What is skewed X-linked inactivation?
Skewed X inactivation is arbitrarily defined, often as a pattern where 80% or more of the cells show a preferential inactivation of one X chromosome.
What causes X-inactivation?
X-chromosome inactivation occurs randomly for one of the two X chromosomes in female cells during development. Inactivation occurs when RNA transcribed from the Xist gene on the X chromosome from which it is expressed spreads to coat the whole X chromosome.
What is skewed XCI?
This phenomenon, known as skewed XCI (or nonrandom XCI), occurs when at least 80% of cells within a tissue inactivate the same parental X chromosome. The factors underlying primary skewed XCI are varied and several mechanisms are possible8.
What gene is most responsible for X-inactivation?
XISTThis region contains an unusual ncRNA gene,XIST, that appears to be a key master regulatory locus for X inactivation.
What phenomenon occurs in females as a result of inactivation?
Definition. Lyonization (also called X-inactivation) refers to the normal phenomenon in which one of the two X chromosomes in every cell of a female individual is inactivated during embryonic development.
What changes occur in the chromosome to make it inactive?
What changes occur in the chromosome to make it inactive? Explanation: An X chromosome that has been inactivated does not look or acts like other chromosomes. Chemical analysis shows that the DNA is modified by the addition of numerous methyl groups.
What causes skewed data?
Skewed data often occur due to lower or upper bounds on the data. That is, data that have a lower bound are often skewed right while data that have an upper bound are often skewed left. Skewness can also result from start-up effects.
What happens if data is skewed?
High skewness means a distribution curve has a shorter tail on one end a distribution curve and a long tail on the other. The data set follows a normal distribution curve; however, higher skewed data means the data is not evenly distributed.
What do you mean by skewed?
1. : set, placed, or running obliquely : slanting. : more developed on one side or in one direction than another : not symmetrical.
How can we inactivate a gene?
Targeted Gene Inactivation Using RNAi RNA interference (RNAi) has emerged as a powerful technique for generating loss-of-function phenotypes by downregulating the expression of specific genes in plants and animals.
How do you inactivate genes?
Random deletions or insertions can inactivate a gene by preventing it from producing a functional protein. For example, these changes may make the gene's sequence code for the wrong amino acids, resulting in a nonfunctional protein.
Why do females have Barr bodies?
A Barr Body is an inactivated, condensed X chromosome found in female cells. Since females possess two X chromosomes and males have one X chromosome and a Y chromosomes, Barr bodies are essential to regulate the amount of X-linked gene product being transcribed.
What does the formation of a Barr body inactivates?
Formation of Barr Bodies Xist is responsible for the inactivation of the X-chromosome, whereas Tsix prevents it. X-inactivation is a random process that occurs during embryo development.
How does skewed inactivation occur?
Skewed inactivation can result from a decrease in the size of the pool of cells undergoing X-chromosome inactivation or contributing to the tissue being examine d. Such reductions increase the chance that stochastic variation alone will result in skewed inactivation. Confined placental mosaicism (CPM), which may account for a substantial proportion of the skewed X-chromosome inactivation seen in neonates ( 14 ), likely results in skewed inactivation by reducing the number of cells functionally contributing to the embryo. The disomic rescue of a trisomic conceptus will result in CPM, and the subsequent loss of the trisomic cells will substantially reduce the pool of cells in the embryo, substantially increasing the chance of observing skewed X-chromosome inactivation. An interesting possibility is that some of the trisomic cells may survive, and the continued existence of such cells may be the predisposing factor for ovarian cancer. In this case, the skewed inactivation would be a consequence of the CPM that also predisposes to neoplastic progression. Factors from the trisomic chromosome (s) may interact with the BRCA1 mutation to explain the preferential association of skewed X-chromosome inactivation with BRCA1 mutations.
When does X-chromosome inactivation occur?
