A5089295769- Chromosomal and Genetic Variations
- CRISPR and Genetic Engineering
- RNA and protein synthesis mechanisms
- Acute Myeloid Leukemia Research
- Epigenetics and DNA Methylation
- Neuroscience and Neuropharmacology Research
- Genomics and Phylogenetic Studies
- RNA modifications and cancer
- Genetics and Neurodevelopmental Disorders
- RNA Research and Splicing
- Genomic variations and chromosomal abnormalities
- Receptor Mechanisms and Signaling
- Congenital heart defects research
- Cellular transport and secretion
- Autism Spectrum Disorder Research
- Histone Deacetylase Inhibitors Research
- Cancer, Hypoxia, and Metabolism
- Bioinformatics and Genomic Networks
- Genomics and Chromatin Dynamics
- Advanced Proteomics Techniques and Applications
- Cancer-related molecular mechanisms research
- Genetic Associations and Epidemiology
- Machine Learning in Bioinformatics
- Viral Infectious Diseases and Gene Expression in Insects
- Retinal Development and Disorders
Queen Mary University of London
2019-2024
MRC Centre for Regenerative Medicine
2017-2022
University of Edinburgh
2012-2022
Roslin Institute
2017-2018
Wellcome Sanger Institute
2010-2018
Medical Research Council
2017
University of British Columbia
2002-2008
Terry Fox Research Institute
2006-2008
BC Cancer Agency
2002-2007
Lund University
2002
A small number of rare, recurrent genomic copy variants (CNVs) are known to substantially increase susceptibility schizophrenia. As a consequence the low fecundity in people with schizophrenia and other neurodevelopmental phenotypes which these CNVs contribute, large effects on risk likely be rapidly removed from population by natural selection. Accordingly, such must frequently occur as de novo mutations. In sample 662 proband-parent trios, we found that rare CNV mutations were...
Highlights•YTHDF2 is highly expressed across human AML and essential for leukemia initiation•YTHDF2 shortens the half-life of m6A-modified transcripts in AML•Loss YTHDF2 expands HSCs but does not derail hematopoiesis•YTHDF2 protects cells from apoptosis by downregulating TNFR2SummaryAcute myeloid (AML) an aggressive clonal disorder hematopoietic stem (HSCs) primitive progenitors that blocks their differentiation, generating self-renewing leukemic (LSCs). Here, we show mRNA m6A reader...
The inbred mouse is an invaluable model for human biology and disease. Nevertheless, when considering genetic mechanisms of variation disease, it important to appreciate the significant differences in spectra spontaneous mutations that distinguish these species. While insertions transposable elements are responsible only ~0.1% de novo humans, figure 100-fold higher laboratory mouse. This striking difference largely due ongoing activity endogenous retroviral elements. Here we briefly review...
Remnants of more than 3 million transposable elements, primarily retroelements, comprise nearly half the human genome and have generated much speculation concerning their evolutionary significance. We exploited draft sequence to examine distributions retroelements on a genome-wide scale. Here we show that genomic densities 10 major classes are distributed differently with respect surrounding GC content also oldest elements preferentially found in regions lower compared younger relatives. In...
Direct comparison of protein components from human and mouse excitatory synapses is important for determining the suitability mice as models brain disease to understand evolution mammalian brain. The postsynaptic density a highly complex set proteins organized into molecular networks that play central role in behavior disease. We report first direct proteome triplicate isolates cortical densities. comprised 1556 one 1461. A large compositional overlap was observed; more than 70% were also...
Understanding how cognitive processes including learning, memory, decision making and ideation are encoded by the genome is a key question in biology. Identification of sets genes underlying human mental disorders path towards this objective. Schizophrenia common disease with symptoms, high heritability complex genetics. We have identified involved schizophrenia measuring differences DNA copy number across entire 91 cases 92 controls Scottish population. Our data reproduce rare variants...
The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation the m6A reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion compromises acute myeloid leukemia. Here we investigate long-term impact YTHDF2 deletion on HSC maintenance multilineage We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial...
Abstract Acute myeloid leukemia (AML) is a largely incurable disease, for which new treatments are urgently needed. While leukemogenesis occurs in the hypoxic bone marrow, therapeutic tractability of hypoxia-inducible factor (HIF) system remains undefined. Given that inactivation HIF-1α/HIF-2α promotes AML, possible clinical strategy to target HIF-prolyl hydroxylases (PHDs), promote degradation. Here, we reveal genetic Phd1 / Phd2 hinders AML initiation and progression, without impacting...
