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Identification of the Functional Significance of a Novel Genetic Modifier of p53 – Ovca1Du, Shuhua 25 July 2011 (has links)
No description available.
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Conditional linkage methods--searching for modifier genes in a large Amish pedigree with known Von Willebrand disease major gene modificationAbbott, Diana Lee 01 May 2009 (has links)
Von Willebrand Disease (VWD) is the most common bleeding disorder. In addition to known major genes, genetic modifiers, such as ABO blood group, affect quantitative outcome measures for VWD. The data consist of an 854-member Amish pedigree with established linkage of VWD to a locus within the Von Willebrand Factor (VWF) gene on chromosome 12. The DNA sequence of the causative mutation is known. Phenotypic information and genotypic data consisting of VWF mutation status and a genome screen of markers are available for 385 pedigree members. Genetic modifiers of the VWF mutation are investigated using known and new conditional linkage methods that search for modifier genes of a major gene with known mutation.
The MCMC-based program LOKI was used to conduct multipoint linkage analysis of VWD outcome measures while controlling for the VWF mutation. Adjustment for the mutation did not eliminate the linkage signal on chromosome 12 in the same location as the VWF mutation. Evidence for QTLs was also found on six other chromosomes.
Smod, a score statistic that detects evidence of a genetic modifier conditional on linkage to a major gene, was developed for sib pair data. To limit the modifier gene main effect, Smod was developed so that variance due to the modifier locus is bounded above by the variance of the interaction between major gene and modifier gene. The performance of Smod was compared to other published score statistics. Power to detect linkage to the modifier locus depended on major gene and modifier gene risk allele frequencies, relative contribution of the major gene main effect to the interaction effect, and the upper bound on the modifier gene main effect.
The Amish pedigree was broken up into sib pair data and analyzed using Smod and other score statistics. Using these statistics, the strongest evidence for QTLs for VWD was also found on chromosome 12 in the region of the VWF mutation. Combined with the LOKI results, further analysis will help determine if intragenic modification is occurring or if linkage disequilibrium between the mutation and analyzed markers is driving results.
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Methods for comprehensive transcriptome analysis using next-generation sequencing and application in hypertrophic cardiomyopathyChristodoulou, Danos C. 08 October 2013 (has links)
Characterization of the RNA transcriptome by next-generation sequencing can produce an unprecedented yield of information that provides novel biologic insights. I describe four approaches for sequencing different aspects of the transcriptome and provide computational tools to analyze the resulting data. Methods that query the dynamic range of gene expression, low expressing transcripts, micro RNA levels, and start-site usage of transcripts are described.
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Interleukin-8 as a genetic modifier and pharmacologic target for cystic fibrosis pulmonary diseaseHillian, Antoinette D. 01 August 2009 (has links)
No description available.
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The Identification and Characterization of Genetic Modifiers for Bardet-Biedl Syndrome-associated Phenotypes using Caenorhabditis elegansMok, Calvin Ka Fay 30 August 2012 (has links)
Primary cilia are evolutionarily conserved organelles required in a number of signalling pathways influencing the development and behaviour of a diverse range of organisms. More recently, studies into a new class of human diseases known as ciliopathies have helped to shed light on the critical role of this once-ignored signalling centre. Bardet-Biedl syndrome (BBS) proteins localize to the primary cilium and participate in cilium biogenesis and function. BBS is a pleiotropic human disorder with variable severity that is suitable as a disease model for investigating the pathogenesis of a number of common ciliopathy features such as photoreceptor degeneration, renal cysts, and obesity.
The C. elegans genome encodes a number of BBS proteins which undergo intraflagellar transport (IFT) at the primary cilium. Given the conservation between C. elegans and human BBS proteins, I hypothesize the existence of unidentified conserved genetic pathways related to the functions of these proteins. Using C. elegans, I characterize novel features of bbs mutants while identifying sources of genomic variation that may elucidate the variability of human BBS features. I show that C. elegans bbs mutants exhibit smaller body size, delayed development, and decreased exploration behaviour. Moreover, I identify a role for the soluble guanylate cyclases GCY-35/GCY-36 in modifying these bbs phenotypes. I conclude that BBS proteins non-cell autonomously influence a set of body cavity neurons in which GCY-35/GCY-36 function genetically upstream of a cGMP-dependent protein kinase (PKG), EGL-4, to control body size. Furthermore, the role of GCY-35/GCY-36 is unique amongst a large number of guanylate cyclases and BBS proteins may influence body size via an IFT-independent function.
I explore the biological functions of EGL-4 and conclude that it may regulate body size through multiple cellular mechanisms. I also examine potential candidate genes related to cGMP production and turnover, confirming that additional cGMP-related factors can influence body size although not necessarily in body cavity neurons. In conclusion, I propose a model where BBS-expressing sensory neurons influence body size and development through cGMP-PKG signalling in body cavity neurons while functioning in parallel with additional sensory neurons (possibly BBS-independent) that use similar cGMP-PKG signalling dynamics.
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The Identification and Characterization of Genetic Modifiers for Bardet-Biedl Syndrome-associated Phenotypes using Caenorhabditis elegansMok, Calvin Ka Fay 30 August 2012 (has links)
Primary cilia are evolutionarily conserved organelles required in a number of signalling pathways influencing the development and behaviour of a diverse range of organisms. More recently, studies into a new class of human diseases known as ciliopathies have helped to shed light on the critical role of this once-ignored signalling centre. Bardet-Biedl syndrome (BBS) proteins localize to the primary cilium and participate in cilium biogenesis and function. BBS is a pleiotropic human disorder with variable severity that is suitable as a disease model for investigating the pathogenesis of a number of common ciliopathy features such as photoreceptor degeneration, renal cysts, and obesity.
The C. elegans genome encodes a number of BBS proteins which undergo intraflagellar transport (IFT) at the primary cilium. Given the conservation between C. elegans and human BBS proteins, I hypothesize the existence of unidentified conserved genetic pathways related to the functions of these proteins. Using C. elegans, I characterize novel features of bbs mutants while identifying sources of genomic variation that may elucidate the variability of human BBS features. I show that C. elegans bbs mutants exhibit smaller body size, delayed development, and decreased exploration behaviour. Moreover, I identify a role for the soluble guanylate cyclases GCY-35/GCY-36 in modifying these bbs phenotypes. I conclude that BBS proteins non-cell autonomously influence a set of body cavity neurons in which GCY-35/GCY-36 function genetically upstream of a cGMP-dependent protein kinase (PKG), EGL-4, to control body size. Furthermore, the role of GCY-35/GCY-36 is unique amongst a large number of guanylate cyclases and BBS proteins may influence body size via an IFT-independent function.
I explore the biological functions of EGL-4 and conclude that it may regulate body size through multiple cellular mechanisms. I also examine potential candidate genes related to cGMP production and turnover, confirming that additional cGMP-related factors can influence body size although not necessarily in body cavity neurons. In conclusion, I propose a model where BBS-expressing sensory neurons influence body size and development through cGMP-PKG signalling in body cavity neurons while functioning in parallel with additional sensory neurons (possibly BBS-independent) that use similar cGMP-PKG signalling dynamics.
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