A5005526067- Genetics, Aging, and Longevity in Model Organisms
- Genetic Mapping and Diversity in Plants and Animals
- Cancer Genomics and Diagnostics
- Genomics and Rare Diseases
- Evolution and Genetic Dynamics
- Genetic and Kidney Cyst Diseases
- Genetic and phenotypic traits in livestock
- CRISPR and Genetic Engineering
- Genetic diversity and population structure
- Epigenetics and DNA Methylation
- Genetic factors in colorectal cancer
- RNA modifications and cancer
- Mitochondrial Function and Pathology
- Genomic variations and chromosomal abnormalities
- Genetics and Neurodevelopmental Disorders
- Circadian rhythm and melatonin
- RNA Research and Splicing
- Spaceflight effects on biology
- Genetic Syndromes and Imprinting
- Ion channel regulation and function
- Ion Transport and Channel Regulation
- Genomics and Phylogenetic Studies
- Insect symbiosis and bacterial influences
- Microbial Metabolic Engineering and Bioproduction
- Cystic Fibrosis Research Advances
Maastricht University
2025
École Polytechnique Fédérale de Lausanne
2015-2024
Genomics England
2021-2024
NIHR Southampton Biomedical Research Centre
2024
University Hospital Southampton NHS Foundation Trust
2024
University of Manchester
2023
Genomics (United Kingdom)
2023
St Mary's Hospital
2023
Erasmus MC
2023
Queen Mary University of London
2021-2023
Cryptic genetic variation (CGV) is the hidden that can be unlocked by perturbing normal conditions. CGV drive emergence of novel complex phenotypes through changes in gene expression. Although our theoretical understanding has thoroughly increased over past decade, insight into polymorphic expression regulation underlying scarce. Here we investigated transcriptional architecture response to rapid temperature nematode Caenorhabditis elegans. We analyzed regulatory (and mapped eQTL) across...
Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. contrasted our results to two independent datasets, International Cancer Genome Consortium (ICGC) Hartwig Foundation, involving 18,640 cancers total. Our add 40...
Abstract The Hawaiian strain (CB4856) of Caenorhabditis elegans is one the most divergent from canonical laboratory N2 and has been widely used in developmental, population, evolutionary studies. To enhance utility strain, we have generated a draft sequence CB4856 genome, exploiting variety resources strategies. When compared against reference, genome 327,050 single nucleotide variants (SNVs) 79,529 insertion–deletion events that result total 3.3 Mb missing 1.4 present but not N2. As...
The mutational landscape is shaped by many processes. Genic regions are vulnerable to mutation but preferentially protected transcription-coupled repair
Abstract The value of genome-wide over targeted driver analyses for predicting clinical outcomes cancer patients is debated. Here, we report the whole-genome sequencing 485 chronic lymphocytic leukemia enrolled in trials as part United Kingdom’s 100,000 Genomes Project. We identify an extended catalog recurrent coding and noncoding genetic mutations that represents a source future studies provide most complete high-resolution map structural variants, copy number changes global genome...
Dravet syndrome is an archetypal rare severe epilepsy, considered 'monogenic', typically caused by loss-of-function SCN1A variants. Despite a recognizable core phenotype, its marked phenotypic heterogeneity incompletely explained differences in the causal variant or clinical factors. In 34 adults with SCN1A-related syndrome, we show additional genomic variation beyond contributes to phenotype and diversity, excess of variants epilepsy-related genes as set examples blended phenotypes,...
Extrachromosomal DNA (ecDNA) is a major contributor to treatment resistance and poor outcome for patients with cancer
The enormous variation in human lifespan is part due to a myriad of sequence variants, only few which have been revealed date. Since many life-shortening events are related diseases, we developed Mendelian randomization-based method combining 58 disease-related GWA studies derive longevity priors for all HapMap SNPs. A Bayesian association scan, informed by these priors, parental age death the UK Biobank study (n=116,279) 16 independent SNPs with significant Bayes factor at 5% false...
There is considerable insight into pathways and genes associated with heat-stress conditions. Most involved in stress response have been identified using mutant screens or gene knockdowns. Yet, there limited understanding of the temporal dynamics global expression stressful environments. Here, we studied profiles during 12 hours heat nematode C. elegans. Using a high-resolution time series increasing exposures, found distinct shift patterns between 3-4 response, separating an initially...