X-chromosome inactivation occurs early during female mammalian development to transcriptionally silence one of the two X chromosomes, thereby achieving dosage compensation with males who have only a single X chromosome and the sex-determining Y chromosome ( 1 ). The choice of which X chromosome to inactivate is generally random in somatic tissue; however, once chosen, the inactivation is stably maintained, and the same chromosome is inactivated in all progeny cells. Therefore, females are mosaics of two populations of cells that differ in the X chromosome that is active. For more than three decades, researchers have used this mosaicism as a tool to examine the potential clonal origin of neoplasias in females ( 2 ), since, if the tumor (s) arose from a single cell after the time of X-chromosome inactivation, then it will have the same X chromosome active in all cells. This skewed (nonrandom) pattern of inactivation has been observed in a wide range of neoplastic tissues [ see ( 3 ) for recent review] and can be considered a consequence of the monoclonal origin of the neoplasia. However in this issue of the Journal, Buller et al. ( 4 ) report the finding of an elevated incidence of nonrandom X-chromosome inactivation in the somatic tissue of females with invasive ovarian cancer and BRCA1 mutations.
What is Belmont JW?
Belmont JW. Genetic control of X inactivation and processes leading to X-inactivation skewing.
What is Lyon MF?
Lyon MF. Gene action in the X-chromosome of the mouse ( Mus musculus L. ).
What happens if a female has an X autosome translocation?
Cytogenetic abnormalities: In females with an X–autosome translocation, the normal X chromosome will be preferentially inactivated , maintaining the diploid state for the autosome involved in the translocation. If the translocation disrupts or interferes with the expression of a gene on the X chromosome, or if the X chromosome involved in the translocation carries a variant allele, that female will manifest the disorder. The finding of X–autosome translocations in manifesting female carriers of Duchenne muscular dystrophy was instrumental in the mapping and cloning of the dystrophin gene.
Why do carriers have reciprocal X autosome translocations?
In this situation, the normal X with the healthy allele selectively inactivates in all cells. This happens because inactivation of the translocated X would spread through the disrupted, nonfunctioning gene to the adjoining autosomal genes, which would be lethal.
How does DMD affect males?
Although DMD primarily affects males through inheritance of the mutated copy of the DMD gene from a carrier mother, one-third of all DMD cases occur from spontaneous mutations of the gene.
What happens when a gene is on the X chromosome?
Elimination of cells expressing the variant allele: If a gene on the X chromosome is required for cell survival, the normal gene will always be found on the active X chromosome and the defective gene on the inactive X chromosome in the mature cell population, even though X inactivation occurred as a random process.
What happens if a translocation disrupts the expression of a gene on the X chromosome?
If the translocation disrupts or interferes with the expression of a gene on the X chromosome, or if the X chromosome involved in the translocation carries a variant allele , that female will manifest the disorder.
Why is dystrophinopathy slower in females?
Female patients can show asymmetric weakness due to varied X-inactivation patterns in different muscles. Also, the disease in female patients is generally less rapidly progressive than in male patients with similar presentations. The reason for the slower progression is the tendency of female muscle to become more dystrophin-normal with age (genetic and biochemical normalization). 14
Why do female carriers have muscle weakness?
Around 10% of female carriers have some muscle weakness (so-called ‘manifesting carriers’) due to skewed X-inactivation, the proportion of X chromosomes expressing the mutant gene being greater than in normal carriers.
How many X-linked genes are there?
