A5026560476- Cancer Genomics and Diagnostics
- Evolution and Genetic Dynamics
- Acute Myeloid Leukemia Research
- Ubiquitin and proteasome pathways
- Protein Degradation and Inhibitors
- Single-cell and spatial transcriptomics
- Epigenetics and DNA Methylation
- Genomics and Phylogenetic Studies
- CRISPR and Genetic Engineering
- Protein Structure and Dynamics
- Erythrocyte Function and Pathophysiology
- Material Dynamics and Properties
- Hematopoietic Stem Cell Transplantation
- Advanced Thermodynamics and Statistical Mechanics
- T-cell and B-cell Immunology
- Micro and Nano Robotics
- Cellular Mechanics and Interactions
- DNA Repair Mechanisms
- Graph theory and applications
- Fungal and yeast genetics research
- Complex Network Analysis Techniques
- Force Microscopy Techniques and Applications
- Polymer crystallization and properties
- Genetic factors in colorectal cancer
- Interconnection Networks and Systems
Cancer Research UK Cambridge Center
2019-2025
University of Cambridge
2010-2025
Cancer Institute (WIA)
2024
Hutchison/MRC Research Centre
2020
Stanford University
2014-2018
Stony Brook University
2016-2018
London Institute for Mathematical Sciences
2015
Cavendish Hospital
2011
Evolutionary dynamics in hematopoiesis Cells accumulate mutations as we age, and these can be a source of diseases such cancer. How cells containing evolve, are maintained, proliferate within the body has not been well characterized. Using quantitative framework, Watson et al. applied population genetic theory to estimate mutation accumulation blood from sequencing data derived nearly 50,000 healthy individuals (see Perspective by Curtis). By evaluating how differ between cell populations,...
Clonal hematopoiesis is a prevalent age-related condition associated with greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A (DNMT3A) are the most common driver this state. DNMT3A variants occur across gene some particularly malignancy, but functional relevance and mechanisms pathogenesis majority unknown. Here, we systematically investigated activity protein stability 253 disease-associated mutations, found that 74% were loss-of-function mutations. Half...
Donor hematopoietic clones with pathogenic mutations engraft and persist in unrelated stem cell transplant recipients.
Using quantitative measurements of protein aggregation rates, we develop a kinetic picture conversion from soluble to fibrillar state which shows that single free energy barrier controls the addition molecules into amyloid fibrils, while characteristic sublinear concentration dependence emerges as natural consequence finite diffusion times. These findings suggest this reaction does not follow simple chemical mechanism, but rather operates in way analogous landscape models folding defined by...
Abstract Mosaic chromosomal alterations (mCAs) are common in cancers and can arise decades before diagnosis. A quantitative understanding of the rate at which these events occur, their functional consequences, could improve cancer risk prediction our somatic evolution. Using mCA clone size estimates from blood approximately 500,000 UK Biobank participants, we estimate mutation rates fitness consequences acquired gain, loss copy-neutral heterozygosity events. Most mCAs have moderate to high...
The representation of driver mutations in preleukemic hematopoietic stem cells (pHSCs) provides a window into the somatic evolution that precedes acute myeloid leukemia (AML). Here, we isolate pHSCs from bone marrow 16 patients diagnosed with AML and perform single-cell DNA sequencing on thousands to reconstruct phylogenetic trees major clones each patient. We develop computational framework can infer levels positive selection operating during statistical properties these trees. Combining...
Haematopoietic stem cells maintain blood production throughout life1. Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of haematopoietic cell pool during murine ageing. We isolated progenitors from young old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse accrue approximately 45 per year, a rate only threefold greater than human despite vastly different organismal...
The most profound effect of disorder on the elastic response solids is nonaffinity local displacements whereby atoms (particles, network junctions) do not simply follow macroscopic strain, as they in perfect crystals, but undergo additional which result a softening response. Whether can produce further effects has been an open and difficult question due to our poor understanding nonaffinity. Here we present systematic analysis this problem by allowing both lattice coordination vary...
Abstract Several large-scale efforts have systematically catalogued protein-protein interactions (PPIs) of a cell in single environment. However, little is known about how the protein interactome changes across environmental perturbations. Current technologies, which assay one PPI at time, are too low throughput to make it practical study dynamics. Here, we develop highly parallel interaction sequencing (PPiSeq) platform that uses novel double barcoding system conjunction with dihydrofolate...
