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  1. Article ; Online: Mouse Models of Aneuploidy

    Olivia Sheppard / Frances K. Wiseman / Aarti Ruparelia / Victor L. J. Tybulewicz / Elizabeth M. C. Fisher

    The Scientific World Journal, Vol

    2012  Volume 2012

    Abstract: Abnormalities of chromosome copy number are called aneuploidies and make up a large health load on the human population. Many aneuploidies are lethal because the resulting abnormal gene dosage is highly deleterious. Nevertheless, some whole chromosome ... ...

    Abstract Abnormalities of chromosome copy number are called aneuploidies and make up a large health load on the human population. Many aneuploidies are lethal because the resulting abnormal gene dosage is highly deleterious. Nevertheless, some whole chromosome aneuploidies can lead to live births. Alterations in the copy number of sections of chromosomes, which are also known as segmental aneuploidies, are also associated with deleterious effects. Here we examine how aneuploidy of whole chromosomes and segmental aneuploidy of chromosomal regions are modeled in the mouse. These models provide a whole animal system in which we aim to investigate the complex phenotype-genotype interactions that arise from alteration in the copy number of genes. Although our understanding of this subject is still in its infancy, already research in mouse models is highlighting possible therapies that might help alleviate the cognitive effects associated with changes in gene number. Thus, creating and studying mouse models of aneuploidy and copy number variation is important for understanding what it is to be human, in both the normal and genomically altered states.
    Keywords Technology ; T ; Medicine ; R ; Science ; Q
    Language English
    Publishing date 2012-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Evidence for evolutionary divergence of activity-dependent gene expression in developing neurons

    Jing Qiu / Jamie McQueen / Bilada Bilican / Owen Dando / Dario Magnani / Karolina Punovuori / Bhuvaneish T Selvaraj / Matthew Livesey / Ghazal Haghi / Samuel Heron / Karen Burr / Rickie Patani / Rinku Rajan / Olivia Sheppard / Peter C Kind / T Ian Simpson / Victor LJ Tybulewicz / David JA Wyllie / Elizabeth MC Fisher /
    Sally Lowell / Siddharthan Chandran / Giles E Hardingham

    eLife, Vol

    2016  Volume 5

    Abstract: Evolutionary differences in gene regulation between humans and lower mammalian experimental systems are incompletely understood, a potential translational obstacle that is challenging to surmount in neurons, where primary tissue availability is poor. ... ...

    Abstract Evolutionary differences in gene regulation between humans and lower mammalian experimental systems are incompletely understood, a potential translational obstacle that is challenging to surmount in neurons, where primary tissue availability is poor. Rodent-based studies show that activity-dependent transcriptional programs mediate myriad functions in neuronal development, but the extent of their conservation in human neurons is unknown. We compared activity-dependent transcriptional responses in developing human stem cell-derived cortical neurons with those induced in developing primary- or stem cell-derived mouse cortical neurons. While activity-dependent gene-responsiveness showed little dependence on developmental stage or origin (primary tissue vs. stem cell), notable species-dependent differences were observed. Moreover, differential species-specific gene ortholog regulation was recapitulated in aneuploid mouse neurons carrying human chromosome-21, implicating promoter/enhancer sequence divergence as a factor, including human-specific activity-responsive AP-1 sites. These findings support the use of human neuronal systems for probing transcriptional responses to physiological stimuli or indeed pharmaceutical agents.
    Keywords transcription ; gene expression ; calcium signaling ; neuronal activity ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2016-10-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Massively parallel sequencing reveals the complex structure of an irradiated human chromosome on a mouse background in the Tc1 model of Down syndrome.

    Susan M Gribble / Frances K Wiseman / Stephen Clayton / Elena Prigmore / Elizabeth Langley / Fengtang Yang / Sean Maguire / Beiyuan Fu / Diana Rajan / Olivia Sheppard / Carol Scott / Heidi Hauser / Philip J Stephens / Lucy A Stebbings / Bee Ling Ng / Tomas Fitzgerald / Michael A Quail / Ruby Banerjee / Kai Rothkamm /
    Victor L J Tybulewicz / Elizabeth M C Fisher / Nigel P Carter

    PLoS ONE, Vol 8, Iss 4, p e

    2013  Volume 60482

    Abstract: Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely ... ...

    Abstract Down syndrome (DS) is caused by trisomy of chromosome 21 (Hsa21) and presents a complex phenotype that arises from abnormal dosage of genes on this chromosome. However, the individual dosage-sensitive genes underlying each phenotype remain largely unknown. To help dissect genotype--phenotype correlations in this complex syndrome, the first fully transchromosomic mouse model, the Tc1 mouse, which carries a copy of human chromosome 21 was produced in 2005. The Tc1 strain is trisomic for the majority of genes that cause phenotypes associated with DS, and this freely available mouse strain has become used widely to study DS, the effects of gene dosage abnormalities, and the effect on the basic biology of cells when a mouse carries a freely segregating human chromosome. Tc1 mice were created by a process that included irradiation microcell-mediated chromosome transfer of Hsa21 into recipient mouse embryonic stem cells. Here, the combination of next generation sequencing, array-CGH and fluorescence in situ hybridization technologies has enabled us to identify unsuspected rearrangements of Hsa21 in this mouse model; revealing one deletion, six duplications and more than 25 de novo structural rearrangements. Our study is not only essential for informing functional studies of the Tc1 mouse but also (1) presents for the first time a detailed sequence analysis of the effects of gamma radiation on an entire human chromosome, which gives some mechanistic insight into the effects of radiation damage on DNA, and (2) overcomes specific technical difficulties of assaying a human chromosome on a mouse background where highly conserved sequences may confound the analysis. Sequence data generated in this study is deposited in the ENA database, Study Accession number: ERP000439.
    Keywords Medicine ; R ; Science ; Q
    Subject code 572
    Language English
    Publishing date 2013-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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