Wellcome Trust Sanger Institute

About: Wellcome Trust Sanger Institute is a nonprofit organization based out in Cambridge, United Kingdom. It is known for research contribution in the topics: Population & Genome. The organization has 4009 authors who have published 9671 publications receiving 1224479 citations.

Signatures of mutation and selection in the cancer genome

Abstract: The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.

Exploring the Genomes of Cancer Cells: Progress and Promise

Abstract: The description and interpretation of genomic abnormalities in cancer cells have been at the heart of cancer research for more than a century. With exhaustive sequencing of cancer genomes across a wide range of human tumors well under way, we are now entering the end game of this mission. In the forthcoming decade, essentially complete catalogs of somatic mutations will be generated for tens of thousands of human cancers. Here, I provide an overview of what these efforts have revealed to date about the origin and behavioral features of cancer cells and how this genomic information is being exploited to improve diagnosis and therapy of the disease.

Circlator: automated circularization of genome assemblies using long sequencing reads

Abstract: The assembly of DNA sequence data is undergoing a renaissance thanks to emerging technologies capable of producing reads tens of kilobases long. Assembling complete bacterial and small eukaryotic genomes is now possible, but the final step of circularizing sequences remains unsolved. Here we present Circlator, the first tool to automate assembly circularization and produce accurate linear representations of circular sequences. Using Pacific Biosciences and Oxford Nanopore data, Circlator correctly circularized 26 of 27 circularizable sequences, comprising 11 chromosomes and 12 plasmids from bacteria, the apicoplast and mitochondrion of Plasmodium falciparum and a human mitochondrion. Circlator is available at http://sanger-pathogens.github.io/circlator/.

Human aging-associated DNA hypermethylation occurs preferentially at bivalent chromatin domains

Abstract: In biological terms, aging can be defined as cellular senescence, which results in a diminished ability to respond to stress, increased homeostatic imbalance and risk of diseases such as cancer, and eventually death Research in a variety of organisms has revealed that many factors are involved in the aging process at the molecular level These include telomere-shortening, accumulation of genetic mutations, oxidative stress, and molecular pathways altered by quantitative and qualitative changes in nutrition (for review, see Vijg and Campisi 2008) More recently, several small-scale profiling studies have found directional epigenetic perturbations associated with aging in mammals (Fraga et al 2005; Bjornsson et al 2008; Boks et al 2009; Christensen et al 2009) Epigenetic modifications, such as DNA methylation and post-translational modifications of histone proteins, are indispensable for many aspects of genome function, including gene expression The perturbation of epigenetic landscapes during aging could potentially influence cellular functions, thereby impacting on the development of various aging-associated phenotypes and/or diseases, such as cancer However, until now, we have lacked a genome-scale view of aging-associated epigenomic dynamics Such information would potentially reveal key genomic regions/features or molecular pathways that are susceptible to aging-related epigenetic perturbations Here, we report the first genome-scale study of epigenomic dynamics during normal human aging Our data support a model in which aging-associated differentially methylated regions (aDMRs) that gain methylation with age (hyper-aDMRs) arise in precursor/stem cells preferentially at bivalent chromatin domain promoters This same category of promoters is frequently hypermethylated in cancers and in vitro cell culture, pointing to a novel mechanistic link between aberrant hypermethylation in cancer, aging, and cell culture

Targeted gene correction of α1-antitrypsin deficiency in induced pluripotent stem cells

Abstract: Human induced pluripotent stem cells (iPSCs) represent a unique opportunity for regenerative medicine because they offer the prospect of generating unlimited quantities of cells for autologous transplantation, with potential application in treatments for a broad range of disorders. However, the use of human iPSCs in the context of genetically inherited human disease will require the correction of disease-causing mutations in a manner that is fully compatible with clinical applications. The methods currently available, such as homologous recombination, lack the necessary efficiency and also leave residual sequences in the targeted genome. Therefore, the development of new approaches to edit the mammalian genome is a prerequisite to delivering the clinical promise of human iPSCs. Here we show that a combination of zinc finger nucleases (ZFNs) and piggyBac technology in human iPSCs can achieve biallelic correction of a point mutation (Glu342Lys) in the α(1)-antitrypsin (A1AT, also known as SERPINA1) gene that is responsible for α(1)-antitrypsin deficiency. Genetic correction of human iPSCs restored the structure and function of A1AT in subsequently derived liver cells in vitro and in vivo. This approach is significantly more efficient than any other gene-targeting technology that is currently available and crucially prevents contamination of the host genome with residual non-human sequences. Our results provide the first proof of principle, to our knowledge, for the potential of combining human iPSCs with genetic correction to generate clinically relevant cells for autologous cell-based therapies.