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66-562: In human genetics , the Atlantic modal haplotype (AMH) or haplotype 15 is a Y chromosome haplotype of Y-STR microsatellite variations, associated with the Haplogroup R1b . It was discovered prior to many of the SNPs now used to identify subclades of R1b and references to it can be found in some of the older literature. It corresponds most closely with subclade R1b1a2a1a(1) [L11]. The AMH

132-466: A pseudoautosomal region , no dosage compensation is needed for females, so it is postulated that these regions of DNA have evolved mechanisms to escape X-inactivation. The genes of pseudoautosomal regions of the Xi do not have the typical modifications of the Xi and have little Xist RNA bound. The existence of genes along the inactive X which are not silenced explains the defects in humans with atypical numbers of

198-482: A chromosome occurs. It is thought that skewing happens either by chance or by a physical characteristic of a chromosome that may cause it to be silenced more or less often, such as an unfavorable mutation. On average, each X chromosome is inactivated in half of the cells, although 5-20% of women display X-inactivation skewing. In cases where skewing is present, a broad range of symptom expression can occur, resulting in expression varying from minor to severe depending on

264-433: A female heterozygous for haemophilia (an X-linked disease) would have about half of her liver cells functioning properly, which is typically enough to ensure normal blood clotting. Chance could result in significantly more dysfunctional cells; however, such statistical extremes are unlikely. Genetic differences on the chromosome may also render one X-chromosome more likely to undergo inactivation. Also, if one X-chromosome has

330-571: A large non-coding RNA that is responsible for mediating the specific silencing of the X chromosome from which it is transcribed. The inactive X chromosome is coated by Xist RNA, whereas the Xa is not (See Figure to the right). X chromosomes that lack the Xist gene cannot be inactivated. Artificially placing and expressing the Xist gene on another chromosome leads to silencing of that chromosome. Prior to inactivation, both X chromosomes weakly express Xist RNA from

396-548: A large RNA which is not believed to encode a protein. The Tsix RNA is transcribed antisense to Xist, meaning that the Tsix gene overlaps the Xist gene and is transcribed on the opposite strand of DNA from the Xist gene. Tsix is a negative regulator of Xist; X chromosomes lacking Tsix expression (and thus having high levels of Xist transcription) are inactivated much more frequently than normal chromosomes. Like Xist, prior to inactivation, both X chromosomes weakly express Tsix RNA from

462-407: A mutation hindering its growth or rendering it non viable, cells which randomly inactivated that X will have a selective advantage over cells which randomly inactivated the normal allele. Thus, although inactivation is initially random, cells that inactivate a normal allele (leaving the mutated allele active) will eventually be overgrown and replaced by functionally normal cells in which nearly all have

528-504: A particular embryonic cell is random in placental mammals such as humans, but once an X chromosome is inactivated it will remain inactive throughout the lifetime of the cell and its descendants in the organism (its cell line). The result is that the choice of inactivated X chromosome in all the cells of the organism is a random distribution, often with about half the cells having the paternal X chromosome inactivated and half with an inactivated maternal X chromosome; but commonly, X-inactivation

594-477: A process known as X inactivation . X inactivation is when one of the two X chromosomes in females is almost completely inactivated. It is important that this process occurs otherwise a woman would produce twice the amount of normal X chromosome proteins. The mechanism for X inactivation will occur during the embryonic stage. For people with disorders like trisomy X , where the genotype has three X chromosomes, X-inactivation will inactivate all X chromosomes until there

660-405: A recessive disease or trait can remain hidden for several generations before displaying the phenotype. Examples of autosomal recessive disorders are albinism , cystic fibrosis . X-linked genes are found on the sex X chromosome. X-linked genes just like autosomal genes have both dominant and recessive types. Recessive X-linked disorders are rarely seen in females and usually only affect males. This

726-426: A single gene on an autosome (non-sex chromosome)—they are called " dominant " because a single copy—inherited from either parent—is enough to cause this trait to appear. This often means that one of the parents must also have the same trait, unless it has arisen due to an unlikely new mutation. Examples of autosomal dominant traits and disorders are Huntington's disease and achondroplasia . Autosomal recessive traits

