Doctor of Philosophy in Medical Genetics (PhD)
The polycomb repressive complex 2 related syndromes: Clinical phenotypes to functional studies in drosophila
Dr. Gibson is a Clinical Geneticist with an interest in overgrowth, severe obesity and lipodystrophy. Our group applies state-of-the-art assessment of body fat mass, fat distribution and circulating hormones to individuals with overgrowth, severe obesity and genetic lipodystrophy syndromes.
In collaboration with the British Columbia Genome Sciences Centre, we combine this detailed metabolic profile with targeted assessment of copy-number variants and specific mutations in an effort to discover the cause of the condition.
Ultimately, our goal is to design therapies for these rare disorders. We then hope to translate these discoveries into viable treatments for prevention of obesity, type 2 diabetes, brain aneurysms and cardiovascular disease in the population as a whole.
Genetics of Rare Obesity and Overgrowth Disorders; Epigenetics of Body Weight and Body Composition; Genetics of Familial Intracranial Aneurysms. Please note that recruitment is extremely competitive. Applicants with external scholarship/fellowship funding are strongly preferred, as are applicants who already have an MD or MBBS degree, or who are applying to UBC's MD-PhD program. High school and undergraduate volunteers are typically accepted only for summer terms. I regret that I do not have time to reply to all requests.
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Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
Studies on genetic forms of diabetes have been pivotal in understanding how genetic mutations impair pancreatic β cell function. We identified a patient who presented with early-onset diabetes similar to known monogenic forms of diabetes. The patient carries a microdeletion that removes a copy of EP300, a gene that encodes the transcriptional coactivator p300. EP300 mutations cause Rubinstein-Taybi syndrome, a rare genetic condition that has been associated with early-onset glucose dysregulation. Whether and how p300 loss may affect β cell function in vivo was not clear. Here, we show that expression of p300 regulates β cell development and function in vivo. By deleting p300 at different developmental stages in mouse β cells, we demonstrate that p300 is required for the proliferation and proper maturation of developing β cells. β cell development requires p300 to acetylate histone H3K27 across the genome and to coactivate transcription. In mature β cells, p300 maintains insulin granule biosynthesis and secretion. To regulate these processes transcriptionally, p300 and NeuroD1/Nkx6.1/Pdx1 co-occupy loci that are critical for β cell function, including insulin. In addition to the mouse studies, we have identified three additional probands who developed hyperinsulinism associated with their rare, potentially gain-of-function EP300 variants. Our data demonstrate a critical role of p300 as a transcriptional coactivator and a histone acetyltransferase in β cells. Taken together, our human data highlight the relevance of p300 to the pathogenesis of genetic forms of diabetes, and our mouse data provide mechanistic insights on how p300 deficiency may lead to glucose dysregulation.
Weaver syndrome (WS) is a rare overgrowth disorder characterized by tall stature, macrocephaly, advanced bone age, facial dysmorphism, intellectual disability and cancer susceptibility, and it is caused by constitutional mutations in the enhancer of zeste homolog 2 gene (EZH2). To expand our understanding of WS pathogenesis, we assembled a cohort of 66 individuals with Weaver-like features, and collected DNA together with detailed clinical information. Sanger sequencing identified eleven individuals with pathogenic mutations in EZH2 (equivalent to a 17% diagnostic rate). A further seven individuals carried mutations in the nuclear receptor-binding SET domain-containing protein 1 gene (NSD1), which cause a similar overgrowth disorder called Sotos syndrome (11% diagnostic rate). Furthermore, we expanded the phenotypic spectrum of WS to include neuronal migration disorders. EZH2 is a histone methyltransferase that acts as the catalytic agent of the Polycomb Repressive Complex 2 (PRC2) to maintain gene repression via methylation of lysine 27 on histone H3 (H3K27). Functional studies investigating the activity of mutant EZH2 from various cancers showed that both gain- and loss-of-function mechanisms exist, thus it was important to determine which mechanism is causing WS. Using a standard histone methyltransferase assay, we observed that WS-associated EZH2 mutations impair PRC2’s histone methyltransferase activity in vitro, suggesting a loss-of-function mechanism of disease. In addition, no correlation between degree of functional impairment and phenotypic severity was noted. Recognizing a clear role for chromatin modifications in the molecular pathophysiology of overgrowth syndromes, we hypothesized that mutations in other chromatin regulators might explain the phenotype observed in the remaining undiagnosed individuals. Using next-generation sequencing in combination with detailed phenotyping, we identified EED as a novel overgrowth gene. EED happens to be the main partner of EZH2 within PRC2, and is necessary for proper H3K27 methylation to occur. Altogether, we have expanded the phenotypic and mutational spectrums of WS, and begun to uncover the underlying mechanism of disease. We also discovered a novel overgrowth gene, EED, reinforcing a role for PRC2 in the regulation of human growth and development.
