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1
Morey, Céline. "Caractérisation du rôle de la région en aval du gène Xist lors de l'inactivation du chromosome X murin par mutagenèse ciblée dans les cellules ES." Paris 5, 2004. http://www.theses.fr/2004PA05N040.
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Chez les mammifères, la compensation de dose des gènes liés à l' X entre les sexes est assurée par l' inactivation transcriptionnelle de l' un des deux chromosomes X, au hasard, chez la femelle. Ce processus dépend des fonctions de comptage et de choix et recquiert l' expression du gène Xist localisé sur le chromosome X. Ce gène produit un grand ARN non-codant qui recouvre le chromosome X inactif. La délétion de 65 kb en aval de Xist, incluant le minisatellite DXPas 34 et l' initiation d' une transcription antisens (Tsix), dans des cellules ES-cellules récapitulant l' inactivation lors de leur différenciation in vitro-induit l'altération du choix et du comptage. Par une stratégie de complémentation cre/oxP, nous avons montré que la restitution de Tsix au site de la délétion de 65 kb dans les cellules XX est insuffisante au rétablissement de l' inactivation aléatoire. . .In mammals, dosage compensation of X-linked genes is ensured by X-chromosome inactivation wherby one X chromosome in each female embryonic cell (ES) is chosen at random to become silenced. X-inactivation depends on the counting of X chromosomes and on the choice of the inactive X, It is mediated by the expression of the Xist non-coding RNA wich coats the inactive X and by the Tsix antisense transcipt, a Tsix antisense transcript, a Xist regulator. A 65 kb deletion extending 3' to Xist and including both Tsix and the DXPas34 minisatellite, disrupts choice and counting. Using a cre/loxP site-specific re-insertion strategy in XX deleted ES cells we showed that targeting back, at the 65 kb mutated locus, the Tsix antisense transcription fails to retore random X-inactivation. In contrast, normal counting can be restored in XO deleted ES cells. .
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Kayserili, Melek A., Dave T. Gerrard, Pavel Tomancak, and Alex T. Kalinka. "An Excess of Gene Expression Divergence on the X Chromosome in Drosophila Embryos: Implications for the Faster-X Hypothesis." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-180730.
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The X chromosome is present as a single copy in the heterogametic sex, and this hemizygosity is expected to drive unusual patterns of evolution on the X relative to the autosomes. For example, the hemizgosity of the X may lead to a lower chromosomal effective population size compared to the autosomes, suggesting that the X might be more strongly affected by genetic drift. However, the X may also experience stronger positive selection than the autosomes, because recessive beneficial mutations will be more visible to selection on the X where they will spend less time being masked by the dominant, less beneficial allele—a proposal known as the faster-X hypothesis. Thus, empirical studies demonstrating increased genetic divergence on the X chromosome could be indicative of either adaptive or non-adaptive evolution. We measured gene expression in Drosophila species and in D. melanogaster inbred strains for both embryos and adults. In the embryos we found that expression divergence is on average more than 20% higher for genes on the X chromosome relative to the autosomes; but in contrast, in the inbred strains, gene expression variation is significantly lower on the X chromosome. Furthermore, expression divergence of genes on Muller's D element is significantly greater along the branch leading to the obscura sub-group, in which this element segregates as a neo-X chromosome. In the adults, divergence is greatest on the X chromosome for males, but not for females, yet in both sexes inbred strains harbour the lowest level of gene expression variation on the X chromosome. We consider different explanations for our results and conclude that they are most consistent within the framework of the faster-X hypothesis.
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Coultas, Susan L. (Susan Lynette). "A comparison of straight-stained, Q-stained, and reverse flourescent-stained cell lines for detection of fragile sites on the human X chromosome." Thesis, North Texas State University, 1985. https://digital.library.unt.edu/ark:/67531/metadc798127/.
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Cell cultures were examined for percentage of fragile sites seen in straight-stained, Q-stained and reverse fluorescent-stained preparations. In all cases, percentage of fragile site expression was decreased when compared to straight-stained preparations. However, fragile sites seen in Q- and RF-stain could be identified as on X chromosomes.
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Turner, Caroline. "Cytogenetic and molecular studies of ring (X) chromosomes." Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297376.
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Avery, Mina. "Educational development in individuals with extra X chromosomes." abstract and full text PDF (free order & download UNR users only), 2008. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:1460746.
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Hussein, Sultana Muhammad School of Pathology UNSW. "Fragile X mental retardation and fragile X chromosomes in the Indonesian population." Awarded by:University of New South Wales. School of Pathology, 1998. http://handle.unsw.edu.au/1959.4/33198.
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The Indonesian archipelago comprises more than 17,000 islands, inhabited by ~200 million people constituting more than 350 recognizable ethnic and tribal groups which can be classified into two broad ethno-linguistic groups [the Austronesian (AN) and non-Austronesian (NAN) speaking peoples] and 3 physical anthropology groups (Deutero Malay, Proto Malay and Papuan). The origins of these groups are of considerable anthropological interest. The anthropology of Indonesia is extremely complex and still controversial. The present populations of Indonesia show very great diversity. The data presented below result from an investigation of the Fragile X A syndrome and the size and distribution of alleles at fragile sites on the X chromosome among Javanese males with developmental disability (DD) and unselected males from 10 major Indonesian ethnic groups. The Fragile X syndrome is caused by expansion of a CGG trinucleotide repeat array in the 5' untranslated region of the FMR-1 gene at Xq27.3. Normal X chromosomes have between 6-54 CGG trinucleotide repeats, whereas premutation alleles have 55-230 and full mutation alleles more than 230 repeats. In a study of predominantly Caucasian males with intellectual disability, the prevalence of Fragile X syndrome is estimated to be approximately 1:4,000. FRAXE mental retardation syndrome is caused by an expansion of a GCC trinucleotide repeat in the 5'UTR of FMR2 gene located 600 kb telomeric to FMR1. The prevalence of FMR2 is 1-2 per 100,000 live births. FMR2 common alleles consist of 11-30 GGC repeats; intermediate alleles between 31-60 GCC repeats; premutation alleles with 61-200 repeats and full mutation alleles have over 200 repeats with attendant methylation of the repeat array The first Indonesian screening program aimed at determining the presence and prevalence of fragile XA syndrome among individuals with mild DD (IQ above 50) from special schools (N=205) and isolated areas (N=50) of Java was undertaken in 1994-1996 by cytogenetic and molecular studies. In this first study 4 fragile X positive children were found among 255 males with DD. The estimated prevalence of fragile-X in males with mild DD from special schools was 1.95% (5/205) and the overall prevalence was 1.57% (4/255). The number of trinucleotide repeats in the 5' untranslated regions of the FMR1 and FMR2 genes were determined by PCR in 254 Fragile XA-negative Javanese male children with DD. The distribution of FMR1 and FMR2 trinucleotide repeat alleles was found to be significantly different in the Indonesian population with DD compared to that in equivalent Caucasian populations. The trimodal distribution of Indonesian FMR1 alleles (29, 30 and 36 repeats) is largely in agreement with findings from other Asian populations). This provides supportive evidence that the origin of Indonesians could be the same as that of the Chinese and Japanese. Sequence analysis was performed on the trinucleotide repeat arrays of the 27 individuals' FMR1 alleles in the 'grey zone' (35-52 repeats). The identification of 16 unrelated individuals with a (CGG)36 allele that also contains a (CGG)6 segment [(CGG)9AGG(CGG)9AGG(CGG)6 AGG(CGG)9 or 9A9A6A9 pattern] is in agreement with earlier observations in the Japanese population. It is proposed that this FMR1 array pattern may be specific for Asian populations and that Javanese and Japanese populations may have arisen from a single progenitor population. The presence of pure 25, 33 and 34 CGGs in FMR1 alleles with 36, 44 and 45 repeats respectively, suggests that these may represent alleles at high risk for instability and may therefore be at early stages of expansion to a premutation. The lack of the characteristic (CGG)6 in all three alleles with ?? 25 pure CGG arrays suggests that the most common Asian 36 repeat allele is not predisposed to slippage expansion. Seven of the 8 alleles with 36 CGG repeats could be sequenced. Seven of 36 CGG repeats FMR1 alleles from the Hiri population has been sequenced and 4 alleles indicated 9A9A6A9 pattern, 1 sample with 10A25 pattern Two of the remaining alleles showed 12A6A6A9 structure, which consisted of a tandem duplication of the (CGG)6 segment. The presence of a tandem duplication of (CGG)6 segments has never been reported in any other population. The other major findings of this study are that FRAXE syndrome is a rare cause of developmental disability in this predominantly-Javanese population. The most common FMR2 (GCC)20 allele in this selected Asian population is significantly longer than that previously reported for Caucasian populations. There was a weak correlation between the overall length of the FMR1 and FMR2 repeat arrays within the normal range (Spearman's Rank Correlation = 0.130, p-value=0.042) in the Indonesian population, which have been no previous associations reported for alleles within the normal range. One approach to studying the origins of the human populations is to study the genetic structure of polymorphic alleles such as those at the FMR1 locus and its linked microsatellite markers DXS548 and FRAXAC1. Length polymorphisms of the FMR1 gene (CGG)n repeat array, DXS548 and FRAXAC1 were studied in a total of 1,008 unselected males from 10 different Indonesian ethnic groups. FMR1 alleles were identified ranging from 8 to 57 CGG repeats. The most common CGG repeat allele was 29 (45.6%) followed by 30 (27.4%) and 36 repeats (8.0%). One hundred and forty four grey zone (3-52 CGG) alleles were found in the study population. Four people of the same ethnic group from an isolated island in Eastern Indonesia (Hiri, Ternate), a representative of the NAN ethnolinguistic group, had CGG repeat lengths of 55-57. The prevalence of these alleles is estimated to be 3.3% (4/120) in the population of Hiri or 0.4% (4/1008) of whole Indonesian population. Thirteen different alleles were found at the DXS548 locus, of which allele numbers 7 [194 bp] (44.1%), 6.5 [195bp] (43.5%) and 6 [196bp] (7.5%) are the most common. Seven rare alleles, some of which have not been previously found in Asian peoples were also identified (190, 191,192, 193, 197,198, 199, 202, 204 and 206) and accounted for 3.9% of the total. The odd number alleles were dominantly found in this study whereas almost none found in Caucasian. The finding of many "odd numbered" alleles DXS548 has never been found in other Asian population and has only been documented extremely rarely in Caucasians and Africans. Five different alleles