- Purpose: Dosage compensation in females (XX) to equalize X-linked gene products with males (XY).
- Mechanism:
- One X chromosome per cell is randomly inactivated early in embryogenesis.
- Mediated by the XIST gene, which produces a long non-coding RNA that coats the chromosome.
- This leads to DNA methylation & histone deacetylation, forming transcriptionally inactive heterochromatin.
- Microscopic Appearance: The inactivated X chromosome is visible as a Barr body on the nuclear periphery.
- Rule: # Barr Bodies = # X chromosomes - 1.
- XX female = 1 Barr body
- XY male = 0 Barr bodies
- XXY (Klinefelter) = 1 Barr body
- Clinical Significance:
- Mosaicism: Because the inactivation is random and fixed, females are mosaics for their X-linked genes. Some cell lines express the maternal X, while others express the paternal X.
- Classic example: Calico cats (gene for coat color is on the X chromosome).
- Manifesting Heterozygote: A female carrier of an X-linked recessive disorder may show mild to severe symptoms if, by random chance, the normal X chromosome is preferentially inactivated in most cells (skewed X-inactivation). t
- Examples: A female carrier for Duchenne muscular dystrophy presenting with muscle weakness, or a carrier for hemophilia A having a bleeding tendency.
- In most female carriers, enough cells express the normal allele to produce sufficient protein, making her asymptomatic.