register interest

Dr Benjamin Schuster-Böckler

Research Area: Bioinformatics & Stats (inc. Modelling and Computational Biology)
Technology Exchange: Bioinformatics and Computational biology
Scientific Themes: Cancer Biology and Genetics & Genomics
Keywords: Genomics, Epigenetics, Mutation, Cancer Heterogeneity and High-Throuput Sequencing
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Benjamin Schuster-Böckler heads the computational genomics group at the Ludwig Institute for Cancer Research.

The main focus of his group are the causes and consequences of mutation rate heterogeneity. In previous work, he established that epigenetic marks in the form of histone modifications have a profound influence on the mutational landscape in cancer cells. More recently, the Schuster-Böckler lab analysed the influence of different DNA modifications on mutability.

The Schuster-Böckler lab is also interested in developing novel genomic methods in the area of single-cell technology. For example, as part of ongoing collaboration they have created tools to assess the robustness of single-cell transcriptome measurements.

Name Department Institution Country
Professor Xin Lu Oxford Ludwig Institute Oxford University, Old Road Campus Research Building United Kingdom
Professor Skirmantas Kriaucionis Oxford Ludwig Institute Oxford University, Old Road Campus Research Building United Kingdom
Dr Chunxiao Song Oxford Ludwig Institute Oxford University, NDM Research Building United Kingdom
Professor Gareth Bond Oxford Ludwig Institute Oxford University, Old Road Campus Research Building United Kingdom
Professor Ian Tomlinson Wellcome Trust Centre for Human Genetics Oxford University, Henry Wellcome Building of Genomic Medicine United Kingdom
Professor Colin R Goding Oxford Ludwig Institute Oxford University, Old Road Campus Research Building United Kingdom
Zak J, Schuster-Boeckler B, Bond G. 2016. Cancer Genetics May Aid Diagnostics of Developmental Disorders. Hum Mutat, 37 (10), pp. 989. | Read more

Bardella C, Al-Dalahmah O, Krell D, Brazauskas P, Al-Qahtani K, Tomkova M, Adam J, Serres S, Lockstone H, Freeman-Mills L et al. 2016. Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis. Cancer Cell, 30 (4), pp. 578-594. | Show Abstract | Read more

Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.

Zhang P, Stracquadanio G, Wang X, Pybus M, Zeron-Medina J, Nornes S, Moore S, Bi Y, Wallace M, Bond E et al. 2016. Pro-survival p53 target genes have evolved clusters of interacting polymorphic response elements that can affect cancer risk European Journal of Cancer, 61 pp. S110-S110. | Read more

Tomkova M, McClellan M, Kriaucionis S, Schuster-Boeckler B. 2016. 5-hydroxymethylcytosine marks regions with reduced mutation frequency in human DNA. Elife, 5 (MAY2016), | Show Abstract | Read more

CpG dinucleotides are the main mutational hot-spot in most cancers. The characteristic elevated C>T mutation rate in CpG sites has been related to 5-methylcytosine (5mC), an epigenetically modified base which resides in CpGs and plays a role in transcription silencing. In brain nearly a third of 5mCs have recently been found to exist in the form of 5-hydroxymethylcytosine (5hmC), yet the effect of 5hmC on mutational processes is still poorly understood. Here we show that 5hmC is associated with an up to 53% decrease in the frequency of C>T mutations in a CpG context compared to 5mC. Tissue specific 5hmC patterns in brain, kidney and blood correlate with lower regional CpG>T mutation frequency in cancers originating in the respective tissues. Together our data reveal global and opposing effects of the two most common cytosine modifications on the frequency of cancer causing somatic mutations in different cell types.