of FRAXAC1 identified with alleles D [106 bp] (62.2%) and C [108bp] (35.6%) accounting for 97.8% of FRAXAC1 alleles in the population. Three rare alleles (104, 110, 112 bp = 2.2%) were identified that have not been previously found in other Asian populations (1-3). There is a striking linkage disequilibrium of FMR1 alleles with FRAXAC1 (p=0.0001), 88% of 29 (CGG)n repeats alleles associated with FRAXAC1 allele D (106bp) versus only 17% with the 30 (CGG)n repeat alleles, which is in agreement with other studies. The value of D' was calculated to be 0.7. The longer alleles of both DXS548 and FRAXAC1 were found mostly in the NAN ethnolinguistic group. Moreover the Irian Jaya people also showed a higher percentage of people with 30 CGG repeats and the 108 bp FRAXAC1. The Eastern Indonesian NAN groups demonstrate a different genetic background probably due to the contribution of Melanesian peoples. The Analysis of Molecular Variance (AMOVA) identified that the vast majority of genetic diversity occurs within, rather than between, ethnic groups. These data are consistent with a model where there is sufficient migration (~20 per generation) between populations to minimise differentiation of population through genetic drift. The results obtained are consistent with three clusters of populations that share similar allele frequencies at the fragile X locus. The most clearly defined cluster is based in the east of Indonesia and includes the two Irian populations, Minahasans and Hiri. A surprising finding was that the Minahasan who are Deutero-Malay in origin and physical appearance are genetically closer to the Irianese. This may reflect the admixture of Melanesian alleles or other eastern Indonesian alleles as a result of their geographic location in that part of Indonesia. The second major cluster is largely based in the west of the country and is composed of the following Deutero-Malay populations; Javanese, Balinese, Acehnese but which also includes people from Ternate (not including those from Hiri). Using Delta Mu and Nei's genetic distance for FMR1 locus in this study the Javanese were shown to have the closest distance to Balinese which is consistent with anthropological data and with published data. The third group is a "western and central" group composed of Bimanese, Dayak and Sundanese who share some features of the western and eastern clusters but mostly resemble the western Indonesian populations. Bima is located in the lesser Sunda in between west Indonesia and east Indonesia. The Bimanese are of mixed Deutero & Proto Malay origin that is consistent with their geographic location. The Bataks are distinctive and sit somewhat apart in this scheme. In this study, Bataks were found not to resemble the other Proto-Malay group studied (the Dayak). The Dayaks were found to have fewer alleles than the Bataks at FRAXAC1 and DXS548. In all four methods of calculating genetic distance Bataks showed a large genetic distance to almost all other ethnic groups. There are differences in allele frequency between east and west Indonesia as well as other Asian nations, but the genetic similarities between these groups are also very impressive. The findings from this study are consistent with other genetic anthropological evidence that the people of Indonesia have the same origin as North-east Asian groups. This model is referred to as the "express train from Taiwan" in which the Austronesian speakers are proposed to have radiated from Taiwan bringing the Malayo-Polynesian language group to the Philippines, Borneo and Sulawesi around 5000-4500 B.P.E. However Richards et al.(1998) have used the diversity in the mtDNA D Loop to propose an alternative to the "express train" model. The "two train7quot; model proposes that the Austronesian languages originated within eastern Indonesia during the Pleistocene era and spread through Melanesia and into the remote Pacific within the past 6,000 years. Unfortunately the high migration rates between population groups that were demonstrated in this thesis and the known migration patterns of populations through Indonesia preclude determining whether the observed allelic heterogeneity is a function of the original population or due to the admixture of several gene pools in more recent times.
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Holm, Sofia. "Molecular genetic studies of psoriasis susceptibility in 6p21.3 /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-225-X.
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Khalil, Ahmad M. "Histone modifications and chromatin dynamics of the mammalian inactive sex chromosomes title." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0008329.
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Thesis (Ph.D.)--University of Florida, 2004.Typescript. Title from title page of source document. Document formatted into pages; contains 102 pages. Includes Vita. Includes bibliographical references.
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Kayserili, Melek A., Dave T. Gerrard, Pavel Tomancak, and Alex T. Kalinka. "An Excess of Gene Expression Divergence on the X Chromosome in Drosophila Embryos: Implications for the Faster-X Hypothesis." PLOS, 2012. https://tud.qucosa.de/id/qucosa%3A28925.
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The X chromosome is present as a single copy in the heterogametic sex, and this hemizygosity is expected to drive unusual patterns of evolution on the X relative to the autosomes. For example, the hemizgosity of the X may lead to a lower chromosomal effective population size compared to the autosomes, suggesting that the X might be more strongly affected by genetic drift. However, the X may also experience stronger positive selection than the autosomes, because recessive beneficial mutations will be more visible to selection on the X where they will spend less time being masked by the dominant, less beneficial allele—a proposal known as the faster-X hypothesis. Thus, empirical studies demonstrating increased genetic divergence on the X chromosome could be indicative of either adaptive or non-adaptive evolution. We measured gene expression in Drosophila species and in D. melanogaster inbred strains for both embryos and adults. In the embryos we found that expression divergence is on average more than 20% higher for genes on the X chromosome relative to the autosomes; but in contrast, in the inbred strains, gene expression variation is significantly lower on the X chromosome. Furthermore, expression divergence of genes on Muller's D element is significantly greater along the branch leading to the obscura sub-group, in which this element segregates as a neo-X chromosome. In the adults, divergence is greatest on the X chromosome for males, but not for females, yet in both sexes inbred strains harbour the lowest level of gene expression variation on the X chromosome. We consider different explanations for our results and conclude that they are most consistent within the framework of the faster-X hypothesis.
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Fraser, Neil J. "Molecular studies of the human x and y chromosomes." Thesis, University of Oxford, 1987. http://ora.ox.ac.uk/objects/uuid:e22e64bb-64e5-4474-86e2-1c3d5eb6155a.
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The isolation and characterisation of sequences from the X and Y chromosomes will give some insight into the evolutionary relationship between these chromosomes, and may be of use in the study of X-linked disorders. The availability of cDNA and genomic sequences for the human STS locus (associated with the disorder, X-linked ichthyosis) has allowed a preliminary investigation of this locus in man and other species. The localisation of these sequences to Xp22.3, provides confirmation of the sub-regional assignment of the structural gene for STS. STS homologous sequences have been identified on the long arm of the Y chromosome. These sequences also appear present on the X and Y chromosomes of the chimpanzee. In other higher primates, they appear to be X-, but not Y-, linked, suggesting that the situation in man and chimpanzee is the result of a rearrangement between the X and Y chromosomes during the past 15 million years. Another region of X Y homology has been analysed. The locus DXYS27 maps to Yp and Xq21. Restriction enzyme analysis and direct sequence comparison has shown the two loci to be «99% homologous. Phylogenetic studies suggest that the locus is X-, but not Y-, linked in the chimpanzee, suggesting an evolutionarily recent transposition of material from the X to the Y chromosome. The mutations resulting in the X-Y differences appear to have occurred on both the X and Y chromosomes. It has been possible to demonstrate that the Y-specific locus is transferred to the X chromosome in many, but not all, aberrant X-Y interchanges resulting in XX maleness. A sequence has been isolated that detects a hypervariable locus at Xp11.3→Xcen (DXS255) . The hypervariability appears to be due to the presence of a tandemly repeated sequence of variable length. Attempts to clone this repeat have been unsuccessful, as it appears to be unstable in the vector/host systems employed. This sequence will be of value in linkage studies of disease loci known to be present in this region. Hypervariability at this locus has not been identified in other species, suggesting that the repeat sequence is an evolutionarily recent acquisition by the X chromosome. Taken together, the results obtained suggest that the simple model predicting an ancient origin for the bulk of the Y chromosome will have to be reassessed.
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Koenig, Michel. "Etude de marqueurs moléculaires des chromosomes X et Y humains." Grenoble 2 : ANRT, 1986. http://catalogue.bnf.fr/ark:/12148/cb375987796.
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Rouyer, François. "Les echanges genetiques entre les chromosomes x et y humains." Paris 6, 1990. http://www.theses.fr/1990PA066677.
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Les chromosomes x et y humains partagent des sequences d'adn strictement homologues a l'extremite de leurs bras courts. Ces sequences definissent la region pseudo-autosomique, soumise a un crossing-over unique et obligatoire a la meiose male. La position du crossing-over etablit un gradient de liaison genetique croissante au sexe, a partir du telomere. Ces proprietes conferent a la region pseudo-*autosomique un taux de recombinaison 15 a 20 fois plus eleve en meiose male qu'en meiose femelle, ou il est similaire au taux moyen rencontre dans le genome humain. Des echanges x-y anormaux sont responsables du syndrome de masculinite xx par transfert du locus de determination du sexe sur le chromosome x. Des zones preferentielles de cassure apparaissent sur x et y et pourraient correspondre a des homologies partielles. Un echange x-y anormal impliquant une region specifique du y et la region pseudoautosomique du x a ete analyse chez un male xx. L'analyse moleculaire du point de jonction montre qu'il resulte d'une recombinaison homologue entre deux sequences repetee alu. La region pseudoautosomique contient des sequences repetees et dispersees: les elements stir (subtelomeric interspersed repeats). Des experiences d'hybridation in situ indiquent la presence de sequences apparentees aux extremites des autosomes. Un certain nombre d'elements ont ete clones et leur localisation sub-telometrique a ete determinee par hybridation in situ et analyse genetique. Cette derniere fait apparaitre une nette augmentation de la recombinaison a l'extremite des chromosomes, particulierement en meiose male
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Koenig, Michel. "Etude de marqueurs moleculaires des chromosomes x et y humains." Université Louis Pasteur (Strasbourg) (1971-2008), 1986. http://www.theses.fr/1986STR13099.
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Raynaud, Martine. "Etude du profil d'inactivation des chromosomes X chez les conductrices de pathologies liées au sexe avec déficience mentale." Tours, 2002. http://www.theses.fr/2002TOUR3306.
