Why x chromosome inactivation occurs

There are important differences between the mechanisms of X-inactivation in humans and mice. In humans, random X-inactivation has not been observed in the inner cell mass at least until day E7 and imprinted X-inactivation may not occur in the trophoblast cells [ 39 , 40 , 41 ].

In our study, we simulated random X-inactivation to calculate the number of initial lineage-restricted blood precursor cells and demonstrate that the observed skewing patterns in the blood of the healthy female population are most consistent with X-inactivation in an embryonic stage where there are eight cells present that give rise to the hematopoietic compartment.

Previous studies [ 14 , 20 , 21 , 22 , 23 ] reported numerous genes to escape from X-inactivation. However, results were not entirely consistent between studies. This can be attributed to differences in technical and statistical procedures, and differences in the tissues analyzed and the transcripts expressed from the genes in those tissues.

Moreover, it appears that that there is heterogeneity regarding escapee genes between individuals, tissues, and time of development; those are the so-called variable escapees [ 16 ]. We report here a small number of genes 14 in total , for which we established consistent escapee behavior in blood across the population. In conclusion, we provide a robust and comprehensive view on the X-inactivation patterns observed in the general population and provide arguments for the need of careful assessment and interpretation of skewed X-inactivation in the clinical diagnostic practice.

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Am J Hum Genet. Duchenne muscular dystrophy in a female with a translocation involving Xp Translocation X; 6 in a female with Duchenne muscular dystrophy: implications for the localisation of the DMD locus. Orstavik KH. X chromosome inactivation in clinical practice. Hum Genet. Wutz A. Gene silencing in X-chromosome inactivation: advances in understanding facultative heterochromatin formation. Nat Rev Genet. Xist-dependent imprinted X inactivation and the early developmental consequences of its failure.

Nat Struct Mol Biol. J Cell Biol. A gene from the region of the human X inactivation centre is expressed exclusively from the inactive X chromosome. Carrel L, Willard HF. X-inactivation profile reveals extensive variability in X-linked gene expression in females.

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Genome Biol. Analysis of expressed SNPs identifies variable extents of expression from the human inactive X chromosome. Strong purifying selection at genes escaping X chromosome inactivation. Mol Biol Evol. Genes that escape X-inactivation in humans have high intraspecific variability in expression, are associated with mental impairment but are not slow evolving.

Landscape of X chromosome inactivation across human tissues. X chromosome-inactivation patterns of 1, phenotypically unaffected females. Methylation of AR locus does not always reflect X chromosome inactivation state. Age- and tissue-specific variation of X chromosome inactivation ratios in normal women.

Nonrandom X-inactivation patterns in normal females: lyonization ratios vary with age. Clonality and X-inactivation patterns in hematopoietic cell populations detected by the highly informative M27 beta DNA probe. Acquired skewing of X-chromosome inactivation patterns in myeloid cells of the elderly suggests stochastic clonal loss with age. Br J Haematol. A longitudinal study of X-inactivation ratio in human females. Fialkow PJ. Primordial cell pool size and lineage relationships of five human cell types.

Ann Hum Genet. X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. Symptoms in carriers of adrenoleukodystrophy relate to skewed X inactivation. Ann Neurol. Preferential expression of mutant ABCD1 allele is common in adrenoleukodystrophy female carriers but unrelated to clinical symptoms.

Orphanet J Rare Dis. Familial skewed X chromosome inactivation in adrenoleukodystrophy manifesting heterozygotes from a Chinese pedigree. Is skewed X inactivation responsible for symptoms in female carriers for adrenoleucodystrophy? Reactivation of the paternal X chromosome in early mouse embryos.

Regional and temporal changes in the pattern of X-chromosome replication during the early post-implantation development of the female mouse. Single-cell RNA-seq reveals lineage and X chromosome dynamics in human preimplantation embryos. Early X chromosome inactivation during human preimplantation development revealed by single-cell RNA-sequencing. Sci Rep. Cell Stem Cell. Download references. Draisma, Stefan J. White, Johan T. Ramin Monajemi, Harmen H.

Draisma, Bastiaan T. Heijmans, Szymon M. Gijs W. Santen, Johan T. You can also search for this author in PubMed Google Scholar. Correspondence to Peter A. Reprints and Permissions. Shvetsova, E. Skewed X-inactivation is common in the general female population. Eur J Hum Genet 27, — Download citation. Received : 17 April The signs and symptoms of these conditions vary widely and range from mild to severe.

They can be caused by missing or extra copies of the sex chromosomes or by structural changes in the chromosomes. Genetics Home Reference has merged with MedlinePlus. Learn more. The information on this site should not be used as a substitute for professional medical care or advice. Contact a health care provider if you have questions about your health. X chromosome. From Genetics Home Reference. Description The X chromosome is one of the two sex chromosomes in humans the other is the Y chromosome.

