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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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Graduate Student Supervision
Doctoral Student Supervision (Jan 2008 - May 2021)
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.
Master's Student Supervision (2010 - 2020)
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.
Recent Tri-Agency Grants
The following is a selection of grants for which the faculty member was principal investigator or co-investigator. Currently, the list only covers Canadian Tri-Agency grants from years 2013/14-2016/17 and excludes grants from any other agencies.
- Regulation of islet cell proliferation by p300 - Canadian Institutes of Health Research (CIHR) - Project Scheme: 2016 1st Live Pilot (2016/2017)
- Insights from rare overgrowth syndromes for common diseases - Canadian Institutes of Health Research (CIHR) - Project Scheme: 2016 1st Live Pilot (2016/2017)
- Exome sequencing of patients with Weaver-like features links another cancer gene, EED, to overgrowth syndromes - Canadian Institutes of Health Research (CIHR) - Travel Awards - Institute Community Support (2015/2016)
- Rare obesity disorders informing common disease - Canadian Institutes of Health Research (CIHR) - Operating Grant (2013/2014)
- Fundamental mechanisms of energy balance: Lipid transport - Natural Sciences and Engineering Research Council of Canada (NSERC) - Discovery Grants Program - Individual (2013/2014)
- Rare obesity disorders informing common disease - Canadian Institutes of Health Research (CIHR) - CIHR Clinician Scientist - Phase 2 (2013/2014)
- MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis. (2020)
Brain : a journal of neurology,
- A distinct neurodevelopmental syndrome with intellectual disability, autism spectrum disorder, characteristic facies, and macrocephaly is caused by defects in CHD8. (2019)
Journal of human genetics,
- A distinct neurodevelopmental syndrome with intellectual disability, autism spectrum disorder, characteristic facies, and macrocephaly is caused by defects in CHD8. (2019)
Journal of Human Genetics,
- PRC2-complex related dysfunction in overgrowth syndromes: A review of EZH2, EED, and SUZ12 and their syndromic phenotypes. (2019)
American journal of medical genetics. Part C, Seminars in medical genetics,
- Rare SUZ12 variants commonly cause an overgrowth phenotype. (2019)
American journal of medical genetics. Part C, Seminars in medical genetics,
- Two Patients With KCNT1-Related Epilepsy Responding to Phenobarbital and Potassium Bromide. (2019)
Journal of child neurology,
- Severe obesity and global developmental delay in preschool children (2018)
- A maternal high-fat, high-sucrose diet has sex-specific effects on fetal glucocorticoids with little consequence for offspring metabolism and voluntary locomotor activity in mice (2017)
PLoS ONE, 12 (3)
- A Review of the Genetics of Intracranial Berry Aneurysms and Implications for Genetic Counseling (2017)
Journal of Genetic Counseling, 26 (1), 21-31
- A systematic review of genetic syndromes with obesity (2017)
Obesity Reviews, 18 (6), 603-634
- TSC2 c.1864C>T variant associated with mild cases of tuberous sclerosis complex (2017)
American Journal of Medical Genetics, Part A, 173 (3), 771-775
- A novel microdeletion affecting the CETP gene raises HDL-associated cholesterol levels (2016)
Clinical Genetics, 89 (4), 495-500
- Absence of mutations in HCRT , HCRTR1 and HCRTR2 in patients with ROHHAD (2016)
Respiratory Physiology & Neurobiology, 221, 59--63
- Core Concepts in Human Genetics: Understanding the Complex Phenotype of Sport Performance and Susceptibility to Sport Injury (2016)
Medicine and Sport Science, 61, 1-14
- EED-associated overgrowth in a second male patient (2016)
Journal of Human Genetics, 61 (9), 831-834
- Ghrelin, Ghrelin O-Acyltransferase, and Carbohydrate Metabolism During Pregnancy in Calorie-Restricted Mice (2016)