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Des déviations du profil d'inactivation des chromosomes X peuvent être corrélées à l'expression des maladies liées au sexe. Nous avons réalisé l'étude du profil d'inactivation dans les leucocytes du sang dans 102 familles de pathologies liées à l'X avec retard mental : 36 familles de déficience mentale liée à l'X (dm/X) d'origine française et 6 familles de syndrome de Nance-Horan, pour lesquelles l'étude clinique et l'étude de localisation ont été réalisées à Tours, 17 familles de syndrome FG étudiées à Tours à partir d'une coopération internationale, 21 familles de dm/X de Belgique, 6 d'Allemagne, 16 de Hollande, pour lesquelles seule l'étude des profils d'inactivation a été réalisée à Tours. Dans 8 familles de dm/X, parmi les 36 familles de dm/X d'origine française, les femmes conductrices ont une inactivation très déviée et les femmes non conductrices ont une inactivation aléatoire. Une fonction pourrait être commune entre les gènes mutés dans ces familles : ils pourraient avoir un rôle dans la prolifération des cellules ou dans leur survie ; ou encore, ils pourraient intervenir dans le processus d'inactivation. Pour 24 parmi les 36 familles de dm/X d'origine française, les profils d'inactivation des conductrices sont aléatoires, qu'elles soient ou non symptomatiques. Dans les familles de syndrome de Nance-Horan, il semble exister une corrélation entre le profil d'inactivation observé dans les leucocytes et la sévérité du phénotye. La localisation génétique du syndrome FG est hétérogène. La mise en évidence d'un profil d'inactivation particulier chez les conductrices dans certaines familles aurait permis de suspecter l'implication d'un même gène. L'analyse révèle en effet différents types de profils d'inactivation, mais sans que l'on puisse établir une correspondance avec le territoire de localisation.
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Horn, Jacqueline Morag. "Investigation of the X inactivation centre region in mice." Thesis, Institute of Cancer Research (University Of London), 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.326155.
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Philippe, Christophe. "Cartographie physique du chromosome X humain : 1) contribution à la cartographie physique de la région q13-q22 du chromosome X humain : 2) analyse de deux cas de pathologies récessives liées à l'X chez des femmes porteuses de translocation (X ; Autosome) équilibrées." Vandoeuvre-les-Nancy, INPL, 1994. http://docnum.univ-lorraine.fr/public/INPL_T_1994_PHILIPPE_C.pdf.
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Ce travail contribue à l'établissement de la carte physique de la région q13-q22 du chromosome X humain. Nous avons rassemblé huit translocations X ; Autosomes (t(X;A)) équilibrées chez des femmes présentant des troubles de la fonction ovarienne. Dans une première partie, nous définissons huit nouveaux points de cassure dans la région Xq13-q22. Ces balises sont tout d'abord isolées par hybridation somatique interspécifique à partir des t(X;A) ; elles sont ensuite localisées par rapport aux marqueurs de la région proximale des bras longs du chromosome X humain. En regroupant nos t(X;A) avec des délétions de la région Xq21 publiées précédemment, nous proposons un panel de réarrangements qui subdivise la région Xq21 en 21 segments, soit plus d'une borne par mégabase d'adn. Cette collection constitue donc un bon canevas pour la construction d'une carte physique, génétique et fonctionnelle détaillée de la région q21 du chromosome X humain. La deuxième partie de ce travail consiste en la caractérisation moléculaire fine des points de cassure sur l'X pour les deux t(X;A) présentées dans cette étude qui sont associées avec des pathologies récessives liées à l'X. D'une part, chez la patiente TDo, atteinte de choroïdérémie et porteuse d'une t(X;7)(q21;p12), nous confirmons la localisation du point de cassure sur l'X dans le gène CHM, entre le troisième et le quatrième exon. D'autre part, le point de cassure sur le chromosome X chez la patiente PMI, porteuse d'une t(X;13)(q13;q31) en association avec un retard mental, a permis le clonage positionnel d'un gène qui pourrait être un bon candidat pour l'un des nombreux retards mentaux non spécifiques liés à l'X que compte la région proximale des bras longs du chromosome X humain
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Nora, Elphège-Pierre. "Architecture chromosomique du locus Xic : implications pour la régulation de l'inactivation du chromosome X." Thesis, Paris 11, 2011. http://www.theses.fr/2011PA112130/document.
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Le développement embryonnaire précoce des mammifères femelles s’accompagne de l’inactivation transcriptionnelle d’un de leurs deux chromosomes X. Cet évènement est initié suite à l’expression mono-allélique de l’ARN non codant Xist, qui est contrôlée par de nombreux éléments cis-régulateurs présents dans le centre d’inactivation du chromosome X (Xic) – tel son anti-sens répresseur Tsix. Mon travail de thèse a consisté à développer des approches permettant d’appréhender le paysage structural dans lequel s’exerce cette régulation. La caractérisation de l’architecture tridimensionnelle du Xic, par des techniques basées sur la capture de conformation chromosomique (3C) et l’hybridation in situ en fluorescence (FISH), m’a permis de mettre en évidence que les promoteurs respectifs de Xist et Tsix sont engagés dans des interactions physiques intimes avec des loci distaux, localisés au sein du Xic, et de montrer qu’au moins certaines de ces régions exercent un effets régulateurs à longue-distance. Les éléments du Xic contactés par les régions promotrices de Xist et de Tsix sont en outre fondamentalement différents, chacune engageant des associations chromosomiques sur plusieurs centaines de kilobases dans leur direction 5’ respective.Ce travail a également permis de révéler des propriétés insoupçonnées de l’architecture chromosomiques. En effet, le Xic apparaît scindé en plusieurs sous-régions, couvrant chacune entre 200kb et 1Mb, à l’intérieur desquelles les interactions chromosomiques sont préférentiellement établies. L’existence de ces domaines d’interaction s’intègre avec d’autres propriétés structurales du génome, tels la composition de la chromatine sous-jacente et l’association à la lamine nucléaire, mais n’apparaît pas en dépendre directement. En étudiant la dynamique de la conformation chromosomique du Xic au cours de la différenciation cellulaire, j’ai pu constater la robustesse de cette organisation, sauf sur le chromosome X inactif, qui se distingue par la perte des contacts chromosomiques préférentiels détectables sur son homologue actif.Enfin, j’ai pu mettre en évidence que la variabilité du repliement général du chromosome X amène à un instant donné chaque allèle de Tsix à contacter physiquement des jeux de séquences distales différents, suggérant que l’environnement structural instantané de chacun de ces allèles à l’orée de l’activation mono-allélique de Xist est différent. Ce travail, combinant des approches à l’échelle de la population cellulaire d’une part et de la fibre de chromatine unique d’autre part, apporte une nouvelle vision du paysage structural et régulateur dans lequel s’inscrit le contrôle de l’activité transcriptionnelle de Xist, et fourni de nouvelles perspectives concernant les principes fondamentaux de l’organisation topologique des chromosomes chez les mammifèresEarly development of female mammals is accompanied by transcriptional inactivation of one of their two X chromosomes. This event is initiated following mono-allelic expression of the Xist non-coding RNA – what is achieved by the interplay of numerous cis-regulatory elements present within the X inactivation center (Xic), such as its repressive antisense Tsix. Our work aimed at throwing light on the structural landscape that underlies such long-range regulation. Characterization of the three-dimensional architecture of the Xic, by the means of Chromosome Conformation Capture (3C)-based techniques and in situ fluorescence hybridization (FISH), revealed that the respective promoters of Xist and Tsix contact many distal genomic elements within the Xic, and that at least one of such interacting region exerts long-range cis-transcriptional control. Noticeably, Xist and Tsix promoters associate with different sets of elements in their respective 5’ direction that are spread out over several hundreds of kilobases These experiments also revealed unforeseen properties of chromatin architecture. Indeed, the Xic appears to be partitioned in several sub-regions, each spanning between 200kb and 1Mb, inside which chromosomal interactions are preferentially established. The existence of these interaction domains integrates with other structural features of the genome, such as underlying chromatin composition and association with the nuclear lamina, but does not seem to directly depend on them. By analyzing chromosome conformation of the Xic during cell differentiation we document the robustness of this organizational principle, with the noticeable exception of the inactive X chromosome that assumes a folding pattern that is more random than its active homolog. Finally we also bring evidence that variability in the folding pattern of the two X chromosomes in the same cell brings each Tsix allele in association with different sets of chromosomal partners at a given moment, suggesting that the instantaneous structural environment of each allele at the onset of mono-allelic Xist up-regulation is different.By combining approaches at the scale of cell populations on the one hand, and at the single chromatin fiber level on the other, this study provides a first vision of the structural landscape in which Xist regulation takes place, and brings new insights concerning fundamental properties of chromosome organization in mammals
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Augui, Sandrine. "Interactions chromosomiques et inactivation du chromosome X : éléments génétiques et mécanismes impliqués dans la reconnaissance du nombre de chromosomes X et dans la coordination des centres d'inactivation." Paris 11, 2009. http://www.theses.fr/2009PA112373.
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Le locus Xic contrôle l'initiation de l'inactivation du chromosome X. Il est nécessaire à la reconnaissance du nombre de chromosomes X (Sensing) et au déclenchement de l'expression monoallélique de Xist. Nous avons étudié la dynamique nucléaire des Xics au cours de la mise en place de l'inactivation dans les cellules ES. Nous avons montré que lors de l'initiation de l'inactivation, les deux Xics interagissent physiquement. Cet appariement transitoire permettrait la coordination des Xics afin de ne mettre en place l'inactivation qu'en présence de deux chromosomes X et au niveau d'un seul. Nous avons montré que cet appariement impliquait une région du Xic nommée Xpr pour "X-pairing region". Des expériences de transgénèse montrent que cette région est capable d'induire la trans-interaction des Xics de façon autonome et peut aussi induire l'activation du gène Xist endogène. Xpr serait ainsi le premier activateur en trans de Xist identifié à ce jour. La présence ectopique de Xpr semble en outre associée à une instabilité génétique dans les cellules ES. Notre modèle propose que l'appariement homologue des régions Xpr serait impliqué dans la coordination des Xics en ne permettant l'activation de Xist qu'en présence de plusieurs chromosomes X, et au niveau du nombre de X nécessaires pour rétablir la compensation de dose. En l'occurrence, des lignées males double transgéniques pour Xpr et Xist/Tsix semblent mettre en place au cours de leur différenciation un processus aléatoire d'inactivation, comparable à celui observé dans des lignées femelles, suggérant que Xpr+Xist/Tsix récapitulerait l'ensemble des fonctions du Xic et représenterait donc la région minimum du XicIn mammals, dosage compensation is achieved by the inactivation of one of the two X-chromosome during early development in females. X inactivation process is controlled by a complex locus, the X-inactivation centre (Xic), which includes the Xist gene and its antisense transcription unit Tsix/Xite. The Xic senses X chromosome number and initiates inactivation by triggering mono-allelic up-regulation of Xist RNA, and reciprocally, down-regulation of Tsix from one of the two X chromosomes in females. However, the mechanisms underlying sensing and reciprocal Xist/Tsix regulation remain obscure. We recently showed that a previously untested segment of the Xic, lying several hundred kilobases upstream of Xist and enriched in histone H3K27me3 and H3K9me2 marks, brings the two Xic's together prior to the onset of X inactivation (Augui et al, Science 318:1362, 2007). This X-pairing-region (Xpr) can autonomously drive Xic trans-interactions even as an ectopic single copy transgene. Furthermore its presence in male ES cells is selected against, suggesting that it may have a role in triggering Xist up regulation. We proposed that the pairwise interactions driven by this novel X-pairing-region (Xpr) of the Xic might enable a cell to sense that more than one X-chromosome is present in an XX cell, by activating biallelic Xist expression. Furthermore we believe that Xpr pairing then facilitates association between the Tsix/Xite regions, thus rendering biallelic Xist expression monoallelic. Finally, we think that Xpr could be the missing functional region of the Xic since Xpr + Xist/Tsix transgenes seem to recapitulate all Xic function in a male cell line
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Lappin, Fiona M. "REDEFINITION OF THE PSEUDOAUTOSOMAL BOUNDARY OF THE CARICA PAPAYA SEX CHROMOSOMES." Miami University / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=miami1376205368.