Health Conditions Related to Chromosomal Changes The following chromosomal conditions are associated with changes in the structure or number of copies of x chromosome. More About This Health Condition. Intestinal pseudo-obstruction Intestinal pseudo-obstruction, a condition characterized by impairment of the coordinated waves of muscle contractions that move food through the digestive tract peristalsis , can be caused by genetic changes involving the X chromosome.

Klinefelter syndrome Klinefelter syndrome is a chromosomal condition in boys and men that can affect physical and intellectual development. Microphthalmia with linear skin defects syndrome A deletion of genetic material in a region of the X chromosome called Xp22 causes microphthalmia with linear skin defects syndrome. Turner syndrome Turner syndrome results when one normal X chromosome is present in a female's cells and the other sex chromosome is missing or structurally altered. X-linked acrogigantism Duplication of a small amount of genetic material on the X chromosome causes X-linked acrogigantism X-LAG , which is characterized by abnormally fast growth beginning in infancy or early childhood.

Other chromosomal conditions Chromosomal conditions involving the sex chromosomes often affect sex determination whether a person has the sexual characteristics of a male or a female , sexual development, and the ability to have biological children fertility. X-inactivation profile reveals extensive variability in X-linked gene expression in females. Turner syndrome: an update and review for the primary pediatrician.

Clin Pediatr Phila. Clinical, hormonal and cytogenetic evaluation of 46,XX males and review of the literature. J Pediatr Endocrinol Metab.

Neurogenic chronic idiopathic intestinal pseudo-obstruction, patent ductus arteriosus, and thrombocytopenia segregating as an X linked recessive disorder. J Med Genet. Filamin A is mutated in X-linked chronic idiopathic intestinal pseudo-obstruction with central nervous system involvement.

Am J Hum Genet. Epub Feb Germline or somatic GPR duplication leads to X-linked acrogigantism: a clinico-pathological and genetic study.

Acta Neuropathol Commun. Diffuse abnormal layering of small intestinal smooth muscle is present in patients with FLNA mutations and x-linked intestinal pseudo-obstruction. Am J Surg Pathol. Mysteries of the X chromosome revealed: "silent" X not always mute. Microphthalmia with linear skin defects syndrome MLS : a male with a mosaic paracentric inversion of Xp. Cytogenet Genome Res. X-chromosome inactivation and human genetic disease. Acta Paediatr Suppl. Microphthalmia with Linear Skin Defects Syndrome.

The DNA sequence of the human X chromosome. Acta Paediatr. Epub Apr 8. A new look at XXYY syndrome: medical and psychological features. Am J Med Genet A. Gigantism and acromegaly due to Xq26 microduplications and GPR mutation. N Engl J Med. Epub Dec 3. The X chromosome: not just her brother's keeper. Nat Genet. Klinefelter syndrome and other sex chromosomal aneuploidies. Orphanet J Rare Dis. The genes on the X chromosomes are important for how the body grows and functions. Females have two X chromosomes in each cell!

Scientists discovered that, when female babies are developing, they have a special mechanism that randomly turns off one of their two X chromosomes [ 1 ]. Since not every cell turns off the same X chromosome, the cells can express X-chromosome genes differently from each other.

This is called cellular mosaicism. Cellular mosaicism gives females more diversity than males, meaning that they have more options during development and more ways to prevent disease [ 2 ]. We will describe this more, do not worry! Imagine a calico cat—they are almost always female. Female calico cats have two versions of a gene for their coat color. Both versions are located on their X chromosomes. Patches of fur are either orange or black, depending on which X chromosome is turned off in that patch of hair cells.

Imagine that the X from the mom carries the orange fur gene, and the X from the dad carries the black fur gene. Those cells will express the orange gene and the fur will be orange Figure 1.

XCI only happens in female mammals, including humans, and affects almost all genes on the X chromosome. Many genes can undergo changes, called mutations, which, in some cases, can make a person more likely to get certain diseases. Diseases caused by mutations in genes on the X chromosome are called X-linked diseases. Remember, males do not experience XCI because they only have one X chromosome. So, if males have a disease-causing gene on their X chromosome, it will be active and more likely to cause disease.

However, XCI helps protect females from X-linked diseases. Imagine a girl has a healthy copy of a gene on one X chromosome and a mutant copy of the same gene on her other X chromosome. If the X chromosome with the mutant copy is turned off due to XCI, then the X chromosome with the healthy copy will stay active and express the gene properly. This does not mean she would not get sick, but it will increase her chances of not getting the diseases related to the mutant gene. This is why studying XCI is important!

The patterns of disease gene expression that result from XCI might determine how severely someone is affected by an X-linked disease. One example of an X-linked disease is red-green colorblindness. Red-green colorblindness is a disease in which the affected person cannot tell red from green.

Another example of an X-linked disease is called Norrie disease, and that is what we studied. Norrie disease affects the eyes and can cause blindness in boys. Interestingly, Norrie disease also affects girls, but more mildly. Norrie disease is caused by a mutation on the X-linked gene called norrin. We wanted to understand how XCI affects girls who carry a bad copy of the Norrie disease gene.