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77-479: X-inactivation (also called Lyonization , after English geneticist Mary Lyon ) is a process by which one of 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

154-466: 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

231-448: A Mendelian fashion, but have more complex patterns of inheritance. For some traits, neither allele is completely dominant. Heterozygotes often have an appearance somewhere in between those of homozygotes. For example, a cross between true-breeding red and white Mirabilis jalapa results in pink flowers. Codominance refers to traits in which both alleles are expressed in the offspring in approximately equal amounts. A classic example

308-402: A Y chromosome from their father. X-linked dominant conditions can be distinguished from autosomal dominant conditions in pedigrees by the lack of transmission from fathers to sons, since affected fathers only pass their X chromosome to their daughters. In X-linked recessive conditions, males are typically affected more commonly because they are hemizygous, with only one X chromosome. In females,

385-479: 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

462-461: A copy of the recessive allele in order to have an affected offspring, the parents are referred to as carriers of the condition. In autosomal conditions, the sex of the offspring does not play a role in their risk of being affected. In sex-linked conditions, the sex of the offspring affects their chances of having the condition. In humans, females inherit two X chromosomes , one from each parent, while males inherit an X chromosome from their mother and

539-460: A dominant "A" allele codes for brown hair, and a recessive "a" allele codes for blonde hair, but a separate "B" gene controls hair growth, and a recessive "b" allele causes baldness. If the individual has the BB or Bb genotype, then they produce hair and the hair color phenotype can be observed, but if the individual has a bb genotype, then the person is bald which masks the A gene entirely. A polygenic trait

616-431: 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

693-411: A genotype of Bb. The offspring can inherit a dominant allele from each parent, making them homozygous with a genotype of BB. The offspring can inherit a dominant allele from one parent and a recessive allele from the other parent, making them heterozygous with a genotype of Bb. Finally, the offspring could inherit a recessive allele from each parent, making them homozygous with a genotype of bb. Plants with

770-566: 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

847-547: 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

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924-404: A mentor and her remarkable career which began in a time period where very few women became scientists. The award is presented annually to early- and mid-stage independent female researchers. Genotype Genotype contributes to phenotype , the observable traits and characteristics in an individual or organism. The degree to which genotype affects phenotype depends on the trait. For example,

1001-590: A mutant mice strain with a 'pallid' mutation and published the research. During the course of her PhD she moved to the University of Edinburgh , where she completed her studies under the direction of Douglas Falconer. After her PhD (awarded 1950 ), Lyon joined the group of Conrad Hal Waddington , with whom she worked in the last part of her PhD. The group was funded by the Medical Research Council , and she worked with TC Carter to investigate mutagenesis and

1078-407: 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

1155-490: 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 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

1232-415: A single copy of the X chromosome (see dosage compensation ). The choice of which X chromosome will be inactivated in 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

1309-479: A specified genotype in their phenotype under a given set of environmental conditions. Traits that are determined exclusively by genotype are typically inherited in a Mendelian pattern. These laws of inheritance were described extensively by Gregor Mendel , who performed experiments with pea plants to determine how traits were passed on from generation to generation. He studied phenotypes that were easily observed, such as plant height, petal color, or seed shape. He

1386-441: Is a carrier for a particular condition. This can be done via a variety of techniques, including allele specific oligonucleotide (ASO) probes or DNA sequencing . Tools such as multiplex ligation-dependent probe amplification can also be used to look for duplications or deletions of genes or gene sections. Other techniques are meant to assess a large number of SNPs across the genome, such as SNP arrays . This type of technology

1463-449: Is an autosomal dominant condition, but up to 25% of individuals with the affected genotype will not develop symptoms until after age 50. Another factor that can complicate Mendelian inheritance patterns is variable expressivity , in which individuals with the same genotype show different signs or symptoms of disease. For example, individuals with polydactyly can have a variable number of extra digits. Many traits are not inherited in

1540-441: 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

1617-431: Is commonly used for genome-wide association studies . Large-scale techniques to assess the entire genome are also available. This includes karyotyping to determine the number of chromosomes an individual has and chromosomal microarrays to assess for large duplications or deletions in the chromosome. More detailed information can be determined using exome sequencing , which provides the specific sequence of all DNA in

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1694-485: 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

1771-408: Is one whose phenotype is dependent on the additive effects of multiple genes. The contributions of each of these genes are typically small and add up to a final phenotype with a large amount of variation. A well studied example of this is the number of sensory bristles on a fly. These types of additive effects is also the explanation for the amount of variation in human eye color. Genotyping refers to

1848-538: 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

1925-454: 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

2002-510: Is the ABO blood group system in humans, where both the A and B alleles are expressed when they are present. Individuals with the AB genotype have both A and B proteins expressed on their red blood cells. Epistasis is when the phenotype of one gene is affected by one or more other genes. This is often through some sort of masking effect of one gene on the other. For example, the "A" gene codes for hair color,