Of 271 X-linked genes present in our data, 113 had SNVs with sufficient coverage in at least five individuals (informative genes). As expected, for most of the analyzed genes we do not see evidence for consistent escapee behavior, like for TFE3 (Fig. 4d ). We compared the results of our escapee behavior analysis with previous studies (Fig. 5 ). For the majority of “known” escapee genes, like PUDP (Fig. 4a ), we obtained significant evidence for escape from X-inactivation in blood, but others, like TRAPPC2 (Fig. 4b ), do not show such evidence. Collectively, 21 of the informative genes were previously reported to escape X-inactivation in at least one study [ 14, 20, 21, 22, 23 ], but only 11 of them escape X-inactivation in blood, according to our data. On the contrary, we found three genes that escape X-inactivation according to our data, SSR4, REPS2, and SEPT6 (Fig. 4d–f ), but have not been described as an escapee ( SSR4 and SEPT6) or have been reported to escape X-inactivation in a subgroup of individuals ( REPS2) [ 20 ]. Another gene that appeared significant in our study is GAPDHP65 (Fig. 4g ), but this (pseudo)gene demonstrated a clear reference bias (for SNVs in this gene, only reference allele is expressed), likely due to mapping of reads derived from homologous genes, and should therefore not be regarded as a new escapee gene. Results for all 113 informative genes are presented in Supplementary Table 1. Collectively, we have identified several novel variable escapee genes and our data reveal that many “known” escapee genes are most probably variable escapees.
How many individuals express only the maternal X chromosome?
One can see that 1 out of 16 individuals would express only the paternal X-chromosome and 1 out of 16 individuals would express only the maternal X-chromosome, that is, one out of eight individuals show complete skewing of X-chromosomal expression.
Why does skewing occur?
Firstly, skewing might be caused by selective pressure: a variant on one of the X-chromosomes is associated with lethality or limited survival and will undergo negative selection [ 4 ]. This explains, to a certain degree, symptoms in female carriers of variants associated with X-linked recessive diseases.
How does X inactivation happen?
To test how many blood (hematopoietic) precursor cells would be present at the time of X-inactivation to explain the degree of skewing observed in the general female population, we performed simulations. In case X-inactivation happens when there are four precursor cells present, it is quite likely that all of them, just by chance, inactivate the same (paternal or maternal) chromosome. One can see that 1 out of 16 individuals would express only the paternal X-chromosome and 1 out of 16 individuals would express only the maternal X-chromosome, that is, one out of eight individuals show complete skewing of X-chromosomal expression. When the initial pool consists of 32 cells, this chance is only approximately 5 × 10 −10. We observed that the distribution of paternal ratios in the population, in a scenario where X-inactivation in the embryonic stage where eight cells give rise to the hematopoietic compartment, was most similar to the observed distribution in the female population under study (Fig. 3 ).
What is X inactivation?
X-inactivation is a well-established dosage compensation mechanism ensuring that X-chromosomal genes are expressed at comparable levels in males and females. Skewed X-inactivation is often explained by negative selection of one of the alleles. We demonstrate that imbalanced expression of the paternal and maternal X-chromosomes is common in the general population and that the random nature of the X-inactivation mechanism can be sufficient to explain the imbalance. To this end, we analyzed blood-derived RNA and whole-genome sequencing data from 79 female children and their parents from the Genome of the Netherlands project. We calculated the median ratio of the paternal over total counts at all X-chromosomal heterozygous single-nucleotide variants with coverage ≥10. We identified two individuals where the same X-chromosome was inactivated in all cells. Imbalanced expression of the two X-chromosomes (ratios ≤0.35 or ≥0.65) was observed in nearly 50% of the population. The empirically observed skewing is explained by a theoretical model where X-inactivation takes place in an embryonic stage in which eight cells give rise to the hematopoietic compartment. Genes escaping X-inactivation are expressed from both alleles and therefore demonstrate less skewing than inactivated genes. Using this characteristic, we identified three novel escapee genes ( SSR4, REPS2, and SEPT6 ), but did not find support for many previously reported escapee genes in blood. Our collective data suggest that skewed X-inactivation is common in the general population. This may contribute to manifestation of symptoms in carriers of recessive X-linked disorders. We recommend that X-inactivation results should not be used lightly in the interpretation of X-linked variants.
What is X chromosome inactivation?
X-chromosome inactivation is responsible for sex chromosome dosage compensation in females (XX), and ensures that X-chromosomal genes are not expressed at twice the levels of expression in males (XY) [ 1 ]. It occurs during early female embryonic development [ 2 ], but the exact timing in humans is still elusive.
Where does X-inactivation occur in humans?