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792-411: A trait. Inbreeding , or mating between closely related organisms, can clearly be seen on pedigree charts. Pedigree charts of royal families often have a high degree of inbreeding, because it was customary and preferable for royalty to marry another member of royalty. Genetic counselors commonly use pedigrees to help couples determine if the parents will be able to produce healthy children. A karyotype

858-403: A unique mechanism of dosage compensation . In particular, by way of the process called X-chromosome inactivation (XCI), female mammals transcriptionally silence one of their two Xs in a complex and highly coordinated manner. Genetic Chromosomal X inactivation X-inactivation (also called Lyonization , after English geneticist Mary Lyon ) is a process by which one of

924-638: Is a term that specifically refers to differences in the genotype of various cell populations in the same individual; X-inactivation, which is an epigenetic change that results in a different phenotype, is not a change at the genotypic level. For an individual cell or lineage the inactivation is therefore skewed or ' non-random ', and this can give rise to mild symptoms in female 'carriers' of X-linked genetic disorders. Typical females possess two X chromosomes, and in any given cell one chromosome will be active (designated as Xa) and one will be inactive (Xi). However, studies of individuals with extra copies of

990-420: Is a very useful tool in cytogenetics. A karyotype is picture of all the chromosomes in the metaphase stage arranged according to length and centromere position. A karyotype can also be useful in clinical genetics, due to its ability to diagnose genetic disorders. On a normal karyotype, aneuploidy can be detected by clearly being able to observe any missing or extra chromosomes. Giemsa banding, g-banding , of

1056-441: Is apparent in some localized traits, such as the unique coat pattern of a calico cat . It can be more difficult, however, to fully understand the expression of un-localized traits in these females, such as the expression of disease. Since males only have one copy of the X chromosome, all expressed X-chromosomal genes (or alleles , in the case of multiple variant forms for a given gene in the population) are located on that copy of

1122-441: Is because males inherit their X chromosome and all X-linked genes will be inherited from the maternal side. Fathers only pass on their Y chromosome to their sons, so no X-linked traits will be inherited from father to son. Men cannot be carriers for recessive X linked traits, as they only have one X chromosome, so any X linked trait inherited from the mother will show up. Females express X-linked disorders when they are homozygous for

1188-453: Is highly questionable and should be removed until properly substantiated by empirical data] The descendants of each cell which inactivated a particular X chromosome will also inactivate that same chromosome. This phenomenon, which can be observed in the coloration of tortoiseshell cats when females are heterozygous for the X-linked pigment gene, should not be confused with mosaicism , which

1254-428: Is in contrast to the inheritance of traits on autosomal chromosomes, where both sexes have the same probability of inheritance. Since humans have many more genes on the X than the Y , there are many more X-linked traits than Y-linked traits. However, females carry two or more copies of the X chromosome, resulting in a potentially toxic dose of X-linked genes . To correct this imbalance, mammalian females have evolved

1320-486: Is inactivated, as the alleles on both copies are the same. However, in females that are heterozygous at the causal genes, the inactivation of one copy of the chromosome over the other can have a direct impact on their phenotypic value. Because of this phenomenon, there is an observed increase in phenotypic variation in females that are heterozygous at the involved gene or genes than in females that are homozygous at that gene or those genes. There are many different ways in which

1386-573: Is located on the Y chromosome, determines the maleness of individuals. Besides the maleness inherited in the Y-chromosome there are no other found Y-linked characteristics. A pedigree is a diagram showing the ancestral relationships and transmission of genetic traits over several generations in a family. Square symbols are almost always used to represent males, whilst circles are used for females. Pedigrees are used to help detect many different genetic diseases. A pedigree can also be used to help determine

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1452-411: Is one pattern of inheritance for a trait, disease, or disorder to be passed on through families. For a recessive trait or disease to be displayed two copies of the trait or disorder needs to be presented. The trait or gene will be located on a non-sex chromosome. Because it takes two copies of a trait to display a trait, many people can unknowingly be carriers of a disease. From an evolutionary perspective,

1518-426: Is only one X chromosome active. Males with Klinefelter syndrome , who have an extra X chromosome, will also undergo X inactivation to have only one completely active X chromosome. Y-linked inheritance occurs when a gene, trait, or disorder is transferred through the Y chromosome. Since Y chromosomes can only be found in males, Y linked traits are only passed on from father to son. The testis determining factor , which