2079-513: Is the flower colour in pea plants (see Gregor Mendel ). There are three available genotypes, PP ( homozygous dominant ), Pp (heterozygous), and pp (homozygous recessive). All three have different genotypes but the first two have the same phenotype (purple) as distinct from the third (white). A more technical example to illustrate genotype is the single-nucleotide polymorphism or SNP. A SNP occurs when corresponding sequences of DNA from different individuals differ at one DNA base, for example where

2156-407: Is using a Punnett square . In a Punnett square, the genotypes of the parents are placed on the outside. An uppercase letter is typically used to represent the dominant allele, and a lowercase letter is used to represent the recessive allele. The possible genotypes of the offspring can then be determined by combining the parent genotypes. In the example on the right, both parents are heterozygous, with

2233-763: The X-linked pigment gene, should not be confused with mosaicism , which 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

2310-449: 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

2387-457: The mutagenic effects of irradiation as measured in mice, and on the building of the hypothesis that one of the two X chromosomes of the female is inactivated at an early stage of embryogenesis . The hypothesis, which is now almost universally accepted as proved, offered a solution to the long standing problem of X- dosage compensation in the female mammal, has thrown much light on the nature of sex-chromosome aneuploidy , has influenced ideas on

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2464-425: The petal color in a pea plant is exclusively determined by genotype. The petals can be purple or white depending on the alleles present in the pea plant. However, other traits are only partially influenced by genotype. These traits are often called complex traits because they are influenced by additional factors, such as environmental and epigenetic factors. Not all individuals with the same genotype look or act

2541-921: The Amory Prize, for genetic discoveries relating to mammalian sex chromosomes. In 2004 she was awarded the March of Dimes Prize in Developmental Biology . In 2006 she received the Pearl Meister Greengard Prize awarded by the Rockefeller University . Since 2015 The Genetics Society has awarded the Mary Lyon Medal in her honour. Other awards and honours include: Her nomination for the Royal Society reads: Distinguished for many important contributions to mammalian genetics, notably on

2618-671: The BB and Bb genotypes will look the same, since the B allele is dominant. The plant with the bb genotype will have the recessive trait. These inheritance patterns can also be applied to hereditary diseases or conditions in humans or animals. Some conditions are inherited in an autosomal dominant pattern, meaning individuals with the condition typically have an affected parent as well. A classic pedigree for an autosomal dominant condition shows affected individuals in every generation. Other conditions are inherited in an autosomal recessive pattern, where affected individuals do not typically have an affected parent. Since each parent must have

2695-420: 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

2772-622: 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

2849-414: 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

2926-601: 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

3003-739: 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

3080-680: 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

3157-463: 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

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3234-451: 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

3311-448: 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

3388-411: 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 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

3465-460: 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

3542-442: The coding region of the genome, or whole genome sequencing , which sequences the entire genome including non-coding regions. In linear models, the genotypes can be encoded in different manners. Let us consider a biallelic locus with two possible alleles, encoded by A {\textstyle A} and a {\displaystyle a} . We consider a {\displaystyle a} to correspond to

3619-694: The eldest out of three children of a civil servant and a schoolteacher . She was educated at a grammar school in Birmingham. During that time, she said, she became interested in science thanks to a good schoolteacher and nature books she won in an essay competition. During the Second World War in 1943, she began her studies at Girton College, Cambridge at the University of Cambridge , where she read zoology, physiology, organic chemistry and biochemistry, with zoology as her main subject. At this time, only 500 (less than 10%) female students were allowed to study at

3696-407: The embryo), and in these cells both X chromosomes become active again. Each of these cells then independently and randomly inactivates one copy of 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

3773-521: 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,

3850-409: 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

3927-407: The evidence is coming from mice, the above scheme represents the events in mice. The completion of 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

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4004-414: 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

4081-485: 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

4158-464: 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

4235-500: The genetic risks of radiation . In addition to the 'pallid' mutation mice, she studied mutations such as 'ataxia' (a nervous mutation which caused walking difficulties in the mice) and 'twirler' (a mutation which induced inner ear issues, causing the mice to shake their heads and walk in circles due to lack of balance). In 1955, her group moved to the MRC radiobiology unit in Harwell, where there

4312-455: The inactivated X chromosome (in the nucleus of the red cell's precursor cell) contains the normal or defective G6PD allele. Mary F. Lyon Mary Frances Lyon FRS (15 May 1925 – 25 December 2014) was an English geneticist best known for her discovery of X-chromosome inactivation , an important biological phenomenon. Mary Lyon was born on 15 May 1925 in Norwich, England as