The development of computational methods to assess pathogenicity pre-messenger RNA splicing variants is critical for diagnosis human disease. We assessed the capability eight algorithms, and a consensus approach, prioritize 249 uncertain significance (VUSs) that underwent functional analyses. algorithms differentiate VUSs away from immediate splice site as being 'pathogenic' or 'benign' likely have substantial impact on diagnostic testing. show SpliceAI best single strategy in this regard,...
Bronchiectasis can result from infectious, genetic, immunological and allergic causes. 60-80% of cases are idiopathic, but a well-recognised genetic cause is the motile ciliopathy, primary ciliary dyskinesia (PCD). Diagnosis PCD has management implications including addressing comorbidities, implementing fertility counselling future access to PCD-specific treatments. Diagnostic testing be complex; however, moving rapidly research into clinical diagnostics would confirm bronchiectasis.This...
Abstract Background Whole-genome sequencing (WGS) of cancers is becoming an accepted component oncological care, and NHS England currently rolling out WGS for all children with cancer. This approach was piloted during the 100,000 genomes (100 K) project. Here we share experience East Genomic Medicine Centre (East-GMC), reporting feasibility clinical utility centralised individual locally. Methods Non-consecutive solid tumours were recruited into pilot 100 K project at our Centre. Variant...
The kidney-specific gene UMOD encodes for uromodulin, the most abundant protein excreted in normal urine. Rare large-effect variants cause autosomal dominant tubulointerstitial kidney disease (ADTKD), while common low-impact strongly associate with function and risk of chronic (CKD) general population. It is unknown whether intermediate-effect contribute to CKD. Here, candidate were identified using large-population ADTKD cohorts. Biological phenotypical effects investigated cell models,...
CAG repeat expansions in exon 1 of the AR gene on X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with variety extra-neurological symptoms. The disease has reported male prevalence approximately 1:30 000 or less, but expansion frequency is unknown. We established pipeline, which combines use ExpansionHunter tool visual validation, to detect whole-genome sequencing data, benchmarked it fragment PCR sizing, applied 74 277...
Abstract Background Cancer genome sequencing enables accurate classification of tumours and tumour subtypes. However, prediction performance is still limited using exome-only for types with low somatic mutation burden such as many paediatric tumours. Moreover, the ability to leverage deep representation learning in discovery entities remains unknown. Methods We introduce here Mutation-Attention (MuAt), a neural network learn representations simple complex alterations In contrast previous...
Abstract Background Findings from previous gastric cancer microbiome studies have been conflicting, potentially due to patient and/or tumor heterogeneity. The intratumoral and its relationship with clinicopathological variables not yet characterized in detail. We hypothesized that variation microbial abundance, alpha diversity, composition is related characteristics. Methods Metagenomic analysis of 529 GC samples was performed, including whole exome sequencing data Cancer Genome Atlas (TCGA)...
Organismal development is the most dynamic period of life cycle, yet we have only a rough understanding dynamics gene expression during adolescent transition. Here show that adolescence in Caenorhabditis elegans characterized by spectacular shift conserved and highly polymorphic genes. Using high resolution time series found worms over 10,000 genes changed their expression. These were clustered according to patterns. One cluster involved chromatin remodelling showed brief up-regulation...
A dataset of >700 tissue-specific transcriptomes D. melanogaster reveals population-level molecular circadian clock variation.
PurposeThis study aimed to undertake a multidisciplinary characterization of the phenotype associated with SOX11 variants.MethodsIndividuals protein altering variants in were identified through exome and genome sequencing international data sharing. Deep clinical phenotyping was undertaken by referring clinicians. Blood DNA methylation assessed using Infinium MethylationEPIC array. The expression pattern developing human brain defined RNAscope.ResultsWe reported 38 new patients variants....
Urinary stone disease (USD) is a major health burden affecting over 10% of the United Kingdom population. While associated with lifestyle, genetic factors also strongly contribute. Common variants at multiple loci from genome-wide association studies account for 5% estimated 45% heritability disorder. Here, we investigated extent to which rare variation contributes unexplained USD. Among participants 100,000-genome project, 374 unrelated individuals were identified and assigned diagnostic...
Glioma is a rare brain tumor with poor prognosis. Familial glioma subset of strong genetic predisposition that accounts for approximately 5% cases. We performed whole-genome sequencing on an exploratory cohort 203 individuals from 189 families history familial and additional validation 122 115 families. found significant enrichment deleterious variants seven genes in both cohorts, the most significantly enriched gene was