A5012245312- Pancreatic function and diabetes
- Adipose Tissue and Metabolism
- Genetic Mapping and Diversity in Plants and Animals
- Metabolism, Diabetes, and Cancer
- Cancer Genomics and Diagnostics
- MicroRNA in disease regulation
- Diabetes and associated disorders
- Colorectal Cancer Treatments and Studies
- Bioinformatics and Genomic Networks
- Genetic Associations and Epidemiology
- Diet, Metabolism, and Disease
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- Genetic factors in colorectal cancer
- Molecular Biology Techniques and Applications
- Cholangiocarcinoma and Gallbladder Cancer Studies
- Lung Cancer Treatments and Mutations
- Diet and metabolism studies
- Mitochondrial Function and Pathology
- Cancer-related molecular mechanisms research
- Protein Tyrosine Phosphatases
- FOXO transcription factor regulation
- Dietary Effects on Health
- Circular RNAs in diseases
- Circadian rhythm and melatonin
Centre for Human Genetics
2009-2023
University of Oxford
2008-2023
National Institute for Health Research
2016-2019
Oxford BioMedica (United Kingdom)
2017
NIHR Biomedical Research Centre at The Royal Marsden and the ICR
2017
Howard Hughes Medical Institute
1996-1997
University of Chicago
1996-1997
Western General Hospital
1997
University of Edinburgh
1997
University of Birmingham
1997
Many aspects of physiology and behavior follow a circadian rhythm. Brain muscle Arnt-like protein-1 (BMAL1) is key component the mammalian molecular clock, which controls oscillations. In rat, gene encoding Bmal1 located within hypertension susceptibility loci. We analyzed SNP distribution pattern in congenic interval associated with spontaneously hypertensive rat (SHR), we show that maps close to region genetically divergent between SHR its normotensive (Wistar-Kyoto) counterpart....
MicroRNAs regulate a broad range of biological mechanisms. To investigate the relationship between microRNA expression and type 2 diabetes, we compared global in insulin target tissues from three inbred rat strains that differ diabetes susceptibility.
Large numbers of inbred laboratory rat strains have been developed for a range complex disease phenotypes. To gain insights into the evolutionary pressures underlying selection these phenotypes, we sequenced genomes 27 strains, including 11 models hypertension, diabetes, and insulin resistance, along with their respective control strains. Altogether, identified more than 13 million single-nucleotide variants, indels, structural variants across Analysis strain-specific selective sweeps gene...
Abstract Bladder cancers are a leading cause of death from malignancy. Molecular markers might predict disease progression and behaviour more accurately than the available prognostic factors. Here we use whole-genome sequencing to identify somatic mutations chromosomal changes in 14 bladder different grades stages. As well as detecting known cancer driver mutations, report identification recurrent protein-inactivating CDKN1A FAT1. The former not mutually exclusive with TP53 or MDM2...
Abstract Background Whole genome sequencing is increasingly being used for the diagnosis of patients with rare diseases. However, diagnostic yields many studies, particularly those conducted in a healthcare setting, are often disappointingly low, at 25–30%. This part because although entire genomes sequenced, analysis confined to silico gene panels or coding regions genome. Methods We undertook WGS on cohort 122 unrelated disease and their relatives (300 genomes) who had been pre-screened by...
We have recently shown that mutations in the gene encoding transcription factor hepatocyte nuclear (HNF)-1α are cause of one form maturity-onset diabetes young (MODY3). Here, we report exon-intron organization and partial sequence human HNF-1α gene. In addition, screened ten exons flanking introns this for a group 25 unrelated white subjects from Germany who presented with NIDDM before 35 years age had first-degree relative NIDDM. Mutations were identified nine these individuals, suggesting...
Abstract Background MicroRNAs (miRNAs) are non-coding RNA molecules involved in post-transcriptional control of gene expression a wide number genes, including those glucose homeostasis. Type 2 diabetes (T2D) is characterized by hyperglycaemia and defects insulin secretion action at target tissues. We sought to establish differences global miRNA two insulin-target tissues from inbred rats spontaneously diabetic normoglycaemic strains. Methods used microarray platform measure tissues: liver...