1584-542: Is placed by the PRC2 complex recruited by Xist , all of which are associated with gene silencing. PRC2 regulates chromatin compaction and chromatin remodeling in several processes including the DNA damage response. Additionally, a histone variant called macroH2A ( H2AFY ) is exclusively found on nucleosomes along the Xi. DNA packaged in heterochromatin, such as the Xi, is more condensed than DNA packaged in euchromatin , such as

1650-456: Is that 12–20% of genes on the inactivated X chromosome remain expressed, thus providing women with added protection against defective genes coded by the X-chromosome. Some suggest that this disparity must be evidence of preferential (non-random) inactivation. Preferential inactivation of the paternal X-chromosome occurs in both marsupials and in cell lineages that form the membranes surrounding

1716-784: Is the most frequently occurring haplotype amongst human males in Atlantic Europe . It is characterized by the following marker alleles : It reaches the highest frequencies in the Iberian Peninsula , in Great Britain and Ireland . In the Iberian Peninsula it reaches 70% in Portugal as a whole, more than 90% in NW Portugal and nearly 90% in Galicia (NW Spain ), while the highest value

1782-511: Is to be found among Spain and the Basques . One mutation in either direction, would be AMH 1.15+. The AMH 1.15 set of haplotypes is also referred to as the Atlantic modal cluster or AMC. Human genetics Genes are the common factor of the qualities of most human-inherited traits. Study of human genetics can answer questions about human nature, can help understand diseases and the development of effective treatment and help us to understand

1848-418: Is unevenly distributed across the cell lines within one organism ( skewed X-inactivation ). Unlike the random X-inactivation in placental mammals, inactivation in marsupials applies exclusively to the paternally-derived X chromosome. The paragraphs below have to do only with rodents and do not reflect XI in the majority of mammals. X-inactivation is part of the activation cycle of the X chromosome throughout

1914-517: The Human Genome Project was able to sequence all the DNA in the human genome, and to discover that the human genome was composed of around 20,000 protein coding genes. Medical genetics is the branch of medicine that involves the diagnosis and management of hereditary disorders . Medical genetics is the application of genetics to medical care. It overlaps human genetics, for example, research on

1980-449: The epiblast (cells that will give rise to the embryo). The maternal and paternal X chromosomes have an equal probability of inactivation. This would suggest that women would be expected to suffer from X-linked disorders approximately 50% as often as men (because women have two X chromosomes, while men have only one); however, in actuality, the occurrence of these disorders in females is much lower than that. One explanation for this disparity

2046-401: The sex of an individual is determined by a pair of sex chromosomes ( gonosomes ). Females have two of the same kind of sex chromosome (XX), and are called the homogametic sex . Males have two distinct sex chromosomes (XY), and are called the heterogametic sex . Sex linkage is the phenotypic expression of an allele related to the chromosomal sex of the individual. This mode of inheritance

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2112-445: The "power houses" of a cell, have their own DNA. Mitochondria are inherited from one's mother, and their DNA is frequently used to trace maternal lines of descent (see mitochondrial Eve ). Mitochondrial DNA is only 16kb in length and encodes for 62 genes. The XY sex-determination system is the sex-determination system found in humans , most other mammals , some insects ( Drosophila ), and some plants ( Ginkgo ). In this system,

2178-420: The Tsix gene. Upon the onset of X-inactivation, the future Xi ceases to express Tsix RNA (and increases Xist expression), whereas Xa continues to express Tsix for several days. Rep A is a long non coding RNA that works with another long non coding RNA, Xist, for X inactivation. Rep A inhibits the function of Tsix, the antisense of Xist, in conjunction with eliminating expression of Xite. It promotes methylation of

2244-623: The Tsix region by attracting PRC2 and thus inactivating one of the X chromosomes. The inactive X chromosome does not express the majority of its genes, unlike the active X chromosome. This is due to the silencing of the Xi by repressive heterochromatin , which compacts the Xi DNA and prevents the expression of most genes. Compared to the Xa, the Xi has high levels of DNA methylation , low levels of histone acetylation , low levels of histone H3 lysine-4 methylation , and high levels of histone H3 lysine-9 methylation and H3 lysine-27 methylation mark which