Hormone and Metabolic Research,
- Mutations in FLNC are Associated with Familial Restrictive Cardiomyopathy (2016)
Human Mutation, 37 (3), 269-279
- Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: Time to address gaps in care (2016)
Clinical Genetics, 89 (3), 275-284
- Weaver Syndrome-Associated EZH2 Protein Variants Show Impaired Histone Methyltransferase Function In Vitro (2016)
Human Mutation, 37 (3), 301-307
- A high-fat diet rich in corn oil reduces spontaneous locomotor activity and induces insulin resistance in mice (2015)
Journal of Nutritional Biochemistry, 26 (4), 319-326
- A novel mutation in EED associated with overgrowth (2015)
Journal of Human Genetics, 60 (6), 339-342
- Acylated ghrelin is not required for the surge in pituitary growth hormone observed in pregnant mice (2015)
- Alternating hypoglycemia and hyperglycemia in a toddler with a homozygous p.R1419H ABCC8 mutation: An unusual clinical picture (2015)
Journal of Pediatric Endocrinology and Metabolism, 28 (3-4), 345-351
- Beneficial metabolic phenotypes caused by loss-of-function APOC3 mutations (2015)
Clinical Genetics, 87 (1), 31-32
- Episodic ataxia associated with a de novo SCN2A mutation (2015)
European Journal of Paediatric Neurology,
- Leptin and adiponectin: Examining their clinical significance in obesity (2015)
University of Toronto Medical Journal, 92 (2), 24-26
- NSD1 mutations generate a genome-wide DNA methylation signature (2015)
Nature Communications, 6
- Rapid-Onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD): Exome sequencing of trios, monozygotic twins and tumours (2015)
Orphanet Journal of Rare Diseases, 10 (1)
- Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. (2015)
- Vasoactive intestinal polypeptide promotes intestinal barrier homeostasis and protection against colitis in mice (2015)
PLoS ONE, 10 (5)
- Autosomal dominant PIK3R1 mutations cause SHORT syndrome (2014)
Clinical Genetics, 85 (3), 228-229
- Biallelic mutations at PPARG cause a congenital, generalized lipodystrophy similar to the Berardinelli-Seip syndrome (2014)
European Journal of Medical Genetics, 57 (9), 524-526
- Duplication of AKT3 is associated with macrocephaly and speech delay (2014)
American Journal of Medical Genetics, Part A, 164 (7), 1868-1869
- Exome sequencing identifies mutations in KIF14 as a novel cause of an autosomal recessive lethal fetal ciliopathy phenotype (2014)
Clinical Genetics, 86 (3), 220-228
- Genetic Counseling in Direct-to-Consumer Exome Sequencing: A Case Report (2014)
Journal of Genetic Counseling, 23 (5), 742-753
- Somatic mosaicism for the p.His1047Arg mutation in PIK3CA in a girl with mesenteric lipomatosis (2014)
American Journal of Medical Genetics, Part A, 164 (9), 2360-2364
- Mutations in POLR3A and POLR3B are a major cause of hypomyelinating leukodystrophies with or without dental abnormalities and/or hypogonadotropic hypogonadism (2013)
Journal of Medical Genetics, 50 (3), 194-197
- The c.7409G>A (p.Cys2470Tyr) variant of FBN1: Phenotypic variability across three generations (2013)
Molecular Syndromology, 4 (3), 125-135
- Mutations in EZH2 cause weaver syndrome (2012)
American Journal of Human Genetics, 90 (1), 110-118
- Acute disruption of leptin signaling in vivo leads to increased insulin levels and insulin resistance (2011)
Endocrinology, 152 (9), 3385-3395
- Duchenne muscular dystrophy caused by a complex rearrangement between intron 43 of the DMD gene and chromosome 4 (2011)
Neuromuscular Disorders, 21 (3), 178-182
- Effects of glucose and insulin on acyl ghrelin and desacyl ghrelin, leptin, and adiponectin in pregnant women with diabetes (2010)
Metabolism: Clinical and Experimental, 59 (6), 841-847
- Ldlr-/- mice display decreased susceptibility to western-type diet-induced obesity due to increased thermogenesis (2010)
Endocrinology, 151 (11), 5226-5236
