A5038655985- CRISPR and Genetic Engineering
- Pluripotent Stem Cells Research
- Genomics and Chromatin Dynamics
- RNA modifications and cancer
- Chromosomal and Genetic Variations
- Congenital heart defects research
- RNA Research and Splicing
- Genetics and Neurodevelopmental Disorders
- Cancer-related molecular mechanisms research
- Genomic variations and chromosomal abnormalities
- RNA and protein synthesis mechanisms
- Genomics and Rare Diseases
- Epigenetics and DNA Methylation
- Prenatal Screening and Diagnostics
- Hedgehog Signaling Pathway Studies
- Genetic Syndromes and Imprinting
- Primate Behavior and Ecology
- Genetic factors in colorectal cancer
- Genomics and Phylogenetic Studies
- RNA regulation and disease
- HER2/EGFR in Cancer Research
- Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Synthesis and Biological Evaluation
- Cardiomyopathy and Myosin Studies
- Chemotherapy-induced cardiotoxicity and mitigation
King Edward Memorial Hospital
2022-2025
The University of Texas Medical Branch at Galveston
2020-2024
Government of Western Australia Department of Health
2020-2024
Services Australia
2018-2023
University of Chicago
2015-2021
Government of Western Australia
2020
Cancer Research UK
2012-2016
University of Cambridge
2012-2016
Cancer Research UK Cambridge Center
2016
Hutchison/MRC Research Centre
2012
Gorillas are humans' closest living relatives after chimpanzees, and of comparable importance for the study human origins evolution. Here we present assembly analysis a genome sequence western lowland gorilla, compare whole genomes all extant great ape genera. We propose synthesis genetic fossil evidence consistent with placing human–chimpanzee human–chimpanzee–gorilla speciation events at approximately 6 10 million years ago. In 30% genome, gorilla is closer to or chimpanzee than latter...
Gibbons are small arboreal apes that display an accelerated rate of evolutionary chromosomal rearrangement and occupy a key node in the primate phylogeny between Old World monkeys great apes. Here we present assembly analysis northern white-cheeked gibbon (Nomascus leucogenys) genome. We describe propensity for gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes alter transcription by providing premature termination site, suggesting possible molecular mechanism...
Comparative genomics studies in primates are restricted due to our limited access samples. In order gain better insight into the genetic processes that underlie variation complex phenotypes primates, we must have faithful model systems for a wide range of cell types. To facilitate this, generated panel 7 fully characterized chimpanzee induced pluripotent stem (iPSC) lines derived from healthy donors. demonstrate utility comparative iPSC panels, collected RNA-sequencing and DNA methylation...
Critically ill infants and children with rare diseases need equitable access to rapid accurate diagnosis direct clinical management. Over 2 years, the Acute Care Genomics program provided whole-genome sequencing 290 families whose critically were admitted hospitals throughout Australia suspected genetic conditions. The average time result was 2.9 d diagnostic yield 47%. We performed additional bioinformatic analyses transcriptome in all patients who remained undiagnosed. Long-read functional...
Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that otherwise difficult to access. We investigated the use of iPSCs iPSC-derived study impact genetic variation on gene regulation across different as models studies complex disease. To do so, we established a panel from 58 well-studied Yoruba lymphoblastoid lines (LCLs); 14 these were further differentiated into cardiomyocytes. characterized regulatory individuals by measuring...
Genetic effects on gene expression and splicing can be modulated by cellular environmental factors; yet interactions between genotypes, cell type, treatment have not been comprehensively studied together. We used an induced pluripotent stem system to study multiple types derived from the same individuals exposed them a large panel of treatments. Cellular responses involved different genes pathways for were highly variable across contexts. For thousands genes, we identified allelic contexts...
The genomic binding of CTCF is highly conserved across mammals, but the mechanisms that underlie its stability are poorly understood. One transcription factor known to functionally interact with in context X-chromosome inactivation ubiquitously expressed YY1. Because combinatorial can contribute evolutionary stabilization regulatory regions, we tested whether YY1 and co-binding could part account for conservation binding.Combined analysis lymphoblastoid cell lines from seven primates, as...
Despite the importance of understanding how variability across induced pluripotent stem cell (iPSC) lines due to non-genetic factors (clone and passage) influences their differentiation outcome, large-scale studies capable addressing this question have not yet been conducted. Here, we differentiated 191 iPSC generate iPSC-derived cardiovascular progenitor cells (iPSC-CVPCs). We observed cellular heterogeneity iPSC-CVPC samples varying fractions two types: cardiomyocytes (CMs)...
One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived oxygen. To study inter-individual differences in response to hypoxia, we established an vitro model induced pluripotent stem cell-derived from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels four culturing conditions that correspond normoxia, short- or long-term re-oxygenation. characterized thousands regulatory changes as the...