Stracquadanio G, Wang X, Wallace MD, Grawenda AM, Zhang P, Hewitt J, Zeron-Medina J, Castro-Giner F, Tomlinson IP, Goding CR et al. 2016. The importance of p53 pathway genetics in inherited and somatic cancer genomes. Nat Rev Cancer, 16 (4), pp. 251-265. | Show Abstract | Read more

Decades of research have shown that mutations in the p53 stress response pathway affect the incidence of diverse cancers more than mutations in other pathways. However, most evidence is limited to somatic mutations and rare inherited mutations. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The cancer-associated single nucleotide polymorphisms (SNPs) of the p53 pathway have strikingly similar genetic characteristics to well-studied p53 pathway cancer-causing somatic mutations. Our results enable insights into p53-mediated tumour suppression in humans and into p53 pathway-based cancer surveillance and treatment strategies.

Schuster-Böckler B, Lehner B. 2012. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature, 488 (7412), pp. 504-507. | Show Abstract | Read more

Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature—levels of the heterochromatin-associated histone modification H3K9me3—can account for more than 40% of mutation-rate variation, and a combination of features can account for more than 55%. The strong association between mutation rates and chromatin organization is upheld in samples from different tissues and for different mutation types. This suggests that the arrangement of the genome into heterochromatin- and euchromatin-like domains is a dominant influence on regional mutation-rate variation in human somatic cells.

Schuster-Böckler B, Conrad D, Bateman A. 2010. Dosage sensitivity shapes the evolution of copy-number varied regions. PLoS One, 5 (3), pp. e9474. | Show Abstract | Read more

Dosage sensitivity is an important evolutionary force which impacts on gene dispensability and duplicability. The newly available data on human copy-number variation (CNV) allow an analysis of the most recent and ongoing evolution. Provided that heterozygous gene deletions and duplications actually change gene dosage, we expect to observe negative selection against CNVs encompassing dosage sensitive genes. In this study, we make use of several sources of population genetic data to identify selection on structural variations of dosage sensitive genes. We show that CNVs can directly affect expression levels of contained genes. We find that genes encoding members of protein complexes exhibit limited expression variation and overlap significantly with a manually derived set of dosage sensitive genes. We show that complexes and other dosage sensitive genes are underrepresented in CNV regions, with a particular bias against frequent variations and duplications. These results suggest that dosage sensitivity is a significant force of negative selection on regions of copy-number variation.

Bushell KM, Söllner C, Schuster-Boeckler B, Bateman A, Wright GJ. 2008. Large-scale screening for novel low-affinity extracellular protein interactions. Genome Res, 18 (4), pp. 622-630. | Show Abstract | Read more

Extracellular protein-protein interactions are essential for both intercellular communication and cohesion within multicellular organisms. Approximately a fifth of human genes encode membrane-tethered or secreted proteins, but they are largely absent from recent large-scale protein interaction datasets, making current interaction networks biased and incomplete. This discrepancy is due to the unsuitability of popular high-throughput methods to detect extracellular interactions because of the biochemical intractability of membrane proteins and their interactions. For example, cell surface proteins contain insoluble hydrophobic transmembrane regions, and their extracellular interactions are often highly transient, having half-lives of less than a second. To detect transient extracellular interactions on a large scale, we developed AVEXIS (avidity-based extracellular interaction screen), a high-throughput assay that overcomes these technical issues and can detect very transient interactions (half-lives <or= 0.1 sec) with a low false-positive rate. We used it to systematically screen for receptor-ligand pairs within the zebrafish immunoglobulin superfamily and identified novel ligands for both well-known and orphan receptors. Genes encoding receptor-ligand pairs were often clustered phylogenetically and expressed in the same or adjacent tissues, immediately implying their involvement in similar biological processes. Using AVEXIS, we have determined the first systematic low-affinity extracellular protein interaction network, supported by independent biological data. This technique will now allow large-scale extracellular protein interaction mapping in a broad range of experimental contexts.

Schuster-Böckler B, Bateman A. 2008. Protein interactions in human genetic diseases. Genome Biol, 9 (1), pp. R9. | Show Abstract | Read more

We present a novel method that combines protein structure information with protein interaction data to identify residues that form part of an interaction interface. Our prediction method can retrieve interaction hotspots with an accuracy of 60% (at a 20% false positive rate). The method was applied to all mutations in the Online Mendelian Inheritance in Man (OMIM) database, predicting 1,428 mutations to be related to an interaction defect. Combining predicted and hand-curated sets, we discuss how mutations affect protein interactions in general.