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Qiu, Zheng-qing. "Effect of gamete of origin and gene dose in X-linked hypophosphatemic mice." Thesis, McGill University, 1993. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=69690.
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The expectation for a gene dose effect in an X-linked phenotype is that the corresponding metrical trait in heterozygous females will lie between values for affected hemizygous males and unaffected males and females. I made sequential measurements (at 30, 60, 90, 120 and 150 days) of serum phosphate concentration and tail length in mice with X-linked hypophosphatemia (mutant genotypes: Hyp/+, Hyp/Y and Hyp/Hyp) and in their normal littermates (genotypes: +/+ +/Y). I also measured renal mitochondrial 24-OHase activity in mice fed control and low phosphate diets and representing all five genotypes. I further studied serum AP activity and vertebral bone histomorphometry in the five genotypes. The mutant animals all had uniformly and significantly different values than unaffected littermates. There was no evidence of a gene dose effect because values were not significantly different among the three mutant genotypes.I also studied the influence of gamete of origin on serum phosphate, tail length, renal mitochondrial 24-OHase activity, serum AP activity and vertebral bone histomorphometry in the Hyp/+ offspring of affected males (Hyp/Y) or affected females (Hyp/+ or Hyp/Hyp). I found no effect on the distribution of trait values.
I conclude that parental origin of the mutant allele does not explain the absence of a gene dose effect in Hyp mice.
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Ritchie, Rachael J. "Characterisation of the molecular basis of fragility of fragile sites in Xq27.3-q28." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.296939.
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Escouflaire, Clémentine. "Détection chez le bovin de polymorphismes génétiques au niveau du génome mitochondrial et des chromosomes sexuels et caractérisation de leurs effets sur les caractères de production, reproduction et santé." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASA015.
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Malgré leurs rôles dans l’expression de caractères de fertilité et dans le métabolisme énergétique, le génome mitochondrial et les chromosomes sexuels ne sont actuellement pas pris en compte dans les évaluations génomiques bovines françaises. Cette thèse a pour but d’étudier la variabilité génétique du génome mitochondrial et des chromosomes X et Y, de détecter des polymorphismes génétiques et de caractériser leurs effets sur les caractères de production, reproduction et santé. L’étude des schémas de transmission uniparentale, a mis en évidence une disparité entre une faible diversité des haplotypes du chromosome Y et un grand nombre de lignées mitochondriales dans de nombreuses races bovines. La présence à très faible fréquence de porteurs d’haplogroupes dont la divergence est antérieure à la domestication des bovins taurins a été identifié par génotypage. Deux études ont été réalisées pour estimer l’effet des différents variants identifiés sur le génome mitochondrial et le chromosome Y sur certains caractères d’intérêt zootechnique. Puis, une approche de génétique inverse a permis d’exploiter des données des séquences pour détecter sur le chromosome X des mutations candidates responsables d’anomalies et des mutations pouvant avoir un effet sur la fertilité mâle ou femelle ou entraînant un biais d’inactivation du chromosome X. En parallèle, le mécanisme génétique d’une anomalie liée au chromosome X responsable d’un cas de dysplasie ectodermique hypohidrotique a été décrit chez une génisse de race Holstein. Enfin, des pistes de réflexions sont proposées afin d’initier une meilleure prise en compte des chromosomes sexuels et du génome mitochondrial dans la sélection des bovinsIn spite of the roles of the mitochondrial genome and sex chromosomes in the expression of fertility traits and energy metabolism, currently they are not considered in French bovine genomic evaluations. This work is aiming to study the genetic variability of the mitochondrial genome and the X and Y chromosomes, to detect genetic polymorphisms, and to characterize their effects on production, reproduction and health traits. Analysis of uniparental transmission patterns revealed a discrepancy between the low diversity of Y-chromosome haplotypes and the large number of mitochondrial lines in many cattle breeds. Identification of carriers of haplogroups whose divergence predates the domestication of taurine cattle has been made at a very low frequency by genotyping. Initial studies have been carried out to estimate the effect of the variants identified on the mitochondrial genome and the Y chromosome on certain traits of interest to the breeding sector. Then, a reverse genetics approach has been applied to use sequence data to detect candidate mutations responsible for defects and mutations that may have an effect on male or female fertility or lead to an X chromosome inactivation bias. In parallel, the genetic mechanism of an X-linked defect responsible for a case of hypohidrotic ectodermal dysplasia was investigated in a Holstein heifer. In conclusion, several lines for future research are proposed to initiate a better consideration of sex chromosomes and the mitochondrial genome in the selection of cattle
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Cardoso, Carlos. "Etude fonctionnelle de la protéine XNP impliquée dans les syndromes de retard mentaux liés au chromosome X." Aix-Marseille 2, 1999. http://www.theses.fr/1999AIX22065.
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Lamartine, Jérôme. "Cartographie physique de la région du syndrome lymphoprolifératif lié au chromosome X (XLP) et recherche de gènes candidats." Lyon 1, 1996. http://www.theses.fr/1996LYO1T213.
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Rak, Justyna. "Female predominance for systemic sclerosis and rheumatoid arthritis : explanations through human leukocyte antigens, microchimerism and X chromosome = Prédominance des femmes dans la sclérodermie systémique et la polyarthrite rhumatoïde : explications par les gènes HLA-DRB, le microchimérisme et le chromosome X." Aix-Marseille 2, 2008. http://theses.univ-amu.fr.lama.univ-amu.fr/2008AIX22056.pdf.
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Le but de cette thèse est d’expliquer la prépondérance des femmes dans deux maladies auto-immunes (MAI) : la Sclérodermie systémique (ScS) et la Polyarthrite Rhumatoïde (PR) en étudiant les gènes HLA, le microchimérisme (Mc) et le chromosome X. La PR et la SSc sont toutes deux associées à des allèles HLA-DRB de susceptibilité. Cependant, chez les femmes ces associations peuvent être moins prononcées, ce qui n'explique donc pas leur prédisposition aux MAI. Les cellules ou ADN microchimériques, séquelle naturelle de la grossesse, pourrait contribuer à l’ "auto"-immunité chez la femme. Les résultats ont été cependant controversé dans la ScS. Notre étude explique en partie la controverse en distinguant deux modèles particuliers de Mc. Les femmes ayant une ScS diffuse ont préférentiellement du Mc dans les PBMC, contrairement aux femmes ayant une ScS limitée, qui le maintiennent dans d’autres cellules du sang. D’autre part, pour la première fois, nous montrons que les allèles de susceptibilité HLA peuvent être transférés via le Mc chez des femmes atteintes de PR négatives pour ces allèles. En effet, 41% des femmes PR négatives pour HLA-DRB1*04 avaient du Mc positif pour HLA-DRB1*04 contre seulement 8% des sujets contrôles. Nous avons montré que les conditions inflammatoires, telles que celles observées chez les femmes ayant des atteintes rénales chroniques, peuvent augmenter le Mc dans les PBMC. Les cellules Mc seraient alors attirées vers les sites inflammatoires. La relation HLA entre cellules de l’hôte et cellules Mc ainsi que la capacité immunitaire de l’hôte pourraient contribuer à un rôle délétère, neutre ou même bénéfique du Mc. Nous avons montré que les femmes ayant des maladies auto-immunes ont une inactivation biaisée du chromosome X, influençant vraisemblablement certains gènes comme FOXP3, marqueur des cellules T régulatrices. De façon générale, nous avons identifié les acteurs d’un jeu complexe prédisposant les femmes pour l’auto-immunitéThe goal of this thesis is to explain female predominance in two autoimmune diseases (AID): Systemic sclerosis (SSc) and Rheumatoid Arthritis (RA) by studying HLA genes, microchimerism (Mc) and X chromosome. Both RA and SSc are associated with particular HLA-DRB susceptibility genes. However, HLA associations can be less pronounced in women, which then does not explain their predisposition to AID. Mc cells and/or DNA, natural sequel from pregnancy, could contribute to “auto”-immunity. Results have been controversial in SSc. Our study distinguishes two distinct profiles which explains part of the controversy. Women with diffuse SSc retain Mc preferentially in PBMC, whereas women with limited SSc retain it in other blood cells. Moreover, for the first time, we show that HLA susceptibility alleles can be transferred to women with RA who lack these alleles. Indeed 41% of women with RA, negative for HLA-DRB1*04, have HLA-DRB1*04 Mc in their PBMC versus only 8% of controls. We found that inflammatory conditions such as observed in women with end stage renal disease (before renal transplant) promote high concentrations of Mc in PBMC. Mc cells may then be attracted to inflammatory sites. The HLA relationship between the host and Mc cells as well as the host’s immune capability may then drive toward a detrimental, neutral or even beneficial role. Indeed, we showed that women with AID have skewed X chromosome inactivation (XCI), which might influence some X chromosome genes, such as FOXP3, a mandatory gene for T regulatory cells. Overall, we identified some of the actors of an intricate game conducting to female predisposition in AID
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Mekada, Kazuyuki, Kazuhiro Koyasu, Masashi Harada, Yuichi Narita, Shrestha Krishna C, and Sen-Ichi Oda. "Karyotype and X-Y chromosome pairing in the Sikkim vole (Microtus (Neodon) sikimensis)." Cambridge University Press, 2002. http://hdl.handle.net/2237/10266.
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Chevret, Edith. "Ségrégations méiotiques des chromosomes sexuels chez les sujets 46,XY et chez les sujets porteurs d'anomalies numériques de ces chromosomes : analyse par hybridation in situ fluorescente (FISH) sur les noyaux de spermatozoides humains." Université Joseph Fourier (Grenoble ; 1971-2015), 1995. http://www.theses.fr/1995GRE10072.