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
To our knowledge age-related loss of chromosome Y (LOY) in circulating leukocytes is the most common somatic genetic aberration. Many recent epidemiology studies have found robust associations between LOY in leukocytes and age-related diseases such as blood and solid tumour cancers, Alzheimer’s disease, and macular degeneration. Despite these associations, the prevalence and mechanisms of LOY in non-hematopoietic cell-types are not well characterized. In response, the need for bioinformatic methods to analyse Y chromosome ploidy across multiple genomic/transcriptomic datatypes has escalated. In the past, the Y chromosome was commonly removed from genomic analyses for several reasons including low gene count, haploidy, lack of biological interest and short-read mapping difficulties. Resultingly, methods for investigating chromosome Y specific trends using next-generation sequencing have suffered and require improvement. The main objective of this thesis was two-fold. First, to improve methods of Y chromosome aneuploidy detection using whole genome sequencing and single-nuclei RNA sequencing. Second, to use these improved methods to provide estimates of loss of Y (LOY) in brain tissue – which had not previously been established in humans. Using genomic characteristics such as mappability, GC content, and read alignment filtering I was able to improve LOY detection in both WGS and single-nuclei RNA-seq. Given high sequence similarity between the X and Y chromosome, strict mappability filtering improves, and smooths read depth estimates of Y chromosome aneuploidy. Using these methods we estimate that of the elderly male population represented in this cohort (median age = 87.5), LOY was found in 13.8% (11/123) of blood samples, 0% (0/159) in prefrontal cortex and 0% (0/78) cerebellum samples. Despite this, we found a significant association between age and reduced Y ploidy in the dorsolateral prefrontal cortex (R=-0.35, p=3.9x10-⁵), suggesting low-frequency LOY may be occurring in the cortex. In single-nuclei data from the dorsolateral prefrontal cortex we found 8.6% of cells lacked a Y chromosome. LOY was enriched in the glial cells, and particularly the microglia where 33% of male cells were affected. Although further evidence is required, LOY within the frontal cortex (and specifically the microglia) may represent an understudied factor in cognitive decline and neurodegeneration.
Intracranial aneurysms (IA), a common disease that occurs when cerebral arteries weaken and expand, can lead to subarachnoid hemorrhage upon rupture. The prevalence of IA is estimated to be around 3% and is known to increase with age. A small subset of the patient population has a familial form IA, where two or more first- to third- degree relatives have IA. At this time, one gene, THSD1, has been associated with familial IA (FIA). Here we present the preliminary findings from whole exome sequencing on five families diagnosed with FIA. Each family appears to have Mendelian segregation of disease (autosomal dominant, autosomal recessive, or X-linked) and has had their aneurysms clinically confirmed through brain imaging. Sequencing data from the proband of each family was used to identify family-specific candidate genes and was overlapped between families to identify genes that contain rare, possibly pathogenic variants in three or more families. Four genes -- DST, CRIPAK, DNAH1, and TTN --were found to contain rare variants in four out of the five families. Three top candidate genes were selected based on gene function or previous association to cerebral vascular disease from 38 genes that contain rare variants in three out of the five families.
The discovery of leptin and other humoral signals which regulate food intake and energy expenditure has greatly contributed to our understanding of molecular pathways controlling energy homeostasis. Leptin produced by adipocytes, insulin produced by the pancreas, and ghrelin produced by the stomach all contribute to the body’s energy balance. One question remaining is whether the lipid transport system also plays a role.Our hypothesis is that lipid clearance is important in the maintenance of energy homeostasis. The low-density lipoprotein receptor (Ldlr) is a key molecule involved with lipid clearance. The experiments presented in this thesis used the Ldlr-/- mouse to study the Ldlr’s role in energy balance. One aim of this thesis was to provide a detailed analysis of the energy balance phenotype of the Ldlr-/- mouse. Another aim of this thesis was to use the Ldlr-/- mouse to study the potential interaction between Ldlr and the leptin signaling pathway.Adult Ldlr-/- mice and Ldlr+/+ controls on a C57BL/6J background were fed either a chow or a high-fat, high-sucrose Western-type diet (WTD) for eight weeks. Physiological studies of food intake, energy expenditure, activity, heat production, insulin sensitivity, and leptin responsiveness were performed. As well, the effect of these diet interventions on circulating leptin and on leptin gene expression was examined.On the chow diet, Ldlr-/- mice had lower energy expenditure and higher activity levels relative to controls. On the WTD, Ldlr-/- mice gained less weight relative to Ldlr+/+ mice, specifically gaining less fat mass. Increased thermogenesis in Ldlr-/- mice fed the WTD was detected. Additionally, leptin responsiveness was blunted in chow-fed Ldlr-/- mice, suggesting a novel role for the Ldlr pathway that extends to leptin’s regulation of energy balance.In addition to its known role in lipid transport, these results from the Ldlr-/- mouse demonstrate the importance of the Ldlr in regulating energy homeostasis and suggest a direct physiological link between dyslipidemia and energy balance.