A5091641624- Genomics and Rare Diseases
- Inflammatory Bowel Disease
- Cancer Genomics and Diagnostics
- CRISPR and Genetic Engineering
- Genetics and Neurodevelopmental Disorders
- Peptidase Inhibition and Analysis
- Preterm Birth and Chorioamnionitis
- Genetic Associations and Epidemiology
- Protein Degradation and Inhibitors
- Atherosclerosis and Cardiovascular Diseases
- SARS-CoV-2 and COVID-19 Research
- Viral gastroenteritis research and epidemiology
- COVID-19 Clinical Research Studies
- Systemic Lupus Erythematosus Research
- Heat shock proteins research
- Genetics, Bioinformatics, and Biomedical Research
- Genomic variations and chromosomal abnormalities
- Immunodeficiency and Autoimmune Disorders
- Pelvic floor disorders treatments
- Computational Drug Discovery Methods
- Reproductive tract infections research
- Single-cell and spatial transcriptomics
- Microscopic Colitis
- Ubiquitin and proteasome pathways
- Biomedical Text Mining and Ontologies
University of California, Berkeley
2017-2025
University of California, San Francisco
2019-2024
March of Dimes
2023-2024
Vital Therapies (United States)
2023
University of Maryland, College Park
2019
Advanced Bioscience Laboratories (United States)
2019
Institute for Bioscience and Biotechnology Research
2019
University of Southampton
2013-2017
Southampton General Hospital
2013-2017
Wessex Regional Genetics Laboratory
2017
Abstract Regular, systematic, and independent assessments of computational tools that are used to predict the pathogenicity missense variants necessary evaluate their clinical research utility guide future improvements. The Critical Assessment Genome Interpretation (CAGI) conducts ongoing Annotate-All-Missense (Missense Marathon) challenge, in which variant effect predictors (also called impact predictors) evaluated on added disease-relevant databases following prediction submission...
Identification of pregnancies at risk preterm birth (PTB), the leading cause newborn deaths, remains challenging given syndromic nature disease. We report a longitudinal multi-omics study coupled with DREAM challenge to develop predictive models PTB. The findings indicate that whole-blood gene expression predicts ultrasound-based gestational ages in normal and complicated (r = 0.83) and, using data collected before 37 weeks gestation, also delivery date both 0.86) those spontaneous 0.75)....
Interpretation of genomic variation plays an essential role in the analysis cancer and monogenic disease, increasingly also complex trait with applications ranging from basic research to clinical decisions. Many computational impact prediction methods have been developed, yet field lacks a clear consensus on their appropriate use interpretation. The Critical Assessment Genome (CAGI, /'kā-jē/) is community experiment objectively assess for predicting phenotypic impacts variation. CAGI...
Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease in which outcomes vary among different racial groups. We leverage cell-sorted RNA-seq data (CD14+ monocytes, B cells, CD4+ T and NK cells) from 120 SLE patients (63 Asian 57 White individuals) apply a four-tier approach including unsupervised clustering, differential expression analyses, gene co-expression machine learning to identify subgroups within this multiethnic cohort. K-means clustering on each cell-type resulted...
Every year, 11% of infants are born preterm with significant health consequences, the vaginal microbiome a risk factor for birth. We crowdsource models to predict (1) birth (PTB; <37 weeks) or (2) early (ePTB; <32 from 9 studies representing 3,578 samples 1,268 pregnant individuals, aggregated public raw data via phylogenetic harmonization. The predictive validated on two independent unpublished datasets 331 148 individuals. top-performing (among and 121 submissions 318 teams) achieve area...
Whole-exome sequencing provides a cost-effective means to sequence protein coding regions within the genome, which are significantly enriched for etiological variants. We describe panel of single nucleotide polymorphisms (SNPs) facilitate validation data provenance in whole-exome studies. This is particularly significant where multiple processing steps necessitate transfer sample custody between clinical, laboratory and bioinformatics facilities. SNPs captured by all commonly used exome...
Background: Gene regulatory networks control tissue homeostasis and disease progression in a cell type–specific manner. Ubiquitously expressed chromatin regulators modulate these networks, yet the mechanisms governing how specificity of their function is achieved are poorly understood. BRD4 (bromodomain-containing protein 4), member BET (bromo- extraterminal domain) family ubiquitously acetyl-lysine reader proteins, plays pivotal role as coactivator enhancer signaling across diverse types...
Abstract The novel SARS-CoV-2 virus emerged in December 2019 and has few effective treatments. We applied a computational drug repositioning pipeline to differential gene expression signatures derived from publicly available data. utilized three independent published studies acquire or generate lists of differentially expressed genes between control SARS-CoV-2-infected samples. Using rank-based pattern matching strategy based on the Kolmogorov–Smirnov Statistic, were queried against profiles...
Abstract Regular, systematic, and independent assessment of computational tools used to predict the pathogenicity missense variants is necessary evaluate their clinical research utility suggest directions for future improvement. Here, as part sixth edition Critical Assessment Genome Interpretation (CAGI) challenge, we assess variant effect predictors (or impact predictors) on an evaluation dataset rare from disease-relevant databases. Our evaluates submitted CAGI6 Annotate-All-Missense...