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Les segregations meiotiques des chromosomes 2, 7, 14 et 22 sont etudies par fish deux-couleurs sur les noyaux spermatiques interphasiques de sujets a caryotype somatique normal et de sujets porteurs d'une anomalie numerique constitutionnelle. Ces profils de segregation etant similaires chez les sujets 46,xy et chez les sujets 46,xy/47,xxy et 47,xyy, nous suggerons que la presence du gonosome surnumeraire n'a pas d'influence sur la segregation des autosomes. Les segregations meiotiques des chromosomes x et y sont etudiees par fish trois-couleurs. La cohybridation des deux sondes gonosomales et d'une sonde autosomale (sonde specifique du chromosome 1) est la technique la plus directe pour distinguer les hyperhaploidies des diploidies et en connaitre l'origine. Ainsi 142050 spermatozoides provenant de 5 sujets 46,xy, 27097 spermatozoides provenant d'un sujet 46,xy/47,xxy et 13722 spermatozoides provenant d'un sujet 47,xyy ont ete analyses. Les resultats observes chez le sujet 46,xy/47,xxy, compares a ceux obtenus chez les sujets normaux, nous permettent de proposer pour les spermatocytes 47,xxy, un modele de segregation reguliere des gonosomes, les deux chromosomes x formant un bivalent xx et le chromosome y un univalent. L'analyse de la segregation des gonosomes chez le sujet 47,xyy, d'une part, confirme l'hypothese de l'elimination du chromosome y surnumeraire dans la majorite des cellules germinales 47,xyy a un stade premeiotique, et d'autre part, suggere que quelques spermatogonies 47,xyy seraient aptes a accomplir la meiose. Le devenir de ces cellules pourraient etre lie a leur aptitude a former un bivalent sexuel homologue, l'univalent x etant ensuite perdu au cours de l'anaphase i. L'ensemble de ces resultats nous permettent de proposer un modele theorique de segregation pour les lignees germinales comportant trois chromosomes sexuels. Dans les spermatocytes i (47,xxy ou 47,xyy) les trois gonosomes s'organiseraient de facon a former un bivalent homologue (xx ou yy) associe a un univalent, respectivement, y ou x. Cette organisation serait le prerequis au bon deroulement de la meiose
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Zhang, Zhe. "In silico modeling the effect of single point mutations and rescuing the effect by small molecules binding." Paris 7, 2013. http://www.theses.fr/2013PA077054.
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Le polymorphisme d'un seul nucléotide (SNP, single-nucleotide polymorphism) est la variation (polymorphisme) d'une seule paire de bases du génome, entre individus d'une même espèce. Une forme non synonyme ou une mutation faux sens est une mutation ponctuelle dans laquelle un nucléotide d'un codon est changé, induisant le changement de l'acide aminé associé. Ceci peut affecter la fonction de la protéine et provoquer des pathologies par perturbation du site actif, déstabilisation de la structure ou des interactions protéine-protéine, entre autres, et pour cela cette étude est focalisée sur des mutations faux sens. Le syndrome de Snyder Robinson (SRS) est un cas particulier d'un syndrome génétique lié au chromosome X qui est provoqué par quatre mutations découvertes dans la spermine synthase (SMS). Nous avons développé une approche rationnelle in slico pour analyser l'impact de ces mutations sur la structure et la fonction de la SMS. De plus, nous avons appliqué une approche de criblage virtuel « structure-based » afin d'identifier de petites molécules qui seraient capable de stabiliser le dimère et ainsi de restaurer son activité enzymatique normaleSingle-point mutation in genome, for example, single-nucleotide polymorphism (SNP) or rare genetic mutation, is the change of a single nucleotide for another in the genome sequence. Some of them will result in an amino acid substitution in the corresponding protein sequence (missense mutations); others will not. This investigation focuses on genetic mutations resulting in a change in the amino acid sequence of the corresponding protein. This choice is motivated by the fact that missense mutations are frequently found to affect the native function of proteins by altering their structure, interaction and other properties and cause diseases. Particular disease is the Snyder-Robinson syndrome (SRS), which is an X-linked mental retardation found to be caused by missense mutations in human spermine synthase (SMS). In this thesis, a rational approach to predict the effects of missense mutations on SMS wild-type characteristics was carried. Following this work, a structure-based virtual screening of small molecules was applied to rescue the disease-causing effect by binding the small molecules to the corresponding malfunctioning SMS mutant
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Wittwer, Pia Ethena. "Physical and genetical investigation of the Xp11.3 region on the short arm of the human X-chromosome." Thesis, University of the Western Cape, 2004. http://etd.uwc.ac.za/index.php?module=etd&.
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The pattern of inactivation in the DXS8237E-UBE1-PCTK1 region is of particular interest, since the mechanisms of X chromosome inactivation and the escape from inactivation are, as yet, not fully understood. The inactivation status of the DXS8237E and PCTKl gene differ: the first undergoes normal inactivation and the second escapes this process. The status of the UBEl gene has been controversial, although it is widely excepted that it does escape X chromosome inactivation. Physical mapping of the region employing YACs and subsequently P ACs has been undertaken, but was restricted in scope by the high frequency of rearrangements occurring. DNA sequences between DXS8237E, UBE1, PCTKl and the distal gene, UHX1, have been investigated with regard to LINEI elements, which are thought to playa role in X-inactivation. The results obtained strongly suggest a link between LINE1 elements and X chromosome inactivation. Sequence analysis results also contributed to the understanding of difficulties with restriction mapping of the region. Further, this work includes the first reported establishment of the UBEl exonintron boundaries. Additionally, genomic sequence analysis showed that only 46kb separate DXS8237E from UHX1, which confirms that this region is extremely gene rich.
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Brun, Christine. "Organisation en boucles de la molécule d'ADN et réplication : tude de la région 14B-15B du chromosome X et de l'unité des gènes ribosomiques de Drosophila melanogaster." Aix-Marseille 2, 1992. http://www.theses.fr/1992AIX22017.
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La molecule d'adn, constitutive du chromosome eucaryote, est organisee en boucles dont les bases sont ancrees dans un reseau proteique interne nomme scaffold. L'implication des sites d'attachement de la molecule d'adn au scaffold (=sar) dans les mecanismes de replication a ete etudiee dans deux regions distinctes du genome de la drosophile: la region 14b-15b du chromosome x, mesurant 800 kb, qui a ete clonee dans le laboratoire et dont l'organisation en boucles a ete determinee lors d'une etude anterieure, et l'unite des genes codant pour les arns ribosomiques. Dans une premiere etape, l'activite de replication autonome (=ars) de fragments de restriction representatifs de la region 14b-15b a ete testee par transformation heterologue de levure. 27 fragments manifestent une activite ars. 25 d'entre eux sont des sars. Il existe donc une correlation entre les deux types d'activites: une sous-classe de sars de drosophile est impliquee dans les mecanismes de replication extrachromosomique chez la levure. De plus, l'association au scaffold est conservee entre les deux especes: lors d'un test de re-association in vitro, 61% des sars testes sont capables de s'associer a des scaffolds de levure. Dans une deuxieme etape, l'existence d'une relation entre sites d'attachement, sequences ars dans la levure et origines de replication chromosomiques a ete abordee. Pour cela, l'organisation en boucles de l'unite repetee des genes ribosomiques a ete determinee. Trois sars ont ete identifies a l'interieur des trois espaceurs presents dans l'unite. Ils definissent trois boucles d'adn contenant la region codant pour l'arn 18s, une partie de la region codant pour l'arn 28s et une region entourant le site +1 de transcription, respectivement. Ces 3 sars de drosophile sont egalement capables de s'associer a des scaffolds de levure. Trois regions de l'unite sont impliquees dans les mecanismes de replication extrachromosomique chez la levure. Elles correspondent aux regions en interaction avec le scaffold. De plus, la technique d'electrophorese bidimensionnelle neutre/neutre a permis de localiser une origine de replication chromosomique dans un fragment d'adn couvrant deux des espaceurs. Ces resultats montrent donc qu'au moins dans un cas, une proximite topologique existe entre des sequences impliquees dans l'association de la molecule d'adn au scaffold, dans la replication extrachromosomique chez la levure et dans l'initiation de la replication chromosomique. Cela suggere une relation fonctionnelle etroite entre ces trois types de sequences
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Pessia, Eugénie. "Comment le X vient-il à la rescousse du Y ? : évolution de la compensation de dosage des XY humains et autres questions sur l'évolution des chromosomes sexuels eucaryotes." Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10261/document.
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Un premier pan de ma thèse concerne deux différents mécanismes de sauvetage du Y par le X. Premièrement, j'ai participé à une controverse sur la compensation de dosage chez les mammifères. Une hypothèse avait été proposée dans les années 60 par Susumo Ohno, proposant un mécanisme de compensation en deux temps. Chez les mâles, la perte de nombreux gènes sur le Y entraîne un déséquilibre de dosage car ces gènes qui étaient précédemment présents en deux copies sont devenus unicopie, soit une division d'expression par deux. Selon l'hypothèse d'Ohno, chez les mammifères en réponse à cela le X aurait doublé son expression, mais dans les deux sexes menant ainsi à une expression trop élevée chez les femelles. Ce deuxième problème de dosage aurait alors été résolu par la mise en place d'une inactivation aléatoire de l'un des deux X chez les femelles. Tandis que la deuxième partie de l'hypothèse d'Ohno, l'inactivation du X, a été très étudiée, la première partie est restée spéculative jusqu'aux années 2000. En étudiant des données d'expression du X humain j'ai pu montrer, de manière concomitante avec d'autres auteurs, que la première partie de l'hypothèse d'Ohno n'est pas totalement vraie car seule une partie des gènes sont sur-exprimés. J'ai ensuite participé à l'écriture d'une revue visant à donner une explication alternative à la compensation de dosage pour l'évolution de l'inactivation du X chez les femelles mammifères. Deuxièmement, j'ai étudié la présence de conversion génique X-Y dans plusieurs gènes, au sein de nombreuses espèces de primates. Mes travaux me mènent à discuter le fait que ce type d'évènement soit effectivement favorisé par la sélection. Je pose l'hypothèse que ces conversions géniques ont été maintenues de manière neutre. Ces deux travaux ne vont pas dans le sens d'un chromosome X sauvant le Y avec beaucoup de zèle. Dans un dernier temps, m'éloignant des espèces modèles, j'ai étudié les chromosomes sexuels particuliers d'une algue brune : Ectocarpus siliculosus. Cela m'a permis de vérifier si le scénario évolutif actuel des chromosomes sexuels est toujours valide dans un groupe d'eucaryotes séparé des animaux depuis plus d'un milliard d'annéesThe first part of my thesis concerns two different mechanisms of the Y being rescued by the X. Firstly, I contributed to a controversy on mammalian dosage compensation. During the 60s Susumo Ohno hypothesized a two-step dosage compensation mechanism. In males, the high loss of Y-linked genes led to a dosage imbalance: these genes were previously present in two allelic copies and became unicopy, meaning that their expression has been halved. According to Ohno’s hypothesis, in response to this imbalance the mammalian X would have doubled its expression in the two sexes, resulting in a to high expression in females. This second dosage imbalance would have been resolved by the random inactivation of one of the two Xs in females. Whereas the second part of Ohno’s hypothesis, the X-chromosome inactivation, has been well studied, the first part remained speculative until the 2000s. I studied human X-linked expression data and was able to show, concomitantly with other authors, that the first part of Ohno’s hypothesis is not totally true as only some of the X-linked genes are hyperexpressed. I later participated in the writing of a review aiming to give an alternative hypothesis for the evolution of X-chromosome inactivation in mammalian females than dosage compensation. Secondly, I studied signatures of X-Y gene conversion in several genes within numerous primate species. Myresults led me to discuss if these events were indeed selected for. I hypothesize that these gene conversion events occurred in a neutral manner. These two different studies suggest that the X chromosome may not be as much a help for the Y as has been suggested. Lastly, moving away from model species, I studied the peculiar sex chromosomes of a brown alga: Ectocarpus siliculosus. This work allowed me to test if the current hypotheses on sex chromosome evolution still hold in a eukaryotic group that diverged from animals more than one billion years ago
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Grön, M. (Mathias). "Effects of human X and Y chromosomes on oral and craniofacial morphology:studies of 46,XY females, 47,XYY males and 45,X/46,XX females." Doctoral thesis, University of Oulu, 1999. http://urn.fi/urn:isbn:9514253744.