The number of imprinted genes in the mammalian genome is predicted to be small, yet we show here, a survey 97 traits measured outbred mice, that most phenotypes display parent-of-origin effects are partially confounded with family structure. To address this contradiction, using reciprocal F1 crosses, investigated knocking out two nonimprinted candidate genes, Man1a2 and H2-ab1, reside at loci but effects. We expression multiple becomes dysregulated sex-, tissue-, parent-of-origin-dependent...
Background Single gene tests to predict whether cancers respond specific targeted therapies are performed increasingly often. Advances in sequencing technology, collectively referred as next generation (NGS), mean the entire cancer genome or parts of it can now be sequenced at speed with increased depth and sensitivity. However, translation NGS into routine care has been slow. Healthcare stakeholders unclear about clinical utility concerned could an expensive addition diagnostics, rather...
Molecular indicators of colorectal cancer prognosis have been assessed in several studies, but most analyses restricted to a handful markers. We aimed identify prognostic biomarkers for by sequencing panels multiple driver genes.
Genetic susceptibility to type 2 diabetes involves many genes, most of which are still unknown. The lipid phosphatase SHIP2 is a potent negative regulator insulin signaling and sensitivity in vivo thus good candidate gene. Here we report the presence gene mutations associated with rats humans. R1142C mutation specifically identified Goto-Kakizaki (GK) spontaneously hypertensive rat strains disrupts potential class II ligand for Src homology (SH)-3 domain slightly impairs cell culture. In...
One form of maturity-onset diabetes the young, Type 3 (MODY3), results from mutations in gene coding for hepatocyte nuclear factor-1α (HNF-1α), a transcription factor first described liver. MODY3 is characterized by defective glucose-stimulated insulin secretion. Earlier observations glycosuria with normal blood glucose levels some MODY families suggest an additional renal manifestation respective genetic defect. We measured threshold five diabetic carriers missense mutation (Arg 272 His)...
Recent studies have shown that mutations in the transcription factor hepatocyte nuclear (HNF)-1α are cause of one form maturity-onset diabetes young (MODY3). These identified mRNA and protein coding regions this gene result synthesis an abnormal or protein. Here, we report Italian family which A→C substitution at nucleotide -58 promoter region HNF-1α cosegregates with MODY. This mutation is located a highly conserved disrupts binding site for HNF-4α, encoding HNF-4α being another MODY...
Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode inheritance typically dominant, recent studies indicate LZTR1 may be associated with both dominant recessive forms. Seeking to describe characteristics LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny exomes from 9624 patients recruited Deciphering...
Autosomal dominant polycystic kidney disease (PKD) is the most common genetic that leads to failure in humans. In addition known causative genes PKD1 and PKD2, there are mutations result cystic changes kidney, such as nephronophthisis, autosomal recessive disease, or medullary disease. Recent efforts improve understanding of renal cystogenesis have been greatly enhanced by studies rodent models PKD. Genetic (cy/+) rat showed PKD spontaneously develops a consequence mutation gene different...
Type II SH2 domain–containing inositol 5-phosphatase (INPPL1, or SHIP2) plays an important role in the control of insulin sensitivity. INPPL1 mutations affecting gene function have been found rat models type 2 diabetes and hypertension diabetic patients. We investigated influence nucleotide variation on components metabolic syndrome. Following comprehensive resequencing gene, we genotyped 12 informative polymorphisms 1,304 individuals from 424 British families that were characterized for...
Intrahepatic cholangiocarcinoma (ICC) is an aggressive cancer arising from the bile ducts with a need for earlier diagnosis and greater range of treatment options. KRAS/NRAS mutations are common in ICC tumours 6–32% patients also have isocitrate dehydrogenase 1 2 (IDH1 IDH2) gene associated metabolic changes. This feasibility study investigated sequencing circulating tumour DNA (ctDNA) combined metabolite profiling plasma as method biomarker discovery patients. Plasma was collected four...
With successes of genome-wide association studies, molecular phenotyping systems are developed to identify genetically determined disease-associated biomarkers. Genetic studies the human metabolome emerging but exclusively apply targeted approaches, which restricts analysis a limited number well-known metabolites. We have novel technical and statistical methods for systematic automated quantification untargeted NMR spectral data designed perform robust accurate quantitative trait locus (QTL)...