The majority of genetic traits including most common diseases are believed to be multigenic and arise both from variations in coding sequences as well as from regulatory polymorphisms. Genome-wide approaches are needed to develop models for understanding this complexity. This thesis develops approaches for studying genetic variation affecting gene expression on a genome-wide scale. This included development of experimental design principles and analytical methods for microarray data. These principles were then applied to characterize differences between commonly-used A/J and C57BL/6J inbred mouse strains at the molecular level identifying over 2000 genes differentially expressed between these strains across 4 tissues. To further investigate the role of genetic variation in genome-wide expression changes, we analyzed expression profiles of lung tissue obtained from a panel of recombinant congenic strains (RCS) derived from the same inbred strains. An ANOVA was applied using a model to test the association of expression profiles with donor-strain of origin (DSO, inferred from RCS genotyping data), and with genetic background. This model identified over 1500 genes whose expression levels were associated with DSO status (P<0.05) having adjusted for the variability due to predominant strain of background, suggestive of cis-regulatory variation in these genes. We randomly selected 50 positive genes displaying association between DSO and 80 negative genes for validation using allelic imbalance (AI), a method that uses intragenic SNPs for detecting genes with cis-regulatory variation that measures allele-specific transcript levels in cDNA of heterozygous individuals. Of the genes chosen, 54% of positive versus 27% of negative genes contained at least one SNP within ≥ 1 kbp of 3' UTR sequenced (P<0.05 Fisher exact test). Al was found in 63% of positive genes versus 23% of negative genes (P<0.01 Fisher exact test) representing a greater than 10-fo
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.85931 |
| Date | January 2005 |
| Creators | Lee, Peter Daniel |
| 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: 002261496, proquestno: AAINR21668, Theses scanned by UMI/ProQuest. |
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