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Abstract
The influence of the X and Y chromosomes on the size and shape
of the dental arches and occlusion as well as on craniofacial cephalometric
dimensions, angles and dimensional ratios is studied. The material
consists of Finnish patients with sex chromosome aneuploidies and
normal population controls from the "Kvantti Study" series,
which was collected in the 1970's and 1980's at
the Institute of Dentistry, University of Turku. The patients are
five individuals with complete testicular feminization (CTF), eight
47,XYY males, and fourteen 45,X/46,XX females. The controls
are population female and male controls, as well as five first degree
relatives of the individuals with CTF, three of the 47,XYY males
and nine of the 45,X/46,XX females studied. Dental arch
dimensions and occlusion as well as craniofacial cephalometric dimensions,
angles and dimensional ratios are measured from dental study casts
and standardized lateral cephalograms.
The results show that the presence of the Y chromosome in
46,XY females and the supernumerary Y chromosomal gene(s) in 47,XYY
males result in the enlargement of the dental arches and craniofacial
dimensions without substantial effects on dimensional ratios and
plane angles, but with special influence on the growth of the mandibular
corpus. The reduction of X chromosomal genetic material in 45,X/46,XX
females results in the reduction of craniofacial dimensions, affecting dimensional
ratios and especially plane angles of the cranial base.
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Lähdesmäki, R. (Raija). "Sex chromosomes in human tooth root growth:radiographic studies on 47,XYY males, 46,XY females, 47,XXY males and 45,X/46,XX females." Doctoral thesis, University of Oulu, 2006. http://urn.fi/urn:isbn:9514281705.
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Abstract
Studies on families and individuals with sex chromosome abnormalities and 46,XY females, together with molecular research, have provided proof that both X and Y chromosome genes are expressed in human tooth crown growth. The Y chromosome promotes the formation of both permanent tooth crown enamel and dentin, whereas the effect of the X chromosome is seen mainly in enamel formation. In particular, the effect of the Y chromosome on dentin formation explains the expression of sexual dimorphism in crown size. When crown growth is complete, root dentin is formed and requires proliferation of epithelial cells in Hertwig's epithelial root sheath to initiate the differentiation of root odontoblasts. These epithelial cells determine the size, shape and number of the roots. There is a clear sex difference in tooth crown sizes, men have larger teeth than women. The aim of this research was to study completed permanent tooth root lengths in individuals with sex chromosome abnormalities and 46,XY females, an approach which might also provide some clues for a further insight into the development of sexual dimorphism in human growth. The underlying hypothesis was that the effect of the X and Y chromosomes on crown growth is also expressed in root growth.
The subjects were participants of L. Alvesalo's research project, Kvantti, and comprised 45,X/46,XX females, 47,XYY and 47,XXY males and female sex reversals with insensitivity to androgens (46,XY females). The root lengths were measured from dental panoramic radiographs with a sliding digital calliper. All available teeth (except third molars) with complete root formation on both sides of the jaws were measured.
The results showed longer final permanent tooth root lengths in 47,XYY and 47,XXY males, while the roots in 45,X/46,XX females were shorter compared with the values of normal men and women, respectively. The root lengths of 46,XY females were longer compared to normal women and placed on a level with normal men. The root morphology did not reveal any major deviations from normal variation. In terms of population dental developmental standards it is conceivable that changes in these study groups in final size of their permanent tooth roots become evident during a period beginning eight years after birth and continuing up to the age of 14 years, at least.
It became clear that the effect of the Y chromosome on tooth root growth is greater than that of the X chromosome, and this may cause the observed sexual dimorphism, males having longer roots than females. It is suggested that root growth may be affected by the same genes on the X and Y chromosomes which promote crown growth.
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Ciaudo, Constance. "Caractérisation fonctionnelle de nouveaux facteurs trans impliqués dans le processus d'inactivation du chromosome X murin." Paris 7, 2006. http://www.theses.fr/2006PA077084.
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Chez les mammifères, la compensation de dose du produit des gènes liés au chromosome X entre les sexes est assurée par l'extinction transcriptionnelle de la plupart des gènes de l'un des deux chromosomes X, au hasard, chez la femelle. Le gène Xist (X-inactive specific transcript), localisé dans le Xic (X-inactivation center) et essentiel à l'initiation de cette inactivation en c/s, produit un grand ARN non codant couvrant entièrement le chromosome X inactif dans les tissus somatiques femelles. La recherche systématique de nouveaux gènes impliqués dans le processus d'inactivation du chromosome X par SAGE, en comparant les transcriptomes d'embryons murins mâles et femelles de 6,5 jpc (jours post-coïtum), a permis de mettre en évidence 214 gènes surexprimés dans les embryons femelles. L'inactivation est établie lors de l'embryogenèse précoce, dans les cellules de la masse cellulaire interne. Les cellules embryonnaires souches (ES) qui en sont dérivées récapitulent, lors de leur différenciation in vitro, toutes les étapes de ce processus. Dans ce travail de thèse, nous avons validé ex vivo une soixantaine de gènes, surexprimés dans les embryons femelles, dans des cellules ES mâles et femelles. La mise en place de la technique d'ARN interférence dans notre système modèle, a permis l'étude fonctionnelle de certains de ces candidats. La génération de clones de cellules ES stablement interfères, a mis en évidence qu'une ou plusieurs voies de dégradation (NMD, exosome) des ARN, via les gènes Eif1, Rent1 et Exosc1O, sont impliquées dans la régulation du gène Xist et dans la mise en place du processus d'inactivation du chromosome XIn mammals, each cell of the female contains two X chromosomes and hence, potentially a double dose of ail X-linked genes when compared to XY males, who carry a single X chromosome. X-inactivation is the mechanism that ensures the dosage-compensation of X-linked gene products between the two sexes. X-inactivation is under the control of a specific region of the X chromosome, the X inactivation center (Xic), which contains the Xist gene encoding a large noncoding RNA transcript whose upregulation is critical to the initiation of X-inactivation. As an approach to the identification of some of the potential molecular players in this process we have performed comparative transcriptional profiling of mouse 6. 5 dpc (days post-coïtum) female and male embryos using a modified SAGE (Serial analysis of gene expression) technique which allows the analysis of small quantifies of biological material. At 6. 5 dpc, a moment when random X-inactivation of embryonic tissues has just been achieved, some two hundred transcripts that were significantly enriched in the female gastrula compared to its male counterpart could be identified. The validation of an association with the X-inactivation process of a subset of these transcripts has been studied, ex vivo, in differentiating female and male ES cells and in female ES cells. We identified the Eif1 gene involved in translation initiation and RNA degradation. We show here that female embryonic stem cell lines, silenced by RNA interference for the Eif1 gene, are unable to form Xist RNA domains upon differentiation and fail to undergo X-inactivation. To probe further an effect involving RNA degradation pathways, the inhibition by RNA interference of Rent1, a factor essentiel for nonsense-mediated decay and Exosc1O, a specific nuclear component of the exosome, was analysed and shown to similarly impair Xist upregulation and XCI. Inhibition of the function of one or other of these genes leads to a failure of the female cells to undergo X inactivation, suggesting that post-transcriptional nuclear mRNA degradation pathway(s) are essential for the regulation of Xist RNA metabolism and X chromosome inactivation process
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Wang, Qing. "Syndrome lymphoprolifératif lié au chromosome X (XLP) : contribution à la localisation du locus de la maladie et à la cartographie physique de la région Xq24-25." Lyon 1, 1993. http://www.theses.fr/1993LYO1T025.
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Zanni, Ginevra. "Génétique et physiopathologie des dysgénésies du cervelet liées au chromosome X." Paris 5, 2007. http://www.theses.fr/2007PA05D037.
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Nous avons développé diverses stratégies pour définir et analyser des régions critiques d'anomalies du cervelet sur le chromosome X. Nous avons localisé par analyses de liaison, un nouveau gène d'ataxie congénitale. Le criblage du gène OPHN1 impliqué à l'origine dans un retard mental non spécifique, nous a permis d'identifier des mutations dans 12 % des cas avec hypoplasie cérébelleuse et de mettre en évidence son rôle dans le développement du cervelet humain. Nous avons impliqué le gène AP1S2 dans le syndrome de Fried, un retard mental avec hydrocéphalie, calcifications intracérébrales et atteinte occasionnelle du vermis cérébelleux, en confirmant l'association entre gènes de retard mental et anomalies du cervelet. Outre l'intérêt fondamental dans la compréhension de la génétique et physiopathologie des dysgénésies du cervelet, ces études contribuent à mieux orienter le diagnostic et à proposer un conseil génétique plus précis aux familles avec retard mental ou anomalies du cerveletWe have developed different strategies to define and analyse critical regions of cerebellar dysgenesis on the X chromosome. We have identified by linkage analysis, a new locus for X-linked congenital ataxia in Xq25-q27. By screening OPHN1, a gene originally implicated in non-specific mental retardation, we have identified mutations in 12% of cases with associated cerebellar hypoplasia, outlining its role in human cerebellum development. We have implicated the AP1S2 gene in Fried syndrome, caracterised by mental retardation hydrocephalus, intracerebral calcifications and occasionally vermis hypoplasia, confirming the association between mental retardation genes and cerebellar development anomalies. Beyond the fundamental interest in understanding the genetics and physiopathology of X-linked cerebellar dysgenesis, these studies provide a better diagnostic orientation and a more precise genetic counseling to families with X-linked mental retardation or congenital cerebellar anomalies
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Teller, Kathrin. "Die Architektur des X-Chromosoms." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-90558.
