnormal and does not develop beyond the stage that somites appear.
• The embryos with diploid maternal genomes have well-developed embryos but the extra-embryonic tissues (placenta/yolk sac) are poorly developed.

• The two parental genomes function differently in development and both are required for normal development.
• This is the reason that parthenogenesis (activation of a fertilized egg alone) does not lead to normal development.

Although the paternal and maternal genomes may contain the same genes, imprinting can turn certain genes in either the sperm or egg on or off.

Some of the genes necessary for yolk sac and placenta development are inactivated in the maternal genome and some of those required for development of the embryo are turned off in the paternal genome.

Imprinting in mammals is reversible since any of the chromosomes may eventually end up in male or female germ cells during development.

• Thus, imprinting is erased during early germ cell development and is later established during germ cell differentiation.
• The imprinted genes affect not only early development, but also the later growth of the embryo.

• For example, when embryonic stem cells from gynogenetic embryos are injected into normal embryos, growth is decreased by 50% and when androgenetic embryonic stem cells are introduced into normal embryos the chimera's growth is increased 50%.
• The imprinted genes on the male genome thus significantly increase the growth of the embryo.

• The insulin-like growth factor (IGF-2) gene (Igf-2), which promotes growth, is imprinted in the maternal genome such that it is not expressed but is expressed only from the paternal genome.
• The imprinting of Igf-2 is probably due to imprinting of the H19 gene which regulates expression of Igf-2.

H19 is however imprinted in the opposite direction such that it is expressed only from the maternal genome.

• The gene receptor of the IGF-2 protein, Igf-2r is also imprinted as is the H19 gene so that it is only active in the maternal genome.

• Igf-2r does not encode a receptor but rather a protein required to degrade IGF-2.
• Expression of Igf-2r reduces growth by controlling the amount of IGF-2 that is available.
• Thus, the activation of Igf-2r in the female chromosome reduces growth.

The apparent mechanism is differential DNA methylation of the genes involved.

• The primordial germ cell nuclei of both male and female mammals are very hypomethylated allowing for erasure of the imprinting message.
• During meiosis, de novo methylation occurs such that the pattern of methylation of a given gene may differ depending on whether it is in an egg or sperm and these differences are seen in the chromosomes of embryonic cells.
• Thus, methylation differences between sperm and egg genes may specify whether a gene came from the father or mother.