Schuster-Böckler B, Bateman A. 2007. Reuse of structural domain-domain interactions in protein networks. BMC Bioinformatics, 8 (1), pp. 259. | Show Abstract | Read more

BACKGROUND: Protein interactions are thought to be largely mediated by interactions between structural domains. Databases such as iPfam relate interactions in protein structures to known domain families. Here, we investigate how the domain interactions from the iPfam database are distributed in protein interactions taken from the HPRD, MPact, BioGRID, DIP and IntAct databases. RESULTS: We find that known structural domain interactions can only explain a subset of 4-19% of the available protein interactions, nevertheless this fraction is still significantly bigger than expected by chance. There is a correlation between the frequency of a domain interaction and the connectivity of the proteins it occurs in. Furthermore, a large proportion of protein interactions can be attributed to a small number of domain interactions. We conclude that many, but not all, domain interactions constitute reusable modules of molecular recognition. A substantial proportion of domain interactions are conserved between E. coli, S. cerevisiae and H. sapiens. These domains are related to essential cellular functions, suggesting that many domain interactions were already present in the last universal common ancestor. CONCLUSION: Our results support the concept of domain interactions as reusable, conserved building blocks of protein interactions, but also highlight the limitations currently imposed by the small number of available protein structures.

Schuster-Böckler B, Bateman A. 2007. An introduction to hidden Markov models. Curr Protoc Bioinformatics, Appendix 3 pp. Appendix-3A. | Show Abstract | Read more

This unit introduces the concept of hidden Markov models in computational biology. It describes them using simple biological examples, requiring as little mathematical knowledge as possible. The unit also presents a brief history of hidden Markov models and an overview of their current applications before concluding with a discussion of their limitations.

Finn RD, Mistry J, Schuster-Böckler B, Griffiths-Jones S, Hollich V, Lassmann T, Moxon S, Marshall M, Khanna A, Durbin R et al. 2006. Pfam: clans, web tools and services. Nucleic Acids Res, 34 (Database issue), pp. D247-D251. | Show Abstract | Read more

Pfam is a database of protein families that currently contains 7973 entries (release 18.0). A recent development in Pfam has enabled the grouping of related families into clans. Pfam clans are described in detail, together with the new associated web pages. Improvements to the range of Pfam web tools and the first set of Pfam web services that allow programmatic access to the database and associated tools are also presented. Pfam is available on the web in the UK (http://www.sanger.ac.uk/Software/Pfam/), the USA (http://pfam.wustl.edu/), France (http://pfam.jouy.inra.fr/) and Sweden (http://pfam.cgb.ki.se/).

Schuster-Böckler B, Bateman A. 2005. Visualizing profile-profile alignment: pairwise HMM logos. Bioinformatics, 21 (12), pp. 2912-2913. | Show Abstract | Read more

UNLABELLED: The availability of advanced profile-profile comparison tools, such as PRC or HHsearch demands sophisticated visualization tools not presently available. We introduce an approach built upon the concept of HMM logos. The method illustrates the similarities of pairs of protein family profiles in an intuitive way. Two HMM logos, one for each profile, are drawn one upon the other. The aligned states are then highlighted and connected. AVAILABILITY: A web interface offering online creation of pairwise HMM logos is available at http://www.sanger.ac.uk/Software/analysis/logomat-p. Furthermore, software developers may download a Perl package that includes methods for creation of pairwise HMM logos locally. CONTACT: bsb@sanger.ac.uk.

