ORCID Profile
0000-0001-9720-1914
Current Organisation
University of Oxford
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Publisher: Proceedings of the National Academy of Sciences
Date: 20-11-2013
Abstract: Harvey rat sarcoma viral oncogene homolog ( HRAS ) occupies an important place in medical history, because it was the first gene in which acquired mutations that led to activation of a normal protein were associated with cancer, making it the prototype of the now canonical oncogene mechanism. Here, we explore what happens when similar HRAS mutations occur in male germ cells, an issue of practical importance because the mutations cause a serious congenital disorder, Costello syndrome, if transmitted to offspring. We provide evidence that the mutant germ cells are positively selected, leading to an increased burden of the mutations as men age. Although there are many parallels between this germline process and classical oncogenesis, there are interesting differences of detail, which are explored in this paper.
Publisher: Proceedings of the National Academy of Sciences
Date: 08-02-2016
Abstract: A major goal in genetics is to understand the processes that shape the frequency of new mutations, particularly those causing human disease. Here, we focus on specific mutations in the male germline that, although initially rare, confer a growth or survival advantage to the stem cell, leading to clonal expansion over time: a process similar to early tumor growth and currently described only in humans. Previous studies supporting this “selfish” selection quantified mutations in sperm or testis pieces using methods that destroyed their cellular origins. Here, we pinpoint and identify pathogenic mutations directly within in idual seminiferous tubules, the structures that generate spermatozoa. This methodology provides unprecedented precision in documenting the spectrum and prevalence of selfish mutations in men’s testes.
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.MOLCEL.2011.12.021
Abstract: A substantial amount of organismal complexity is thought to be encoded by enhancers which specify the location, timing, and levels of gene expression. In mammals there are more enhancers than promoters which are distributed both between and within genes. Here we show that activated, intragenic enhancers frequently act as alternative tissue-specific promoters producing a class of abundant, spliced, multiexonic poly(A)(+) RNAs (meRNAs) which reflect the host gene's structure. meRNAs make a substantial and unanticipated contribution to the complexity of the transcriptome, appearing as alternative isoforms of the host gene. The low protein-coding potential of meRNAs suggests that many meRNAs may be byproducts of enhancer activation or underlie as-yet-unidentified RNA-encoded functions. Distinguishing between meRNAs and mRNAs will transform our interpretation of dynamic changes in transcription both at the level of in idual genes and of the genome as a whole.
Publisher: Cold Spring Harbor Laboratory
Date: 24-10-2019
DOI: 10.1101/813618
Abstract: Genome-wide association studies (GWAS) have identified over 150,000 links between common genetic variants and human traits or complex diseases. Over 80% of these associations map to polymorphisms in non-coding DNA. Therefore, the challenge is to identify disease-causing variants, the genes they affect, and the cells in which these effects occur. We have developed a platform using ATAC-seq, DNaseI footprints, NG Capture-C and machine learning to address this challenge. Applying this approach to red blood cell traits identifies a significant proportion of known causative variants and their effector genes, which we show can be validated by direct in vivo modelling.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2018
DOI: 10.1038/S41598-017-14403-Y
Abstract: Telomere length is a risk factor in disease and the dynamics of telomere length are crucial to our understanding of cell replication and vitality. The proliferation of whole genome sequencing represents an unprecedented opportunity to glean new insights into telomere biology on a previously unimaginable scale. To this end, a number of approaches for estimating telomere length from whole-genome sequencing data have been proposed. Here we present Telomerecat, a novel approach to the estimation of telomere length. Previous methods have been dependent on the number of telomeres present in a cell being known, which may be problematic when analysing aneuploid cancer data and non-human s les. Telomerecat is designed to be agnostic to the number of telomeres present, making it suited for the purpose of estimating telomere length in cancer studies. Telomerecat also accounts for interstitial telomeric reads and presents a novel approach to dealing with sequencing errors. We show that Telomerecat performs well at telomere length estimation when compared to leading experimental and computational methods. Furthermore, we show that it detects expected patterns in longitudinal data, repeated measurements, and cross-species comparisons. We also apply the method to a cancer cell data, uncovering an interesting relationship with the underlying telomerase genotype.
Publisher: Oxford University Press (OUP)
Date: 17-01-2013
DOI: 10.1093/HMG/DDT015
Publisher: Cold Spring Harbor Laboratory
Date: 18-02-2020
DOI: 10.1101/2020.02.17.952572
Abstract: DNA folding within nuclei is a highly ordered process, with implications for gene regulation and development. An array of chromosome conformation capture (3C) methods have been developed to investigate how DNA is packaged within nuclei and to interrogate specific interactions. While these methods use different approaches to examine target loci (many-versus-all) or the entire genome (all-versus-all), they all rely on the core principle of endonuclease digestion and proximity-based ligation to re-arrange genomic order to reflect the three-dimensional nuclear conformation. This sequence reorganization creates novel chimeric DNA fragments which require specialist bioinformatic tools to analyze and visualize. Despite this need for specialist bioinformatic skills, the core biological importance of genome folding has seen widespread methodological uptake. To service the needs of experimentalists using the many-versus-all Capture-C family of methods we have developed CaptureCompendium a toolkit of software to simplify the design, analysis and presentation of 3C experiments.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2014
DOI: 10.1038/NG.2871
Abstract: Gene expression during development and differentiation is regulated in a cell- and stage-specific manner by complex networks of intergenic and intragenic cis-regulatory elements whose numbers and representation in the genome far exceed those of structural genes. Using chromosome conformation capture, it is now possible to analyze in detail the interaction between enhancers, silencers, boundary elements and promoters at in idual loci, but these techniques are not readily scalable. Here we present a high-throughput approach (Capture-C) to analyze cis interactions, interrogating hundreds of specific interactions at high resolution in a single experiment. We show how this approach will facilitate detailed, genome-wide analysis to elucidate the general principles by which cis-acting sequences control gene expression. In addition, we show how Capture-C will expedite identification of the target genes and functional effects of SNPs that are associated with complex diseases, which most frequently lie in intergenic cis-acting regulatory elements.
Publisher: Oxford University Press (OUP)
Date: 11-02-2013
DOI: 10.1093/BRAIN/AWT010
Publisher: Springer Science and Business Media LLC
Date: 27-01-2013
DOI: 10.1038/NG.2531
Publisher: Springer Science and Business Media LLC
Date: 18-05-2201
DOI: 10.1038/NG.3304
Publisher: Elsevier BV
Date: 03-2022
Publisher: Elsevier BV
Date: 09-2015
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Simon McGowan.