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Vicoso, Beatriz. "X chromosome evolution in Drosophila." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/3183.
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Although the X chromosome is usually similar to the autosomes in size, gene density and cytogenetic appearance, theoretical models predict that its hemizygosity in males may cause unusual patterns of evolution. The sequencing of several genomes has indeed revealed differences between the X chromosome and the autosomes in the rates of gene divergence, patterns of gene expression and rates of gene movement between chromosomes. In this thesis, I have attempted to investigate some of these patterns and their possible causes. The first two chapters consist of theoretical and empirical work intended to analyse the rates of evolution of coding sequences of X-linked and autosomal loci, with particular emphasis on faster-X evolution, the theory that more effective selection on the X can lead to higher rates of adaptive evolution on this chromosome. By analyzing X-linked and autosomal coding sequence in several species of Drosophila, we found some evidence for more effective selection on the X, particularly evident in the higher levels of codon usage bias detected at X-linked loci. We argue that this could be due to higher levels of recombination on the X chromosome increasing its effective population size (NeX) relative to the autosomal effective population size (NeA). To further investigate this hypothesis, we have modeled the effect of increased NeX/NeA on rates of evolution and confirmed that this can contribute to faster-X evolution. The last two chapters deal with the evolution of sex-biased genes and the possible causes for their differential accumulation on the X. We used EST data to create expression profiles for D. melanogaster male-, female- and unbiased genes. Our results suggest that the expression levels of sex-biased genes are incompatible with the accepted iii model of sex-biased gene evolution. We also show that the deficit of testis-expressed genes that is observed in Drosophila seems to be stronger for highly expressed genes. In fact, for very lowly expressed genes, we observe a small excess of testis-expressed genes on the X. We attempt to discuss this pattern in view of what is currently known about the evolution of sex-biased gene expression.
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Nava, Caroline. "Identification de nouveaux gènes et de facteurs de susceptibilité dans les Troubles du Spectre Autistique par étude des microréarrangements génomiques et de l’exome du chromosome X." Paris 6, 2013. http://www.theses.fr/2013PA066572.
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Les troubles du spectre autistiques (TSA) sont des troubles neurodéveloppementaux caractérisés par une grande hétérogénéité clinique et génétique. Une cause génétique est actuellement identifiée chez près de 30% des patients. L’objectif de l’étude était d’identifier des facteurs génétiques responsables de TSA dans une cohorte de 205 patients recrutés prospectivement. Dans ce but, les gènes codant pour les Neuroligines et SHANK3 ont été analysés ; une recherche de microréarrangements (CNV) a été réalisée par puce à ADN, et une étude de l’exome du chromosome X a été effectuée pour des familles sélectionnées. Les gènes candidats ont été criblés dans le reste de la cohorte et des études fonctionnelles ont été réalisées. Deux nouveaux gènes candidats sur le chromosome X ont été identifiés: TMLHE, codant pour une enzyme de la voie de synthèse de la carnitine, et SLC7A3, codant pour un transporteur d’acides aminés cationiques. Nous avons également identifié des mutations de SHANK3, PHF8, HUWE1, une triplication 15q11q13, une délétion 9p24 et une délétion 3q29 ; ces gènes ou CNV ayant précédemment été impliqués dans les TSA ou la déficience intellectuelle (DI). Deux gènes de transmission autosomique récessive, PTGER3 et DOCK10, ont également été proposés. Cette étude a permis d’identifier de nouveaux gènes contribuant aux TSA et a confirmé la grande hétérogénéité génétique des TSA et le chevauchement avec les gènes de DI. L’observation de plusieurs variants génétiques rares contribuant probablement aux TSA chez certains patients nous a conduits à faire l’hypothèse d’un oligogénisme. Cette étude a également permis d’évaluer la faisabilité de l’exome dans un cadre de diagnosticAutism spectrum disorders (ASD) are neurodevelopmental disorders characterized by an extreme clinical and genetic heterogeneity. In most cases, the causes of the disorders remain unknown; however, a genetic cause is so far identified in 30% of the patients. Our main objective was to identify genetic factors involved in ASD from a cohort of 205 prospectively recruited patients. More specifically, we have screened the genes encoding Neuroligins and SHANK3, analyzed the copy number variants (CNV) using microarrays and sequenced the exome of chromosome X in selected patients. Candidate genes identified by these approaches were screened in our cohort of patients and functional analyses were performed. Two novel genes on chromosome X were identified: TMLHE, encoding the enzyme catalyzing the first step of carnitine biosynthesis, and SLC7A3, encoding a cationic amino acid transporter. We also report mutations in SHANK3, PHF8 and HUWE1, a 15q11q13 triplication, a 9p24 deletion, a 3q29 deletion, and a 16p11. 2 duplication in four patients; mutations in these genes or these CNV were previously described in patients with ASD or intellectual disability (ID). Finally, we describe two genes, PTGER3 and DOCK10, possibly causing autosomal recessive ASD. This study has allowed the identification of new genes associated with ASD and has confirmed the genetic heterogeneity in ASD and the overlap with genes causing ID. The observation of several genetic factors possibly contributing to ASD in some patients prompted us to discuss oligogenic inheritance models. Finally, this study has assessed the possibility of performing a molecular diagnosis by exome sequencing at an individual scale
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Maier, Esther Maria. "X-Inaktivierung bei heterozygoten Überträgerinnen X-chromosomal gebundener Adrenoleukodystrophie." Diss., lmu, 2002. http://nbn-resolving.de/urn:nbn:de:bvb:19-1606.
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Rosenberg-Bourgin, Myriam. "Etude comparative des gènes ribosomaux de chromosomes X et Y de différentes souches de laboratoire chez Drosophila melanogaster." Grenoble 2 : ANRT, 1987. http://catalogue.bnf.fr/ark:/12148/cb37609476w.
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Hidalgo, André Marubayashi. "Fine mapping and single nucleotide polymorphism effects estimation on pig chromosomes 1, 4, 7, 8, 17 and X." Universidade Federal de Viçosa, 2011. http://locus.ufv.br/handle/123456789/4753.
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Mapeamento de loci de caracaterística quantitativas (QTL) geralmente resultam na detecção de regiões genômicas que explicam parte da variação quantitativa da característica. Entretanto essas regiões são muito amplas e não permitem uma acurada identificação dos genes. Dessa forma, torna-se necessário o estreitamento dos intervalos onde os QTL estão localizados. Com a seleção genômica ampla (GWS), foram desenvolvidas ferramentas estatísticas de forma a se estimar os efeitos de cada marcador. A partir dos valores desses efeitos, pode-se analisar quais são os marcadores de maiores efeitos. Assim, objetivou-se realizar o mapeamento fino dos cromossomos suínos 1, 4, 7, 8, 17, e X, usando marcadores microsatélites e polimorfismo de base única (SNP), em uma população F2 produzida pelo cruzamento de varrões da raça naturalizada brasileira Piau com fêmeas comerciais, associados com características de desempenho, carcaça, orgãos internos, cortes e qualidade de carne. Também objetivou-se estimar os efeitos dos marcadores SNP nas características que tiveram QTL detectados, analisar quais são os mais expressivos e verificar se eles estão localizados dentro do intervalo de confiança do QTL. Os QTL foram identificados por meio do método regressão por intervalo de mapeamento e as análises foram realizadas pelo software GridQTL. O efeito de cada marcador foi estimado pela regressão de LASSO Bayesiano, usando o software R. No total, 32 QTL foram encontrados ao nível cromossômico de significância de 5%, destes, 12 eram significativos ao nível cromossômico de 1% e 7 destes eram significativos ao nível genômico de 5%. Seis de sete QTL apresentaram marcadores de efeito expressivo dentro do intervalo de confiança do QTL. Resultados deste estudo confirmaram QTL de outros trabalhos e identificaram vários outros novos. Os resultados encontrados utilizando marcadores microsatélites junto com SNPs aumentaram a saturação do genoma levando a um menor intervalo de confiança dos QTL encontrados. Os métodos usados foram importantes para estimar os efeitos dos marcadores, e também para localizar aqueles com efeitos mais expressivos dentro do intervalo de confiança do QTL, validando os QTL encontrados pelo método da regressão.
Quantitative Trait Loci (QTL) mapping efforts often result in the detection of genomic regions that explain part of the quantitative trait variation. However, these regions are very large and do not allow accurate gene identification, hence the interval must be narrowed where the QTL was located. With the genome wide selection (GWS), many statistical tools have been developed in order to estimate the effects for each marker. With the marker effects values it is possible to analyze which markers have large effects. Hence, the objective of this investigation was to fine map pig chromosomes 1, 4, 7, 8, 17 and X, using microsatellites and SNP markers, in a F2 population produced by crossing naturalized Brazilian Piau boars with commercial females, associated with performance, carcass, internal organs, cut yields and meat quality traits. A further aim was to estimate the effects of single nucleotide polymorphism (SNP) markers on traits with detected QTL, analyze the most expressive ones and verify whether the markers with larger effects were indeed within the QTL confidence interval. QTL were identified by regression interval mapping using the GridQTL software. Individual marker effects were estimated by Bayesian LASSO regression using the R software. In total, 32 QTL for the studied traits were significant at the 5% chromosome-wide level, including 12 significant QTL at the 1% chromosome-wide level and 7 significant at the 5% genome-wide level. Six out of seven QTL with genome-wide significance had markers of large effect within their confidence interval. These results confirmed some previous QTL and identified numerous novel QTL for the investigated traits. Our results have shown that the use of microsatellites and SNP markers that increase the genome saturation lead to QTL of smaller confidence intervals. The methods used were also valuable to estimate the marker effects and to locate the most expressive markers within the QTL confidence interval, validating those QTL found by the regression method.
43
Oldfield, Andrew. "Etude du réseau transcriptionnel du gène Xist, acteur principal de l'inactivation du chromosome X." Phd thesis, Université Pierre et Marie Curie - Paris VI, 2010. http://tel.archives-ouvertes.fr/tel-00815096.