2310-414: The X chromosome show that in cells with more than two X chromosomes there is still only one Xa, and all the remaining X chromosomes are inactivated. This indicates that the default state of the X chromosome in females is inactivation, but one X chromosome is always selected to remain active. It is understood that X-chromosome inactivation is a random process, occurring at about the time of gastrulation in

2376-604: The X chromosome is necessary and sufficient to cause X-inactivation. Chromosomal translocations which place the XIC on an autosome lead to inactivation of the autosome, and X chromosomes lacking the XIC are not inactivated. The XIC contains four non- translated RNA genes, Xist , Tsix , Jpx and Ftx , which are involved in X-inactivation. The XIC also contains binding sites for both known and unknown regulatory proteins . The X-inactive specific transcript ( Xist ) gene encodes

2442-742: The X chromosome, such as Turner syndrome (X0, caused by SHOX gene ) or Klinefelter syndrome (XXY). Theoretically, X-inactivation should eliminate the differences in gene dosage between affected individuals and individuals with a typical chromosome complement. In affected individuals, however, X-inactivation is incomplete and the dosage of these non-silenced genes will differ as they escape X-inactivation, similar to an autosomal aneuploidy . The precise mechanisms that control escape from X-inactivation are not known, but silenced and escape regions have been shown to have distinct chromatin marks. It has been suggested that escape from X-inactivation might be mediated by expression of long non-coding RNA (lncRNA) within

2508-430: The X chromosome. This inactivation event is irreversible during the lifetime of the individual, with the exception of the germline. In the female germline before meiotic entry, X-inactivation is reversed, so that after meiosis all haploid oocytes contain a single active X chromosome. The Xi marks the inactive, Xa the active X chromosome. X denotes the paternal, and X to denotes the maternal X chromosome. When

2574-683: The X chromosomes underwent inactivation. In 1961, Mary Lyon proposed the random inactivation of one female X chromosome to explain the mottled phenotype of female mice heterozygous for coat color genes . The Lyon hypothesis also accounted for the findings that one copy of the X chromosome in female cells was highly condensed, and that mice with only one copy of the X chromosome developed as infertile females. This suggested to Ernest Beutler , studying heterozygous females for glucose-6-phosphate dehydrogenase (G6PD) deficiency, that there were two red cell populations of erythrocytes in such heterozygotes: deficient cells and normal cells, depending on whether

2640-464: The Xa. The inactive X forms a discrete body within the nucleus called a Barr body . The Barr body is generally located on the periphery of the nucleus , is late replicating within the cell cycle , and, as it contains the Xi, contains heterochromatin modifications and the Xist RNA. A fraction of the genes along the X chromosome escape inactivation on the Xi. The Xist gene is expressed at high levels on

2706-458: The Xi and is not expressed on the Xa. Many other genes escape inactivation; some are expressed equally from the Xa and Xi, and others, while expressed from both chromosomes, are still predominantly expressed from the Xa. Up to one quarter of genes on the human Xi are capable of escape. Studies in the mouse suggest that in any given cell type, 3% to 15% of genes escape inactivation, and that escaping gene identity varies between tissues. Many of

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2772-449: The Xist gene. During the inactivation process, the future Xa ceases to express Xist, whereas the future Xi dramatically increases Xist RNA production. On the future Xi, the Xist RNA progressively coats the chromosome, spreading out from the XIC; the Xist RNA does not localize to the Xa. The silencing of genes along the Xi occurs soon after coating by Xist RNA. Like Xist, the Tsix gene encodes

2838-492: The causes and inheritance of genetic disorders would be considered within both human genetics and medical genetics, while the diagnosis, management, and counseling of individuals with genetic disorders would be considered part of medical genetics. Population genetics is the branch of evolutionary biology responsible for investigating processes that cause changes in allele and genotype frequencies in populations based upon Mendelian inheritance . Four different forces can influence

2904-437: The chances for a parent to produce an offspring with a specific trait. Four different traits can be identified by pedigree chart analysis: autosomal dominant, autosomal recessive, x-linked, or y-linked. Partial penetrance can be shown and calculated from pedigrees. Penetrance is the percentage expressed frequency with which individuals of a given genotype manifest at least some degree of a specific mutant phenotype associated with