Schuster-Böckler B, Schultz J, Rahmann S. 2004. HMM Logos for visualization of protein families. BMC Bioinformatics, 5 pp. 7. | Show Abstract | Read more

BACKGROUND: Profile Hidden Markov Models (pHMMs) are a widely used tool for protein family research. Up to now, however, there exists no method to visualize all of their central aspects graphically in an intuitively understandable way. RESULTS: We present a visualization method that incorporates both emission and transition probabilities of the pHMM, thus extending sequence logos introduced by Schneider and Stephens. For each emitting state of the pHMM, we display a stack of letters. The stack height is determined by the deviation of the position's letter emission frequencies from the background frequencies. The stack width visualizes both the probability of reaching the state (the hitting probability) and the expected number of letters the state emits during a pass through the model (the state's expected contribution).A web interface offering online creation of HMM Logos and the corresponding source code can be found at the Logos web server of the Max Planck Institute for Molecular Genetics http://logos.molgen.mpg.de. CONCLUSIONS: We demonstrate that HMM Logos can be a useful tool for the biologist: We use them to highlight differences between two homologous subfamilies of GTPases, Rab and Ras, and we show that they are able to indicate structural elements of Ras.

Tomkova M, McClellan M, Kriaucionis S, Schuster-Böckler B. 2017. DNA Replication and associated repair pathways are involved in the mutagenesis of methylated cytosine. DNA Repair (Amst), 62 pp. 1-7. | Show Abstract | Read more

Transitions of cytosine to thymine in CpG dinucleotides are the most frequent type of mutations observed in cancer. This increased mutability is commonly explained by the presence of 5-methylcytosine (5mC) and its spontaneous hydrolytic deamination into thymine. Here, we describe observations that question whether spontaneous deamination alone causes the elevated mutagenicity of 5mC. Tumours with somatic mutations in DNA mismatch-repair genes or in the proofreading domain of DNA polymerase ε (Pol ε) exhibit more 5mC to T transitions than would be expected, given the kinetics of hydrolytic deamination. This enrichment is asymmetrical around replication origins with a preference for the leading strand template, in particular in methylated cytosines flanked by guanines (GCG). Notably, GCG to GTG mutations also exhibit strand asymmetry in mismatch-repair and Pol ε wild-type tumours. Together, these findings suggest that mis-incorporation of A opposite 5mC during replication of the leading strand might be a contributing factor in the mutagenesis of methylated cytosine.

Bardella C, Al-Dalahmah O, Krell D, Brazauskas P, Al-Qahtani K, Tomkova M, Adam J, Serres S, Lockstone H, Freeman-Mills L et al. 2016. Expression of Idh1R132H in the Murine Subventricular Zone Stem Cell Niche Recapitulates Features of Early Gliomagenesis. Cancer Cell, 30 (4), pp. 578-594. | Show Abstract | Read more

Isocitrate dehydrogenase 1 mutations drive human gliomagenesis, probably through neomorphic enzyme activity that produces D-2-hydroxyglutarate. To model this disease, we conditionally expressed Idh1R132H in the subventricular zone (SVZ) of the adult mouse brain. The mice developed hydrocephalus and grossly dilated lateral ventricles, with accumulation of 2-hydroxyglutarate and reduced α-ketoglutarate. Stem and transit amplifying/progenitor cell populations were expanded, and proliferation increased. Cells expressing SVZ markers infiltrated surrounding brain regions. SVZ cells also gave rise to proliferative subventricular nodules. DNA methylation was globally increased, while hydroxymethylation was decreased. Mutant SVZ cells overexpressed Wnt, cell-cycle and stem cell genes, and shared an expression signature with human gliomas. Idh1R132H mutation in the major adult neurogenic stem cell niche causes a phenotype resembling gliomagenesis.

Zhang P, Stracquadanio G, Wang X, Pybus M, Zeron-Medina J, Nornes S, Moore S, Bi Y, Wallace M, Bond E et al. 2016. Pro-survival p53 target genes have evolved clusters of interacting polymorphic response elements that can affect cancer risk European Journal of Cancer, 61 pp. S110-S110. | Read more

Tomkova M, McClellan M, Kriaucionis S, Schuster-Boeckler B. 2016. 5-hydroxymethylcytosine marks regions with reduced mutation frequency in human DNA. Elife, 5 (MAY2016), | Show Abstract | Read more