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L'inactivation du chromosome X est la réponse trouvée par l'évolution pour pallier à la divergence gonosomique entre mâle (XY) et femelle (XX). Ce phénomène sert donc à mettre les deux sexes sur un pied d'égalité en limitant la quantité de transcrits provenant des chromosomes X présents dans les cellules femelles. Au cours de mon doctorat, j'ai tenté de contribuer à l'étude des mécanismes de régulation transcriptionnelle, notamment l'activation, des deux acteurs principaux de l'inactivation: Xist et Tsix, son transcrit antisens. Pendant ces 4 anne��es, j'ai entrepris de cartographier le profil de fixation de plusieurs protéines le long du locus Xist/Tsix, dans le but de comprendre les mécanismes permettant une surexpression de Xist lors de la disparition de ses facteurs répressifs en cours de différenciation. J'ai donc pu établir un modèle de régulation transcriptionnelle de l'ARN non-codant Xist, impliquant plusieurs protéines connues pour leur rôle dans la régulation transcriptionnelle (CTCF et YY1) aussi bien que dans la formation de structures tridimensionnelles (la cohésine). La pertinence de ce modèle est renforcée par nos études montrant que de nombreux aspects de ce modèle sont conservés à travers l'évolution (notamment chez l'homme). J'ai également pu contribuer à la découverte de nouveaux activateurs de Tsix, certains facteurs de pluripotence se fixant au minisatellite DxPas34 afin de réguler l'élongation de la transcription de l'antisens. Ces résultats apportent donc d'importantes informations concernant les mécanismes régulant la mise en place du phénomène d'inactivation du chromosome X au cours du développement précoce de l'embryon.
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Sprong, Amy Nicole. "X Chromosome Aneuploidy: A Look at the Effects of X Inactivation." Miami University Honors Theses / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=muhonors1209079846.
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Bustamante, Jacinta Cecilia. "Défaut héréditaire de CYBB et prédisposition mendélienne aux infections mycobactériennes." Paris 5, 2007. http://www.theses.fr/2007PA05A003.
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Le syndrome de susceptibilité mendélienne aux infections mycobactériennes (MSDM) est un syndrome rare caractérisé par une susceptibilité accrue à des germes intracellulaires peu virulents (bacille de Calmette-Guérin, mycobactéries environnementales) sans évidence d'autre infection (sauf des infections à salmonelles). Des mutations causales de six gènes affectent la boucle d'activation IL12/IL23-IFNγ. Nous avons étudié quatre hommes d'une famille non consanguine ; avec des infections mycobactériennes récurrentes. Nous avons identifié deux régions d'intérêt sur le chromosome X avec un LOD score maximum de 1,93. Une mutation, Q231P, a été retrouvée sur le gène CYBB chez ces patients. CYBB, élément essentiel du système NADPH dans les phagocytes, est responsable d'un autre déficit immunitaire, la granulomatose septique chronique. Cette mutation affecte uniquement l'explosion oxydative dans les macrophages dérivés in vitro. Ce travail permet de définir une nouvelle forme liée au chromosome X du MSMD, et il indique que l'explosion oxydative est importante pour l'immunité antimycobactérienne dans les macrophages tissulaires chez l'hommeMendelian susceptibility to mycobacterial disease (MSMD) is a rare syndrome conferring predisposition to clinical disease caused by weakly virulent mycobacteria (bacille Calmette Guérin vaccines and environmental mycobacteria), as well as more virulent. M. Tuberculosis and salmonella. Mutations found in six genes involved IL12/IL23-IFNγ mediated immunity. We studied a multiples family in which four otherwise healthy adult males show mycobacterial diseases (BCG-osis and tuberculosis). By multipoint linkage analysis, a maximal Lod score of 1. 93 was found for two candidate regions on X-chromosome. The patients harbor a novel mutation in CYBB (Q231P), which abolishes the respiratory burst in monocyte-derived macrophages. This gene is an essential component of NADPH in phagocytes. Germline CYBB mutations are commonly associated with chronic granulomatous disease. The MSMD-causing mutation in CYBB selectively affects the respiratory burst in macrophages. This experiment of nature indicates that the pathway in human macrophages is crucial for protective immunity to mycobacteria
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Cotton, Allison Marie. "Patterns of DNA methylation on the human X chromosome and use in analyzing X-chromosome inactivation." Thesis, University of British Columbia, 2012. http://hdl.handle.net/2429/40363.
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The process of X-chromosome inactivation achieves dosage compensation between
mammalian males and females. In females one X chromosome is transcriptionally silenced
through a variety of epigenetic modifications including DNA methylation. Most X-linked genes
are subject to X-chromosome inactivation and only expressed from the active X chromosome.
On the inactive X chromosome, the CpG island promoters of genes subject to X-chromosome
inactivation are methylated in their promoter regions, while genes which escape from Xchromosome
inactivation have unmethylated CpG island promoters on both the active and
inactive X chromosomes.
The first objective of this thesis was to determine if the DNA methylation of CpG island
promoters could be used to accurately predict X chromosome inactivation status. The second
objective was to use DNA methylation to predict X-chromosome inactivation status in a variety
of tissues. A comparison of blood, muscle, kidney and neural tissues revealed tissue-specific
X-chromosome inactivation, in which 12% of genes escaped from X-chromosome inactivation in
some, but not all, tissues. X-linked DNA methylation analysis of placental tissues predicted four
times higher escape from X-chromosome inactivation than in any other tissue. Despite the
hypomethylation of repetitive elements on both the X chromosome and the autosomes, no
changes were detected in the frequency or intensity of placental Cot-1 holes.
The third objective of this thesis was to use DNA methylation to investigate X-chromosome
inactivation in female samples with chromosomally abnormal karyotypes. The spread of Xchromosome
inactivation into the autosomal portion of six unbalanced X;autosome
translocations revealed similarities between X;autosome translocations involving the same
autosome and therefore suggested a role for DNA sequence in influencing X-chromosome
inactivation status of genes. Autosomal genes that escaped from inactivation were found to
have significantly lower L1 and LTR but higher Alu content than genes which were subject to
inactivation. Lastly, DNA methylation was used to predict the number of inactive X
chromosomes in triploid placental samples. Triploid samples provide an excellent system in
which to study the counting step of X-chromosome inactivation and DNA methylation analysis
provides a means to determine the number of inactive X chromosomes using only a DNA
sample.
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Chen, Zheng-Yi. "Molecular biology of X-chromosome disease." Thesis, University of Oxford, 1992. http://ora.ox.ac.uk/objects/uuid:8214a2f6-0bfa-4ea4-8f48-b8a20f29318c.
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Genomic clones were isolated and characterized using the human monoamine oxidase A (MAOA) cDNA to screen a phage library, constructed from a human 4X cell line (48, XXXX). The genomic contig derived from overlapping phage clones showed that the size of the MAOA gene is over 80 kb. Exon-containing fragments from these phage clones were subcloned and sequenced. The data from this showed that the MAOA gene consists of 15 exons. A YAC (yeast artificial chromosome) isolated using the MAOA cDNA was characterized. This YAC was found to contain both the MAOA and the MAOB genes. Using PFGE (pulsed-field gel electrophoresis) to investigate the YAC, it was found that the MAOA and the MAOB genes are located within 50 kb and adjacent to each other. The two genes are localized in a 3'-to-3' fashion, suggesting their expression may be regulated independently. The analysis of the homology shown by the two genes clearly demonstrated that they were derived from duplication of a common ancestral gene. A CpG island was discovered to be associated with the 5' end of both genes. A restriction map of -2.5 Mb of genomic DMA around the MAO genes was generated by PFGE. Long-range mapping defined the physical relationship between the marker L1.28 and the MAO genes as L1.28_MAOA_MAOB. A number of genetic diseases have been linked to the Xp11.3 region. Strong linkage was known to exist between the Norrie disease locus and L1.28. Studies showed that some of the Norrie patients have deletions encompassing the region which contains L1.28 as well as the MAO genes. Another YAC isolated by using L1.28 as the probe was also characterized. A phage library was constructed from the L1.28 YAC and the end clones were isolated. Studies on some of the Norrie deletion patients showed that the proximal end clone of the YAC was retained in one of the deletion patients. Previous studies had shown that the Norrie disease locus was also localized proximal to the 5' end of the MAOB gene. The combined information placed the disease locus to an interval of 240 kb within the YAC. More phage clones were characterized in order to define further the region for the Norrie locus which was finally localized within 160 kb. A YAC fragment of 160 kb was isolated and used to screen two human retinal cDNA libraries. Among the cDNAs isolated, one group was found to be deleted in some of the Norrie patients previously without any known deletion, which established their candidacy as the transcripts of the Norrie disease locus. Further characterization of the candidate gene showed that it is conserved across species. The expression of the gene was detected in various tissues. The homology shared between the NDP gene and some of the growth factor binding proteins suggests its role in neural cell proliferation and differentiation.
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Norris, Dominic Paul. "X chromosome inactivation in the mouse." Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282142.
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Apedaile, Anwyn Emily. "Dynamics of DNA methylation on the mammalian X-chromosome during X-inactivation." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444592.
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Luikenhuis, Sandra 1972. "Studies on X chromosome inactivation and the X-linked disease Rett syndrome." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/28676.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2004.Includes bibliographical references.
(cont.) the RTT phenotype.
Deletion of the Xist gene results in skewed X-inactivation. To distinguish primary non-random choice from post-choice selection, we analyzed X-inactivation in early embryonic development in the presence of two different Xist deletions. We found that Xist is an important choice element, and that in the absence of an intact Xist gene, the X chromosome will never be chosen as the active X. To understand the molecular mechanisms that affect choice we analyzed the role of replication timing prior to X-inactivation. The X chromosomes replicated asynchronously before X-inactivation but analysis of cell-lines with skewed X-inactivation showed no preference for one of the two Xist alleles to replicate early, indicating that asynchronous replication timing prior to X-inactivation does not play a role in skewing of X-inactivation. Expression of the Xist is negatively regulated by its antisense gene, Tsix. In order to determine the role of transcription in Tsix function, we modulated Tsix transcription with minimal disturbance of the genomic sequence. Loss of Tsix transcription lead to non-random inactivation of the targeted chromosome, whereas induction of Tsix expression caused the targeted chromosome always to be chosen as the active X. These results for the first time establish a function for antisense transcription in the regulation of Xist expression. The X-linked disease Rett syndrome (RTT), a neurodevelopmental disorder, is caused by mutations in the MECP2 gene. We used a mouse model to test the hypothesis that RTT is exclusively caused by neuronal MeCP2 deficiency. Expression of an Mecp2 transgene in postmitotic neurons resulted in symptoms of severe motor dysfunction. Transgene expression in Mecp2 mutant mice, however, rescued
by Sandra Luikenhuis.
Ph.D.