Life Sciences Commons^™

Identification Of Dna Methylation Episignatures For Classification And Phenotype/Genotype Correlation In Mendelian Neurodevelopmental Disorders, John Reilly

Electronic Thesis and Dissertation Repository

ABSTRACT: Diagnosis for neurodevelopmental disorders poses numerous challenges, related to the lack of specific findings and limited understanding of clinical impact of the majority of genetic variation. Epigenomics mechanisms involve chemical modifications in DNA that involve a range of cellular mechanisms. DNA methylation is an epigenetic mechanism involving addition and removal of methyl groups to cytosine residues. These methylation signals form episignatures; patterns of methylation that can be used as biomarkers capable of differentiating neurodevelopmental disorders. EpiSigns have enabled molecular diagnosis of a number of genetic conditions, classification of variants of unknown significance, and provided insights into the pathophysiology of …

The Genetics Of Pain: An Exploration Of Gene-By-Environment Interactions And Their Effects On Pain, Mohamad F. Fakhereddin

Electronic Thesis and Dissertation Repository

The findings presented in this dissertation are part of the bigger SYMBIOME project which aims to use the biopsychosocial model of pain to develop a prognostic clinical phenotype for people that experience musculoskeletal (MSK) trauma. Chapter 2 presents an exploratory analysis to assess the relationships between genetic polymorphisms and pain severity and interference. Early childhood trauma was also explored as a moderator between genetic polymorphisms and pain outcomes. For pain severity, major allele carriers (A/A and G/A) of FKBP5 rs9394314 reported significantly higher scores than minor allele carriers (G/G). Further, major allele carriers who had at least one adverse childhood …

Genetic Approaches For The Study Of Complex Human Diseases, Julieta Lazarte

Electronic Thesis and Dissertation Repository

The field of human genetics has evolved from its initial narrow focus on single-gene Mendelian disorders, which largely affect children, to our current understanding that for most diseases there is continuum of rare to common variants which can exert a range of phenotypic effects. Despite advances in sequencing capabilities and our overall understanding of diseases, there remains a large proportion of heritability unexplained. Through the use of next-generation sequencing technologies and DNA microarray, I have explored a spectrum of genetic variations from rare, single and structural variants to common variants in individuals with i) “lone” atrial fibrillation; ii) familial hypercholesterolemia; …

Epigenetics A Decolonizing Science, Wade Paul

Electronic Thesis and Dissertation Repository

Epigenetics is the study of gene expression that does not entail alterations to the actual DNA. Decolonization is a theoretical and political movement that seeks to deconstruct colonial institutions and ideologies and reconstruct new and balanced approaches that accept and respect Indigenous worldviews. This project studies the decolonizing potential of epigenetics. Using genealogy as the method, the study establishes a long history of reductionist and deterministic thought that shaped the study of genetic science. Particular instances like thrift gene theory are explored to highlight how genetic explanations have been detrimental to the health and wellbeing of Indigenous people and illustrate …

Advanced Phenotyping Of Otosclerosis In An Ontario Population And Two Large Newfoundland Families, Matthew B. Lucas

Electronic Thesis and Dissertation Repository

Otosclerosis is a relatively common hearing loss disorder characterized by abnormal bone growth in the otic capsule leading to stapes fixation. In approximately half of cases, otosclerosis is inherited as an autosomal dominant trait. Typically, gene discovery efforts rely on surgical confirmation, audiometry and occasionally acoustic reflexes to identify affected cases of otosclerosis within families, requiring that the otosclerosis was at an advanced stage to be detected. This makes it difficult to identify individuals with early otosclerosis. The use of advanced phenotyping to identify cases of otosclerosis was tested in an Ontario otosclerotic population as well as in two large …

The Now Trial: A Pragmatic Randomized Controlled Trial Of Personalized, Genetic-Based Lifestyle Advice, Justine Rochelle Horne

Electronic Thesis and Dissertation Repository

Background: The impact of nutrigenomics and lifestyle genomics interventions on health outcomes and behaviours remains controversial and under-explored.

Objectives: To determine the short-term (3-month), moderate-term (6-month) and long-term (12-month) impact of providing personalized, genetic-based lifestyle information and advice on anthropometric measures, as well as dietary intake and adherence.

Methods: The nutrigenomics, overweight/obesity and weight management trial (NOW Trial) is a pragmatic randomized controlled trial that was incorporated into the Group Lifestyle Balance™ (GLB) program (N=140). Inclusion criteria: overweight or obesity (BMI ≥ 25 kg/m²), ≥ 18 years of age, English-speaking, having access to internet at least …

Gene Discovery In Mendelian And Complex Diseases, Sali Farhan

Electronic Thesis and Dissertation Repository

Through the Finding of Rare Disease Genes in Canada (FORGE Canada) initiative, individuals affected with rare Mendelian diseases were clinically ascertained with a goal of identifying the genetic origin of their disease. Herein, I describe the methods for identifying the genetic basis of four Mendelian diseases. The application of next generation sequencing led to the discovery of non-synonymous variation in the DNA of individuals affected by rare diseases. The effects of the candidate variants were assessed using a series of functional experiments to complement the human genetics data. The variants observed in patients’ cells are extremely rare, were consistently predicted …

Insights Into The Function Of The Fatc Domain Of Saccharomyces Cervisiae Tra1 Via Mutation And Suppressor Analysis, Samantha A. Pillon

Electronic Thesis and Dissertation Repository

The regulation of transcription is an important cellular function because it is the first step in gene regulation. In Saccharomyces cerevisiae, two protein complexes, SAGA and NuA4, act as regulators of transcription. A common protein shared between these two complexes, called Tra1, regulates transcriptional activation through its interaction with gene specific transcriptional activators. Tra1 is a member of the PIKK family of proteins, which are characterized by FAT, PI3K and FATC domains. The FATC domain encompasses the terminal 33-35 residues of the protein. Two mutations within the FATC domain, tra1-L3733A and tra1-F3744A, result in slow growth under stress …