Insertion of transposable elements is a major cause genomic expansion in eukaryotes. Less understood, however, about mechanisms underlying contraction genomes. In this study, we show that retroelements can, rare cases, be precisely deleted from primate genomes, most likely via recombination between 10- to 20-bp target site duplications (TSDs) flanking the retroelement. The loci are indistinguishable pre-integration sites, effectively reversing insertion. Through human-chimpanzee-Rhesus...
Neuronal apoptosis inhibitory protein (NAIP, also known as BIRC1) is a member of the conserved inhibitor (IAP) family. Lineage-specific rearrangements and expansions this locus have yielded different copy numbers among primates rodents, with human retaining single functional mouse possessing several copies, depending on strain. Roles for gene in disease been documented, but little about transcriptional regulation NAIP. We show here that NAIP has multiple promoters sharing no similarity...
Endogenous retroviral elements (ERVs) in mice are significant genomic mutagens, causing ∼10% of all reported spontaneous germ line mutations laboratory strains. The majority these due to insertions two high copy ERV families, the IAP and ETn/MusD elements. This level ongoing retrotranspositional activity suggests that inbred highly variable content groups. However, no comprehensive genome-wide studies have been performed assess their polymorphism. Here we compared three test strains, for...
Abstract Differences in general cognitive ability (intelligence) account for approximately half of the variation any large battery tests and are predictive important life events including health. Genome-wide analyses common single-nucleotide polymorphisms indicate that they jointly tag between a quarter variance intelligence. However, no single polymorphism has been reliably associated with It remains possible these many small effects might be aggregated networks functionally linked genes....
Strict regulation of stem cell metabolism is essential for tissue functions and tumor suppression. In this study, we investigated the role fumarate hydratase (Fh1), a key component mitochondrial tricarboxylic acid (TCA) cycle cytosolic metabolism, in normal leukemic hematopoiesis. Hematopoiesis-specific Fh1 deletion (resulting endogenous accumulation genetic TCA block reflected by decreased maximal respiration) caused lethal fetal liver hematopoietic defects (HSC) failure. Reexpression...
Endogenous retroviruses (ERVs) and solitary long terminal repeats (LTRs) have a significant antisense bias when located in gene introns, suggesting strong negative selective pressure on such elements oriented the same transcriptional direction as enclosing gene. It has been assumed that this reflects presence of regulatory signals within LTRs but little work done to investigate phenomenon further. In analysis reported here, we found differences between individual human ERV families their...
Current models of schizophrenia and bipolar disorder implicate multiple genes, however their biological relationships remain elusive. To test the genetic role glutamate receptors interacting scaffold proteins, exons ten glutamatergic 'hub' genes in 1304 individuals were re-sequenced case control samples. No significant difference overall number non-synonymous single nucleotide polymorphisms (nsSNPs) was observed between cases controls. However, cluster analysis nsSNPs identified two encoding...
Synapses are fundamental components of brain circuits and disrupted in over 100 neurological psychiatric diseases. The synapse proteome is physically organized into multiprotein complexes polygenic mutations converge on postsynaptic schizophrenia, autism intellectual disability. Directly characterising human synapses their from post-mortem tissue essential to understanding disease mechanisms. However, have not been directly isolated the feasibility isolation unknown.Here we establish a...
Resistance to standard and novel therapies remains the main obstacle cure in acute myeloid leukaemia (AML) is often driven by metabolic adaptations which are therapeutically actionable. Here we identify inhibition of mannose-6-phosphate isomerase (MPI), first enzyme mannose metabolism pathway, as a sensitizer both cytarabine FLT3 inhibitors across multiple AML models. Mechanistically, connection between fatty acid metabolism, that mediated via preferential activation ATF6 arm unfolded...
Betaretroviruses exist in endogenous and exogenous forms hosts that are widely distributed evolutionarily distantly related. Here we report the discovery characterization of several previously unknown betaretrovirus groups genomes Mus musculus Rattus norvegicus. Each group contains both mouse rat elements, more closely related to known betaretroviruses from nonmurine hosts. Some also include members which were not harbor betaretroviruses, such as gray lemur (Microcebus murinus) Seba's...