The present thesis covers two aspects of statistical analysis applied to the genetics of human diseases. First, the significance of LOD-score results for the confirmation of linkage is addressed, with special emphasis on small pedigrees. A new analytical approach is presented for the linkage analysis of heterogenetic traits, using hereditary spastic paraplegia as a model, a disease well suited for the analyses. The critical significance values for confirmation of linkage are evaluated using Bayesian statistics, and empirical P-values for LOD score results are calculated using computer simulation methods. The presented analytical approach resulted in conclusive linkage analyses on small to medium-size families, under the restrictions of genetic heterogeneity. / The second part addresses linkage-disequilibrium based fine mapping in the French Canadian population. The performance of five linkage-disequilibrium based fine-mapping methods is evaluated using French Canadian chromosomes with one of three diseases found in this population: oculopharyngeal muscular dystrophy (OPMD), hidrotic ectodermal dysplasia (HED), and sensorimotor polyneuropathy with or without agenesis of the corpus callosum (ACCPN). The gene for OPMD was recently mapped and cloned, allowing us to evaluate the performance of the methods with the OPMD results, and to make predictions about the ACCPN and HED putative gene positions. In addition, a new approach to linkage-disequilibrium based fine mapping is presented using FrenchCanadian ascending genealogies. The method involves two steps. First, the likely founding couple of a mutation-bearing chromosome is identified using a computerised randomisation statistic. Then, using a delete-d jackknife resampling scheme, the distribution of gene mapping estimates is calculated from the count of ancestral recombinants and ancestral meioses joining the identified founding couple to the disease gene carriers. Gene mapping estimates are calculated from each marker individually, and confidence intervals of the estimates are derived from the jackknife distributions. The method, when applied to French Canadian families with OPMD, successfully confirmed the localisation of PABP2 responsible for OPMD and performed better than other linkage disequilibrium-based mapping models.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.36581 |
| Date | January 1999 |
| Creators | Dubé, Marie-Pierre. |
| Contributors | Rouleau, Guy 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 Biology.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001762064, proquestno: NQ64551, Theses scanned by UMI/ProQuest. |
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