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Title: Forward genetic analysis of mammalian immunity
Author: Siggs, Owen M.
Awarding Body: University of Oxford
Current Institution: University of Oxford
Date of Award: 2012
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Mutation, whether spontaneous or induced, is the premier tool for understanding gene function. One approach is to create mutations in a specific gene, and then use the resulting cell or organism to search for a phenotype. An alternative is to create mutations at random, and focus first on the identification of phenotypes. The mutation that underlies a phenotype can then be tracked down, forming the foundation of testable hypotheses. Using random chemical mutagenesis in mice, I have identified 20 heritable phenotypes affecting either the innate or adaptive branches of immunity. The genetic basis of 18 of these phenotypes was solved, caused by mutations in at least 16 unique genes. Five of these genes were not previously known to be involved in immunity, and a detailed analysis of four of them is provided in this thesis. These include genes encoding the following proteins: the inactive rhomboid protease iRhom2, which is specifically required for the secretion of tumour necrosis factor alpha; the hypothetical phospholipid flippase ATP11C, required for B cell development in the adult bone marrow; the folliculin-interacting protein FNIP1, also required for B cell development; and the zinc finger transcription factor ZBTB1, essential for the development of all lymphocyte lineages. These findings uncover new entry points for the understanding of mammalian immunity, and highlight the value of mouse forward genetics in the understanding of mammalian phenomena in general.
Supervisor: Beutler, Bruce; Cornall, Richard Sponsor: General Sir John Monash Foundation
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Immunology ; Genetics (life sciences) ; Mutagenesis ; Toll-like receptors ; Lymphopoiesis