CpG dinucleotides are the main mutational hot-spot in most cancers. The characteristic elevated C>T mutation rate in CpG sites has been related to 5-methylcytosine (5mC), an epigenetically modified base which resides in CpGs and plays a role in transcription silencing. In brain nearly a third of 5mCs have recently been found to exist in the form of 5-hydroxymethylcytosine (5hmC), yet the effect of 5hmC on mutational processes is still poorly understood. Here we show that 5hmC is associated with an up to 53% decrease in the frequency of C>T mutations in a CpG context compared to 5mC. Tissue specific 5hmC patterns in brain, kidney and blood correlate with lower regional CpG>T mutation frequency in cancers originating in the respective tissues. Together our data reveal global and opposing effects of the two most common cytosine modifications on the frequency of cancer causing somatic mutations in different cell types.

Stracquadanio G, Wang X, Wallace MD, Grawenda AM, Zhang P, Hewitt J, Zeron-Medina J, Castro-Giner F, Tomlinson IP, Goding CR et al. 2016. The importance of p53 pathway genetics in inherited and somatic cancer genomes. Nat Rev Cancer, 16 (4), pp. 251-265. | Show Abstract | Read more

Decades of research have shown that mutations in the p53 stress response pathway affect the incidence of diverse cancers more than mutations in other pathways. However, most evidence is limited to somatic mutations and rare inherited mutations. Using newly abundant genomic data, we demonstrate that commonly inherited genetic variants in the p53 pathway also affect the incidence of a broad range of cancers more than variants in other pathways. The cancer-associated single nucleotide polymorphisms (SNPs) of the p53 pathway have strikingly similar genetic characteristics to well-studied p53 pathway cancer-causing somatic mutations. Our results enable insights into p53-mediated tumour suppression in humans and into p53 pathway-based cancer surveillance and treatment strategies.

Schuster-Böckler B, Lehner B. 2012. Chromatin organization is a major influence on regional mutation rates in human cancer cells. Nature, 488 (7412), pp. 504-507. | Show Abstract | Read more

Cancer genome sequencing provides the first direct information on how mutation rates vary across the human genome in somatic cells. Testing diverse genetic and epigenetic features, here we show that mutation rates in cancer genomes are strikingly related to chromatin organization. Indeed, at the megabase scale, a single feature—levels of the heterochromatin-associated histone modification H3K9me3—can account for more than 40% of mutation-rate variation, and a combination of features can account for more than 55%. The strong association between mutation rates and chromatin organization is upheld in samples from different tissues and for different mutation types. This suggests that the arrangement of the genome into heterochromatin- and euchromatin-like domains is a dominant influence on regional mutation-rate variation in human somatic cells.

A comprehensive computational platform to improve liquid biopsies for cancer detection

BackgroundAlthough recent advances in cancer research offer new ways to treat cancer, early detection still represents the best opportunity for curing cancer. Earlier stage treatment not only greatly improves patient survival but also costs considerably less. Therefore, a non-invasive, low cost and reliable cancer diagnostic assay could greatly benefit cancer patients and the public. In this regard, circulating cell-free DNA (cfDNA) holds tremendous potential to develop such a diagnostic assay. ...

View project

Analysing genetic heterogeneity through single-cell genomics

Somatic mutations occur during almost every cell division. The resulting genetic heterogeneity contributes to ageing and, most prominently, can lead to cancer. Mutations are known to be caused by external mutagens, such as tobacco smoke, as well as by cell-intrinsic mechanisms, for example the expression of certain genes or epigenetic modifications on DNA. Surprisingly, however, the underlying causes behind many types of mutations are still not well understood.One of the key goals of the ...

View project

A comprehensive computational platform to improve liquid biopsies for cancer detection

BackgroundAlthough recent advances in cancer research offer new ways to treat cancer, early detection still represents the best opportunity for curing cancer. Earlier stage treatment not only greatly improves patient survival but also costs considerably less. Therefore, a non-invasive, low cost and reliable cancer diagnostic assay could greatly benefit cancer patients and the public. In this regard, circulating cell-free DNA (cfDNA) holds tremendous potential to develop such a diagnostic assay. ...

View project

1220

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