SummaryAt least half of the human genome is derived from repetitive elements, which are often lineage specific and silenced by a variety genetic epigenetic mechanisms. Using transchromosomic mouse strain that transmits an almost complete single copy chromosome 21 via female germline, we show heterologous regulatory environment can transcriptionally activate transposon-derived regions. In nucleus, hundreds locations on newly associate with activating histone modifications in both somatic...
TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience same adverse effects from all this class, or if specific be preferable certain individuals based on their risk profile. To investigate this, we studied of treatment DOX,...
Despite anatomical similarities, there are differences in susceptibility to cardiovascular disease (CVD) between primates; humans prone myocardial ischemia, while chimpanzees fibrosis. Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) allow for direct inter-species comparisons of the gene regulatory response CVD-relevant perturbations such as oxygen deprivation, a consequence ischemia. To gain insight into evolution susceptibility, we characterized expression levels iPSC-CMs...
Abstract Missense and truncating variants in the X-chromosome-linked CLCN4 gene, resulting reduced or complete loss-of-function (LOF) of encoded chloride/proton exchanger ClC-4, were recently demonstrated to cause a neurocognitive phenotype both males females. Through international clinical matchmaking interrogation public variant databases we assembled database 90 rare missense families: 41 unique 18 recurrent 49 families. For 43 families, including 22 33 females, collated detailed...
Congenital titinopathy has recently emerged as one of the most common congenital muscle disorders. Objective To better understand presentation and clinical needs under‐characterized extreme end severity spectrum. Methods We comprehensively analyzed clinical, imaging, pathology, autopsy, genetic findings in 15 severely affected individuals from 11 families. Results Prenatal features included hypokinesia or akinesia growth restriction. Six pregnancies were terminated. Nine infants born at near...
Transposable elements (TEs) comprise almost half of primate genomes and their aberrant regulation can result in deleterious effects. In pluripotent stem cells, rapidly evolving KRAB-ZNF genes target TEs for silencing by H3K9me3. To investigate the evolution TE silencing, we performed H3K9me3 ChIP-seq experiments induced cells from 10 human 7 chimpanzee individuals. We identified four million orthologous found SVA ERV families to be marked most frequently little evidence inter-species...
Abstract Background Over 400 million people worldwide are living with a rare disease. Next Generation Sequencing (NGS) identifies potential disease causative genetic variants. However, many identified as variants of uncertain significance (VUS) and require functional laboratory validation to determine pathogenicity, this creates major diagnostic delays . Methods In study we test rapid variant assessment pipeline using CRISPR homology directed repair introduce single nucleotide into inducible...
Genetic counselors (GCs) face unique challenges in the acute care setting. Acute environments—such as neonatal and pediatric intensive units—are characterized by urgency, complexity, rapid decision making. These settings require GCs to navigate a delicate balance between addressing immediate clinical needs of patients providing comprehensive genetic information families, while demanding adaptation existing skills for practice.Rapid genomic testing (rGT) is increasingly becoming standard...
Abstract Background Genomic sequencing in congenital heart disease (CHD) patients often discovers novel genetic variants, which are classified as variants of uncertain significance (VUS). Functional analysis each VUS is required specialised laboratories, to determine whether the causative or not, leading lengthy diagnostic delays. We investigated stem cell cardiac modelling and transcriptomics for purpose variant classification using a GATA4 (p.Arg283Cys) patient with CHD. Methods performed...
Abstract Lamina‐associated polypeptide 2 alpha (LAP2α) plays a role in maintaining nuclear structure, assembly/disassembly, and transcriptional regulation. Elevated LAP2α mRNA expression has been previously reported to associate with certain cancer types. The aim of this study was investigate cervical transformed cells identify factors that its differential expression. found be elevated tissue by microarray, qRT‐PCR, immunofluorescence analyses. also showed cell lines fibroblasts compared...
Abstract Induced pluripotent stem cells (iPSCs) are an essential tool for studying cellular differentiation and cell types that otherwise difficult to access. We investigated the use of iPSCs iPSC-derived study impact genetic variation across different as models studies complex disease. established a panel from 58 well-studied Yoruba lymphoblastoid lines (LCLs); 14 these were further differentiated into cardiomyocytes. characterized regulatory individuals by measuring gene expression,...
Abstract One life-threatening outcome of cardiovascular disease is myocardial infarction, where cardiomyocytes are deprived oxygen. To study inter-individual differences in response to hypoxia, we established an vitro model induced pluripotent stem cell-derived from 15 individuals. We measured gene expression levels, chromatin accessibility, and methylation levels four culturing conditions that correspond normoxia, hypoxia short or long-term re-oxygenation. characterized thousands regulatory...