- Pseudohypoparathyroidism type 1a and the GNAS p.R231H mutation: Somatic mosaicism in a mother with two affected sons (2010)
American Journal of Medical Genetics, Part A, 152 (11), 2784-2790
- The metabolic phenotype of SCD1-deficient mice is independent of melanin-concentrating hormone (2010)
Peptides, 31 (1), 123-129
- Clinical study of two brothers with a novel 33 bp duplication in the ARX gene (2009)
American Journal of Medical Genetics, Part A, 149 (7), 1482-1486
- Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization (2009)
BMC Genomics, 10
- Genetic association studies for complex traits: Relevance for the sports medicine practitioner (2009)
British Journal of Sports Medicine, 43 (5), 314-316
- Key concepts in human genetics: Understanding the complex phenotype (2009)
Medicine and Sport Science, 54, 1-10
- Absence of stearoyl-CoA desaturase-1 ameliorates features of the metabolic syndrome in LDLR-deficient mice (2008)
Journal of Lipid Research, 49 (1), 217-229
- Phenotype-genotype characterization of alpha-thalassemia mental retardation syndrome due to isolated monosomy of 16p13.3 (2008)
American Journal of Medical Genetics, Part A, 146 (2), 225-232
- Schinzel-Giedion syndrome: Report of splenopancreatic fusion and proposed diagnostic criteria (2008)
American Journal of Medical Genetics, Part A, 146 (10), 1299-1306
- Mycophenolate mofetil and atherosclerosis: Results of animal and human studies (2007)
Annals of the New York Academy of Sciences, 1110, 209-221
- Novel deletions of 14q11.2 associated with developmental delay, cognitive impairment and similar minor anomalies in three children (2007)
Journal of Medical Genetics, 44 (9), 556-561
- Body weight is modulated by levels of full-length Huntingtin (2006)
Human Molecular Genetics, 15 (9), 1513-1523
- Mycophenolate mofetil and animal models (2006)
Lupus, 15 (11\_s), 27-34
- Oligonucleotide microarray analysis of genomic imbalance in children with mental retardation (2006)
American Journal of Human Genetics, 79 (3), 500-513
- The beat goes on: ciliary proteins are defective in Meckel syndrome. (2006)
Clinical genetics, 69 (5), 400-401
- A new Marfan-like syndrome caused by pertubed transforming growth factor-β signaling (2005)
Clinical Genetics, 68 (4), 330-331
- Another four bite the dust: mutations in a ubiquitously expressed filamin protein cause several skeletal dysplasias (2004)
Clinical Genetics, 66 (2), 110--111
- Congenital leptin deficiency due to homozygosity for the Δ133G mutation: Report of another case and evaluation of response to four years of leptin therapy (2004)
Journal of Clinical Endocrinology and Metabolism, 89 (10), 4821-4826
- Melanin-concentrating hormone receptor mutations and human obesity: Functional analysis (2004)
Obesity Research, 12 (5), 743-749
- Mutational analysis of the serotonin receptor 5HT2c in severe early-onset human obesity (2004)
Canadian Journal of Physiology and Pharmacology, 82 (6), 426-429
- So many asthma loci, so little time (2004)
Clinical Genetics, 66 (2), 107--108
- Searching for the 'natural': the case for the gene 'for' homosexuality. (2003)
Human reproduction and genetic ethics, 9 (2), 30-35
- Contiguous deletion of the X-linked adrenoleukodystrophy gene (ABCD1) and DXS1357E: A novel neonatal phenotype dimilar to peroxisomal biogenesis disorders. (2002)
American Journal of Human Genetics,
- Metabolism: Partial leptin deficiency and human adiposity (2001)
Nature, 414 (6859), 34-35
- First trimester fetal heart rate: Response to chorionic villus sampling in the chromosomally normal fetus (1997)
Fetal Diagnosis and Therapy, 12 (4), 236-240
- The immunoglobulin heavy chain and disease association: Application to pemphigus vulgaris (1994)
Human Genetics, 94 (6), 675-683
- Susceptibility to multiple sclerosis is associated with the proximal immunoglobulin heavy chain variable region (1991)
Journal of Clinical Investigation, 87 (4), 1266-1273