2970-460: The chromosome. Females, however, will primarily express the genes or alleles located on the X-chromosomal copy that remains active. Considering the situation for one gene or multiple genes causing individual differences in a particular phenotype (i.e., causing variation observed in the population for that phenotype), in homozygous females it does not particularly matter which copy of the chromosome

3036-416: The chromosomes to fluoresce a unique color. Genomics is the field of genetics concerned with structural and functional studies of the genome. A genome is all the DNA contained within an organism or a cell including nuclear and mitochondrial DNA. The human genome is the total collection of genes in a human being contained in the human chromosome, composed of over three billion nucleotides. In April 2003,

3102-489: The copies of the X chromosome is inactivated in therian female mammals . The inactive X chromosome is silenced by being packaged into a transcriptionally inactive structure called heterochromatin . As nearly all female mammals have two X chromosomes, X-inactivation prevents them from having twice as many X chromosome gene products as males, who only possess a single copy of the X chromosome (see dosage compensation ). The choice of which X chromosome will be inactivated in

3168-544: The disorder and become carriers when they are heterozygous. X-linked dominant inheritance will show the same phenotype as a heterozygote and homozygote. Just like X-linked inheritance, there will be a lack of male-to-male inheritance, which makes it distinguishable from autosomal traits. One example of an X-linked trait is Coffin–Lowry syndrome , which is caused by a mutation in ribosomal protein gene. This mutation results in skeletal, craniofacial abnormalities, mental retardation, and short stature. X chromosomes in females undergo

3234-424: The egg (carrying X ), is fertilized by a sperm (carrying a Y or an X ) a diploid zygote forms. From zygote, through adult stage, to the next generation of eggs, the X chromosome undergoes the following changes: The X activation cycle has been best studied in mice, but there are multiple studies in humans. As most of the evidence is coming from mice, the above scheme represents the events in mice. The completion of

3300-409: The embryo) retain this early imprinted inactivation, and thus only the maternal X chromosome is active in these tissues. In the early blastocyst , this initial, imprinted X-inactivation is reversed in the cells of the inner cell mass (which give rise to the embryo), and in these cells both X chromosomes become active again. Each of these cells then independently and randomly inactivates one copy of

3366-524: The embryo, whereas in placental mammals either the maternally or the paternally derived X-chromosome may be inactivated in different cell lines. The time period for X-chromosome inactivation explains this disparity. Inactivation occurs in the epiblast during gastrulation, which gives rise to the embryo. Inactivation occurs on a cellular level, resulting in a mosaic expression, in which patches of cells have an inactive maternal X-chromosome, while other patches have an inactive paternal X-chromosome. For example,

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3432-410: The escaping chromosomal domains. Stanley Michael Gartler used X-chromosome inactivation to demonstrate the clonal origin of cancers. Examining normal tissues and tumors from females heterozygous for isoenzymes of the sex-linked G6PD gene demonstrated that tumor cells from such individuals express only one form of G6PD, whereas normal tissues are composed of a nearly equal mixture of cells expressing

3498-415: The existence of a single Xa in cells with many X chromosomes and by the existence of two active X chromosomes in cell lines with twice the normal number of autosomes. Sequences at the X inactivation center ( XIC ), present on the X chromosome, control the silencing of the X chromosome. The hypothetical blocking factor is predicted to bind to sequences within the XIC. The effect of female X heterozygosity

3564-402: The female life. The egg and the fertilized zygote initially use maternal transcripts, and the whole embryonic genome is silenced until zygotic genome activation . Thereafter, all mouse cells undergo an early, imprinted inactivation of the paternally-derived X chromosome in 4–8 cell stage embryos . The extraembryonic tissues (which give rise to the placenta and other tissues supporting

3630-476: The frequencies: natural selection , mutation , gene flow (migration), and genetic drift . A population can be defined as a group of interbreeding individuals and their offspring. For human genetics the populations will consist only of the human species. The Hardy–Weinberg principle is a widely used principle to determine allelic and genotype frequencies. In addition to nuclear DNA , humans (like almost all eukaryotes ) have mitochondrial DNA . Mitochondria ,