Most cases of inflammatory bowel disease (IBD) are caused by complex host-environment interaction. There a number conditions associated with single-gene mutation, most very early onset (aged < 6 yr), present unique form and often have atypical features.Whole-exome data for 147 pediatric patients IBD were interrogated panel 51 genes monogenic IBD. Observed variation was categorized according to the American College Medical Genetics (ACMG) guidelines identify rare, novel, known variants that...
New genomic and large-scale data hold the promise of revolutionizing our understanding treatment human disease, are already influencing clinical practice. Multiple barriers stand between acquisition fully realizing these other benefits. In particular, we need powerful well-characterized computational methods for deducing phenotypic impact system-level perturbations. Many such have been developed, but currently, even though some deployed in settings, often remain ignorant how they actually...
X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, although AAV8-mediated gene transfer therapy has shown promise animal models and preliminarily patients. However, 4 patients with XLMTM treated have died from progressive liver failure, hepatobiliary disease now been recognized more broadly association XLMTM. In an attempt to understand whether loss of itself associated pathology, we...
We describe a family with an autosomal dominant familial dyskinesia resembling myoclonus-dystonia associated novel missense mutation in ADCY5, found through whole-exome sequencing. A tiered analytical approach was used to analyse sequencing data from affected grandmother-granddaughter pair. Whole-exome identified 18,000 shared variants, of which 46 were non-synonymous changes not present local cohort control exomes (n = 422). Further filtering based on predicted splicing effect, minor allele...
Abstract The aim of our study was to assess the utility next generation sequencing (NGS) for predicting toxicity and clinical response thiopurine drugs in paediatric patients with inflammatory bowel disease. Exome data 100 were assessed against biochemically measured TPMT enzyme activity, adverse effects. gene a panel 15 other genes implicated analysed using based statistical test (SKAT-O test). Nine out (Crohn’s disease- 67, ulcerative colitis- 23 IBDU-10) had known mutations associated...
Genome sequencing identifies vast number of genetic variants. Predicting these variants' molecular and clinical effects is one the preeminent challenges in human genetics. Accurate prediction impact variants improves our understanding how information conveyed to cellular functions, an essential step towards precision medicine. Over hundred tools/resources have been developed specifically for this purpose. We summarize tools as well their characteristics, Variant Impact Predictor Database...
Abstract Globally, every year about 11% of infants are born preterm, defined as a birth prior to 37 weeks gestation, with significant and lingering health consequences. Multiple studies have related the vaginal microbiome preterm birth. We present crowdsourcing approach predict: (a) or (b) early from 9 publicly available representing 3,578 samples 1,268 pregnant individuals, aggregated raw sequences via an open-source tool, MaLiAmPi. validated crowdsourced models on novel datasets 331 148...
Inflammatory bowel disease (IBD) is a chronic, relapsing inflammatory of the gastrointestinal tract which includes ulcerative colitis and Crohn's disease. Genetic risk factors for IBD are not well understood. We performed family-based whole exome sequencing (WES) analysis on core family (Family A) to identify potential causal mutations then analyzed data from Caucasian pediatric cohort (136 patients 106 controls) validate presence in candidate gene, heat shock 70 kDa protein 1-like (HSPA1L)....
Abstract Homology Directed Repair (HDR) enables precise genome editing, but the implementation of HDR-based therapies is hindered by limited efficiency in comparison to methods that exploit alternative DNA repair routes, such as Non-Homologous End Joining (NHEJ). In this study, we develop a functional, pooled screening platform identify protein-based reagents improve HDR human hematopoietic stem and progenitor cells (HSPCs). We leverage explore sequence diversity at binding interface NHEJ...
Pediatric Inflammatory Bowel Disease (PIBD) is a chronic condition seen in genetically predisposed individuals. Genome-wide association studies have implicated >160 genomic loci IBD with many genes coding for proteins key immune pathways. This study looks at autoimmune disease burden patients diagnosed PIBD and interrogates exome data of subset patients. Patients were recruited from the Southampton Genetics cohort. Clinical diagnosis these individuals was ascertained medical records. For...
Frataxin (FXN) is a highly conserved protein found in prokaryotes and eukaryotes that required for efficient regulation of cellular iron homeostasis. Experimental evidence associates amino acid substitutions the FXN to Friedreich Ataxia, neurodegenerative disorder. Recently, new thermodynamic experiments have been performed study impact somatic variations identified cancer tissues on stability. The Critical Assessment Genome Interpretation (CAGI) data provider at University Rome measured...
The NAGLU challenge of the fourth edition Critical Assessment Genome Interpretation experiment (CAGI4) in 2016, invited participants to predict impact variants unknown significance (VUS) on enzymatic activity lysosomal hydrolase α-N-acetylglucosaminidase (NAGLU). Deficiencies lead a rare, monogenic, recessive storage disorder, Sanfilippo syndrome type B (MPS IIIB). This attracted 17 submissions from 10 groups. We observed that top models were able missense mutations with Pearson's...