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Title: The role of the X chromosome in embryonic and postnatal growth
Author: Snell, Daniel Mark
ISNI:       0000 0004 7230 2833
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2018
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Women born with only a single X chromosome (XO) have Turner syndrome (TS); and they are invariably of short stature. XO female mice are also small: during embryogenesis, female mice with a paternally-inherited X chromosome (XPO) are smaller than XX littermates; whereas during early postnatal life, both XPO and X MO (maternal) mice are smaller than their XX siblings. Here I look to further understand the genetic bases of these phenotypes, and potentially inform areas of future investigation into TS. Mouse pre-implantation embryos preferentially silence the XP via the non-coding RNA Xist. XPO embryos are smaller than XX littermates at embryonic day (E) 10.5, whereas XMO embryos are not. Two possible hypotheses explain this observation. Inappropriate expression of Xist in XPO embryos may cause transcriptional silencing of the single X chromosome and result in embryos nullizygous for X gene products. Alternatively, there could be imprinted genes on the X chromosome that impact on growth and manifest in growth retarded XPO embryos. In contrast, during the first three weeks of postnatal development, both XPO and XMO mice show a growth deficit when compared with XX littermates. This deficit is not observed in the presence of a second sex chromosome - i.e. in normal XX female mice, or in females with a Y chromosome that lacks Sry - suggesting haploinsufficiency of genes with homologues present on, and expressed from, both sex chromosomes as a cause. In this thesis I have investigated the role of Xist in XPO embryonic growth retardation; and utilised mouse stem cells to perform an in vitro screen to identify X-linked imprinted genes. To characterise postnatal haploinsufficiency, I identify four candidate genes and, utilising CRISPR-Cas genome editing, delineate the role of each in the growth deficit phenotype. I further use these X-linked mutants to investigate the functional divergence of the X and Y chromosomes in the context of postnatal survival.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available