Marburg, Univ., Diss., 2009

published_or_final_version / Obstetrics and Gynaecology / Doctoral / Doctor of Philosophy

With the rapid development of next-generation sequencing NGS technology, we are able to investigate various aspects biological problems, including genome and transcriptome sequencing, genomic structural variation and the mechanism of regulatory small RNAs, etc. An enormous number of associated computational methods have been proposed to study the biological problems using NGS reads, at a low cost of expense and time. Regulatory small RNAs and genomic structure variations are two main problems that we have studied. In the area of regulatory small RNA, various computational tools have been designed from the prediction of small RNA to target prediction. Regulatory small RNAs play essential roles in plants and bacteria such as in responses to environmental stresses. We focused on sRNAs that in act by base pairing with target mRNA in complementarity. A comprehensive analysis workflow that is able to integrate sRNA-Seq and RNA-Seq analysis and generate regulatory network haven't been designed yet. Thus, we proposed and implemented two small RNA analysis workflow for plants and bacteria respectively. In the area of genomic structural variations (SV), two types of disease-related SVs have been investigated, including complex low copy repeats (LCRs, also termed as segmental duplications) and tandem duplication (TD). LCRs provide structural basis to form a combination of other SVs which may in turn lead to some serious genetic diseases and TDs of specific areas have been reported for patients. Locating LCRs and TDs in human genome can help researchers to further interrogate the mechanism of related diseases. Therefore, we proposed two computational methods to predict novel LCRs and TDs in human genome. / published_or_final_version / Computer Science / Doctoral / Doctor of Philosophy

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Thesis (M.Sc.). / Written for the Dept. of Plant Science. Title from title page of PDF (viewed 2008/05/29). Includes bibliographical references.

Thesis (Ph. D.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 231-275). Also available in print.

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L’inactivation du chromosome X (XCI) est un mécanisme qui permet l’extinction transcriptionelle d’un des deux chromosomes X chez la femelle. XCI est régulé par une région spécifique nommée centre de l’inactivation du chromosome (Xic), contenant plusieurs gènes produisant de longs ARNs non codants (lncRNAs). Parmi ces lncRNAs, le transcrit Xist est l’effecteur principal pour l’XCI. Xist peut s’accumuler en cis sur le chromosome et recruter la machinerie qui permettra l’initiation et la propagation de l’extinction transcriptionnelle à l’échelle du chromosome.Le laboratoire d’accueil a identifié un nouveau gène du Xic qui produit le lncRNA Ftx. Dans cette étude, on a pu montrer que l’inactivation du chromosome X est fortement perturbée dans les cellules Ftx-/- et s’accompagne par une forte baisse du niveau d’expression et d’accumulation de Xist. Dans ce contexte, certaines cellules parviennent à maintenir l’expression de Xist mais le profil de couverture du chromosome X par Xist est anormal, présentant un profil diffus ; ceci est associé à une extinction transcriptionnelle déficiente des gènes liés à l’X. Dans les lignées hétérozygotes Ftx+/-, l’expression et l’accumulation de Xist est aussi affectée mais dans une moindre mesure, si bien qu’il apparaît que le nombre de copies de Ftx soit important pour sa fonction. Par ailleurs, l’inactivation du chromosome X dans les cellules Ftx+/- est biaisée de telle sorte que le chromosome X portant une copie fonctionnelle de Ftx est préférentiellement inactivé, suggérant un rôle en cis de Ftx. Ces résultats montrent que Ftx est un activateur de Xist et qu’il est essentiel pour la mise en place de l’inactivation / X-chromosome inactivation (XCI) is a female-specific, chromosome-wide regulatory process that, in eutherians, ensures dosage compensation for X-linked genes between sexes. XCI is controlled by a cis-acting locus on the X-chromosome, the X-inactivation center (Xic), enriched in genes producing long non-coding RNAs (lncRNAs). The Xic-linked gene Xist is the master player of XCI, and produces a lncRNA that accumulates in cis on the X-chromosome and recruits the machinery responsible for initiation and propagation of silencing.The laboratory has identified an additional Xic-linked non-coding gene, Ftx. In this study, we could find that, in female Ftx-/- lines, XCI is strongly impaired, with a significant decrease in the levels of Xist expression and in the percentage of cells showing normal Xist accumulation patterns. Importantly, a high proportion of the cells that still retain Xist expression show abnormal X-chromosome coating and a decreased ability to silence X-linked genes. These data reveal that Ftx is a positive Xist regulator and it is required for proper XCI establishment. In female Ftx+/- lines, the levels of Xist expression and the percentage of cells showing normal Xist accumulation patterns are also decreased, albeit to a lower extent compared to Ftx-/- lines, suggesting that Ftx works in a copy-dependent manner. In addition, a high proportion of Ftx+/- cells display skewed X-inactivation, with preferential inactivation of the wild-type X chromosome. This suggests that Ftx role on Xist accumulation is mostly restricted in cis. Taken together, these results demonstrate that Ftx is required for XCI establishment, where it functions as a strong Xist activator

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