4389-490: 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

4466-490: The method used to determine an individual's genotype. There are a variety of techniques that can be used to assess genotype. The genotyping method typically depends on what information is being sought. Many techniques initially require amplification of the DNA sample, which is commonly done using PCR . Some techniques are designed to investigate specific SNPs or alleles in a particular gene or set of genes, such as whether an individual

4543-633: The mutation was positioned on the X chromosome. This, together with new findings at that time concerning the X chromosome, led her to hypothesize about X chromosome silencing. Lyon published many papers on radiation and chemical mutagenesis and on studies of mutant genes. She also did extensive work on the mouse t-complex. She was head of the Genetics Section of the MRC Radiology Unit at Harwell from 1962 to 1987. Although she retired from research in 1990, according to an interview from 2010, she

4620-580: The origin of certain tumours and of chronic granulocytic leukaemia in man, and has provided food for thought about the fundamental mechanism of switching off genes. Lyonisation, as others were quick to call the phenomenon, has perhaps opened more lines of enquiry and stimulated more work than any recent biological concept. In 2018, the International Mammalian Genome Society established the Mary Lyon Award in recognition her role as

4697-421: The paternally-derived X chromosome in 4–8 cell stage embryos . The extraembryonic tissues (which give rise to the placenta and other tissues supporting 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

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4774-455: 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 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

4851-431: 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

4928-543: The presence of a second X chromosome will prevent the condition from appearing. Females are therefore carriers of the condition and can pass the trait on to their sons. Mendelian patterns of inheritance can be complicated by additional factors. Some diseases show incomplete penetrance , meaning not all individuals with the disease-causing allele develop signs or symptoms of the disease. Penetrance can also be age-dependent, meaning signs or symptoms of disease are not visible until later in life. For example, Huntington disease

5005-401: 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

5082-557: The same way because appearance and behavior are modified by environmental and growing conditions. Likewise, not all organisms that look alike necessarily have the same genotype. The term genotype was coined by the Danish botanist Wilhelm Johannsen in 1903. Any given gene will usually cause an observable change in an organism, known as the phenotype. The terms genotype and phenotype are distinct for at least two reasons: A simple example to illustrate genotype as distinct from phenotype

5159-401: The sequence AAGCCTA changes to AAGCTTA. This contains two alleles : C and T. SNPs typically have three genotypes, denoted generically AA Aa and aa. In the example above, the three genotypes would be CC, CT and TT. Other types of genetic marker , such as microsatellites , can have more than two alleles, and thus many different genotypes. Penetrance is the proportion of individuals showing

5236-400: 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,

5313-464: 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 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

5390-486: 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

5467-481: The university, in contrast to more than 5,000 men. Furthermore, despite doing the same work as male students, female students received only “titular" degrees, rather than full Cambridge degrees that would make them members of the university. During her studies at Cambridge, she became interested in embryology. She went on to do her PhD with Ronald Fisher , who was Professor of Genetics in Cambridge, where she characterised

5544-478: Was able to observe that if he crossed two true-breeding plants with distinct phenotypes, all the offspring would have the same phenotype. For example, when he crossed a tall plant with a short plant, all the resulting plants would be tall. However, when he self-fertilized the plants that resulted, about 1/4 of the second generation would be short. He concluded that some traits were dominant , such as tall height, and others were recessive, like short height. Though Mendel

5621-753: Was elected a Fellow of the Royal Society in 1973, a Foreign Associate of the US National Academy of Sciences , and a Foreign Honorary Member of the American Academy of Arts and Sciences . In 1994 she won the Mauro Baschirotto Award in Human Genetics, in 1997 the Wolf Prize for Medicine, for her hypothesis concerning the random inactivation of X-chromosomes in mammals. In 1997 she also received

5698-430: Was not aware at the time, each phenotype he studied was controlled by a single gene with two alleles. In the case of plant height, one allele caused the plants to be tall, and the other caused plants to be short. When the tall allele was present, the plant would be tall, even if the plant was heterozygous. In order for the plant to be short, it had to be homozygous for the recessive allele. One way this can be illustrated

5775-418: Was room for more mouse facilities. There she continued to investigate the mouse mutations. She also scrutinised a 'mottled' mutant, which had a different effect on male and female mice: male embryos sometimes died, and the surviving males had white coats, but females lived and were variegated. Through calculated and deliberated breeding of mutants, she investigated the transition of the mutation and concluded that

5852-456: Was still active in the laboratory a few times a week. It was while working on radiation hazards in 1961 that she discovered X-chromosome inactivation , for which she is best known, and the phenomenon is sometimes known as Lyonization in her honour. Her subsequent research helped elucidate the genetic control mechanisms of the X chromosome and helped explain why female 'carriers' of X-linked genetic disorders can display mild symptoms. Lyon

5929-547: 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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