Arguments are put forward that mean inextensibility is a valid approximation for semiflexible filaments. Using inextensibility, simple analytical expression the free energy single filaments as function of their end-to-end separation obtained. This contains term explicitly represents internal filament well nonzero temperature effects. this energy, force−extension relationships and corresponding nonlinear elasticity networks investigated. Accounting finite longitudinal compliance filaments, we...
Significance A deleterious mutation that is recessive hidden in individuals containing only one copy (i.e., heterozygotes); however, two copies homozygotes) suffer negative effects. This class of responsible for a number human genetic disorders, including cystic fibrosis and Tay-Sachs, addition to causing the widespread phenomenon inbreeding depression. Evidence suggests mutations may be abundant nature, likely due their ability persist long timescales at moderate frequencies. It thus...
A model for filament buckling at finite temperatures is presented. Starting from the classical worm-like chain under constant compression, we use a mean-field approach inextensibility to find complete partition function. We that there simple interpolation formula describes free energy of chains or filaments as function end-to-end separation, which spans whole range stiffnesses. Using this study transition semiflexible and kinetics plays an important role. propose essentially first order-like...
Somatic evolution in ageing tissues underlies many cancers. However, our quantitive understanding of the rules governing this pre-cancerous remains incomplete. Here we exploit a unique collection serial blood samples collected annually up to 15 years prior diagnosis acute myeloid leukaemia (AML) provide quantitative description evolutionary dynamics. Using deep duplex sequencing and theory, quantify acquisition ages fitness effects key driver events AML development. The first mutations are...
Abstract Haematopoietic stem cells maintain blood production throughout life. While extensively characterised using the laboratory mouse, little is known about how population sustained and evolves with age. We isolated progenitors from young old mice, identifying 221,890 somatic mutations genome-wide in 1845 single cell-derived colonies, used phylogenetic analysis to infer ontogeny dynamics of cell pool. Mouse accrue ∼45 per year, a rate only 2-fold greater than human despite vastly...
The theory of immunosurveillance posits that T-cells can selectively eliminate clones harbouring non-self antigens generated by somatic mutations. There is considerable evidence supporting the role immune surveillance in cancer. Whether imposes a negative selective pressure on pre-cancerous clones, however, not well established. Here, we studied association between MHC-variant binding and risk clonal haematopoiesis (CH), pre-cancer state blood driven expansions mutant haematopoietic stem...
Abstract As we age, many tissues become colonised by microscopic clones carrying somatic driver mutations ( 1–10 . Some of these represent a first step towards cancer whereas others may contribute to ageing and other diseases. However, our understanding the clonal landscapes human tissues, their impact on risk, disease, remains limited due challenge detecting present in small numbers cells. Here, introduce new version nanorate sequencing (NanoSeq) 11 , duplex method with error rates <5...
We present a revised theoretical study of statistical properties semiflexible filaments. Using single auxiliary field and mean-field theory, we succeed in obtaining the exact analytical results for force–extension relations chain with arbitrary stiffness, compare it earlier theories experiment. At small persistence-to-contour length ratio, lp/L ≪ 1 behaves classically, as an entropic spring. However, find critical value L/lp ≈ 3.0 3D (or 5.4 2D) above which restoring force becomes negative...
We present a model that assesses the different elastic responses of semiflexible network, which either (i) is constrained to deform in an affine way or (ii) permitted thermally fluctuate and deviate from response. The thermal, non-affine response network achieved using Metropolis Monte Carlo algorithm with dynamic step size. find deformations soften dramatically at low strains make eventual nonlinear strain stiffening far more pronounced. show effect these are very sensitive degree variation...
Somatic mutations acquired in healthy tissues as we age are major determinants of cancer risk. Whether variants confer a fitness advantage or rise to detectable frequencies by chance, however, remains largely unknown. Here, combining blood sequencing data from ∼50,000 individuals, reveal how mutation, genetic drift and differences combine shape the diversity (‘clonal haematopoiesis’). By analysing spectrum variant allele quantify advantages for key pathogenic genes provide bounds on number...