3696-486: The genes on the extra copy of chromosome 21. In these modified stem cells, the Xist-mediated gene silencing seems to reverse some of the defects associated with Down syndrome. In 1959 Susumu Ohno showed that the two X chromosomes of mammals were different: one appeared similar to the autosomes ; the other was condensed and heterochromatic. This finding suggested, independently to two groups of investigators, that one of

3762-464: The genes which escape inactivation are present along regions of the X chromosome which, unlike the majority of the X chromosome, contain genes also present on the Y chromosome . These regions are termed pseudoautosomal regions, as individuals of either sex will receive two copies of every gene in these regions (like an autosome), unlike the majority of genes along the sex chromosomes. Since individuals of either sex will receive two copies of every gene in

3828-546: The genetics of human life. This article describes only basic features of human genetics; for the genetics of disorders please see: medical genetics . For information on the genetics of DNA repair defects related to accelerated aging and/or increased risk of cancer please see: DNA repair-deficiency disorder . Inheritance of traits for humans are based upon Gregor Mendel 's model of inheritance. Mendel deduced that inheritance depends upon discrete units of inheritance, called factors or genes. Autosomal traits are associated with

3894-405: The karyotype can be used to detect deletions , insertions , duplications, inversions, and translocations . G-banding will stain the chromosomes with light and dark bands unique to each chromosome. A FISH, fluorescent in situ hybridization , can be used to observe deletions, insertions, and translocations. FISH uses fluorescent probes to bind to specific sequences of the chromosomes that will cause

3960-491: The link between phenotype and skewing is still being questioned, and should be examined on a case-by-case basis. A study looking at both symptomatic and asymptomatic females who were heterozygous for Duchenne and Becker muscular dystrophies (DMD) found no apparent link between transcript expression and skewed X-Inactivation. The study suggests that both mechanisms are independently regulated, and there are other unknown factors at play. The X-inactivation center (or simply XIC) on

4026-444: The meiosis is simplified here for clarity. Steps 1–4 can be studied in in vitro fertilized embryos, and in differentiating stem cells; X-reactivation happens in the developing embryo, and subsequent (6–7) steps inside the female body, therefore much harder to study. The timing of each process depends on the species, and in many cases the precise time is actively debated. [The whole part of the human timing of X-inactivation in this table

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4092-432: The phenotypic variation can play out. In many cases, heterozygous females may be asymptomatic or only present minor symptoms of a given disorder, such as with X-linked adrenoleukodystrophy. The differentiation of phenotype in heterozygous females is furthered by the presence of X-inactivation skewing. Typically, each X-chromosome is silenced in half of the cells, but this process is skewed when preferential inactivation of

4158-403: The same X-chromosome activated. It is hypothesized that there is an autosomally-encoded 'blocking factor' which binds to the X chromosome and prevents its inactivation. The model postulates that there is a limiting blocking factor, so once the available blocking factor molecule binds to one X chromosome the remaining X chromosome(s) are not protected from inactivation. This model is supported by

4224-403: The skewing proportion. An extreme case of this was seen where monozygotic female twins had extreme variance in expression of Menkes disease (an X-linked disorder) resulting in the death of one twin while the other remained asymptomatic. It is thought that X-inactivation skewing could be caused by issues in the mechanism that causes inactivation, or by issues in the chromosome itself. However,

4290-489: The two different phenotypes. This pattern suggests that a single cell, and not a population, grows into a cancer. However, this pattern has been proven wrong for many cancer types, suggesting that some cancers may be polyclonal in origin. Besides, measuring the methylation (inactivation) status of the polymorphic human androgen receptor (HUMARA) located on X-chromosome is considered the most accurate method to assess clonality in female cancer biopsies. A great variety of tumors

4356-550: Was tested by this method, some, such as renal cell carcinoma, found monoclonal while others (e.g. mesothelioma ) were reported polyclonal. Researchers have also investigated using X-chromosome inactivation to silence the activity of autosomal chromosomes. For example, Jiang et al. inserted a copy of the Xist gene into one copy of chromosome 21 in stem cells derived from an individual with trisomy 21 ( Down syndrome ). The inserted Xist gene induces Barr body formation, triggers stable heterochromatin modifications, and silences most of

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