Mammalian mitochondrial DNA (mtDNA) is a maternally inherited, multi-copy, small circular genome approximately 16 kb in size that codes for 13 polypeptides of the mitochondrial respiratory chain. Typically, mtDNA is present as only one genotype in a cell, a state known as homoplasmy. In rare circumstances, two or more mtDNA sequence variants can be present in a cell, a state known as heteroplasmy, and these sequence variants can segregate during mitosis and meiosis. In this thesis, I have investigated the basis for a novel tissue-specific segregation of mtDNA in a heteroplasmic mouse model that had been previously constructed from two inbred strains (NZB/BinJ and BALB/c mtDNA). In these mice, four tissues showed directional selection for an mtDNA genotype: in the liver and kidney for the NZB mtDNA genotype; and in the spleen and blood for the BALB mtDNA genotype. I investigated the mechanism responsible for selection of NZB mtDNA, focusing on the liver which showed the strongest effect. In this tissue, selection for the NZB mtDNA genotype is constant with time, independent of allele frequency and does not appear to be mediated through an advantage of respiratory chain function or replication rate of mtDNA. To identify the genetic basis for this mtDNA selection, I set up an intersubspecific intercross and used quantitative trait loci (QTL) mapping to map three QTL in F2 mice that are strong gene effects in the liver, kidney, and spleen. These QTLs, Smdq-1 (liver), Smdq-2 (kidney), and Smdq-3 (kidney & spleen) (s&barbelow;egregation of m&barbelow;itochondrial D&barbelow;NA Q&barbelow;TL-#) map to chromosome 5, 2, and 6 respectively. Smdq-1 was a dominant QTL in the liver that mapped to a 2 LOD support interval of approximately 1 cM and accounted for 34% of the variation in the trait. To reduce the interval size of Smdq-1 and confirm the map position, BALB chromosome 5 interval-specific congenic mice lines are being generated across a 20 cM interval. This is the fir
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.38462 |
| Date | January 2002 |
| Creators | Battersby, Brendan James |
| Contributors | Shoubridge, Eric A. (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Human Genetics.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001941002, proquestno: NQ85683, Theses scanned by UMI/ProQuest. |
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