Initiation of random X-inactivation starts in the inner cell mass mouse female blastocyst embryos at embryonic day (E)4, whereas imprinted X-inactivation occurs at day E2 and remains in the trophoblast cells [ 37, 38 ]. 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 ]. Interestingly, XIST and another long noncoding RNA XACT are expressed from both X-chromosomes in blastocysts [ 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.
What is hemophilia clotting disorder?
Hemophilia is the most common hereditary [1] clotting disorder characterized by impaired coagulation leading to bleeding diathesis depending on the severity of the case. There are three types of heritable hemophilia, classified as type A, B, and C, all caused by the mutations in genes responsible for clotting factor (F) VIII, IX, and XI respectively. Genes for FVIII and FIX are located on chromosome X in the human genome, whereas the gene responsible for FXI is on chromosome 4. Hemophilia A (FVIII deficiency) makes up to 80-90% of the total disease burden, hemophilia B makes up to 10-20%, and hemophilia C is mainly concentrated in the Jewish population of Ashkenazi descent [2,3].
How often should I take FVIII?
For prophylaxis, 25 to 40 IUs /kg (body weight) of FVIII and FIX are administered thrice/week for hemophilia A and twice a week for hemophilia B, respectively (Malmo protocol). Long-lasting recombinant products allow once a week or once every two-week use. Inhibitor development with long-term use of replacement factors can significantly reduce the effect of exogenous factors; emicizumab does not have inhibitor issues.
What is DPVV used for?
Desmopressin (DPVV) is used in mild-to-moderate bleeding of hemophilia A; it does not have any role in hemophilia B [16]. DPVV releases subendothelial von Willebrand factor (VWF), and VWF subsequently stabilizes FVIII in plasma, increasing its half-life. Fresh frozen plasma is no longer used in hemophilia patients because of volume overload and viral elimination concerns.
What is the first sign of hemophilia?
In hemophilic children, the initial symptom is usually prolonged bleeding after circumcision and vaccination (from injection site). Vacuum extractor or forceps use during delivery can cause cephalic hematoma or large ecchymosis. Initial laboratory clue to hemophilia is prolonged aPTT (activated partial thromboplastin time) values with normal PT (prothrombin time), bleeding time, and platelet count. Diagnosis is confirmed by measuring the clotting factor (FVIII, FIX) activity in plasma. The average age of diagnosis of hemophilia is nine months of age, with almost all moderate-to-severe cases diagnosed by the age of two.
How does lyonization occur?
Lyonization is a process by which one of two X chromosomes in a female randomly becomes inactivated, forming a bar body early during fetal life; the process of inactivation is just by random selection. The inactive X chromosome becomes a part of heterochromatin as it is transcriptionally inactive due to its tight packing. As nearly all females have two X chromosomes, the process of lyonization prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome. Although this inactivation is random but permanent in the cell, the same chromosome remains inactive throughout that cell's progeny. On average, 50% of the maternal X chromosome and 50% of paternal X chromosomes become inactivated in all the body's somatic cells by random selection. It is depicted by a normal distribution curve in the general population (point a) (Figure 2 ). But as on both extremes, distribution becomes skewed, and one type of chromosomes becomes more inactivated in some populations of females [6-10]. The risk of disease manifestations increases as more normal X chromosomes become inactive as depicted by point b. However, there is a poor correlation between plasma clotting factor level and X chromosome inactivation pattern in some studies [2,11].
How long after a hematologic syringe is a maintenance dose given?
The preceding formulas are for the initial dosing, and the maintenance dose is usually one half of the initial dose given after 12 hours of initial dose in hemophilia A (FVIII) and given after 24 hours in hemophilia B (FIX).
Why do females have hemophilia?
Other possible causes of hemophilia manifestation in females are homozygous hemophilia status, Turner syndrome in hemophilia carriers, and acquired hemophilia [12]. Severe deficiency of vitamin K can cause hemophilia-like manifestations as well as von Willebrand disease, which can mimic type A hemophilia.
