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Cell Nov 2017Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from...
Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
Topics: Humans; INDEL Mutation; Microsatellite Instability; Models, Genetic; Mutation Rate; Neoplasms; Point Mutation; Polymorphism, Single Nucleotide; Selection, Genetic
PubMed: 29056346
DOI: 10.1016/j.cell.2017.09.042 -
Journal of Internal Medicine May 2019Our understanding of human evolution has improved rapidly over recent decades, facilitated by large-scale cataloguing of genomic variability amongst both modern and... (Review)
Review
Our understanding of human evolution has improved rapidly over recent decades, facilitated by large-scale cataloguing of genomic variability amongst both modern and archaic humans. It seems clear that the evolution of the ancestors of chimpanzees and hominins separated 7-9 million years ago with some migration out of Africa by the earlier hominins; Homo sapiens slowly emerged as climate change resulted in drier, less forested African conditions. The African populations expanded and evolved in many different conditions with slow mutation and selection rates in the human genome, but with much more rapid mutation occurring in mitochondrial DNA. We now have evidence stretching back 300 000 years of humans in their current form, but there are clearly four very different large African language groups that correlate with population DNA differences. Then, about 50 000-100 000 years ago a small subset of modern humans also migrated out of Africa resulting in a persistent signature of more limited genetic diversity amongst non-African populations. Hybridization with archaic hominins occurred around this time such that all non-African modern humans possess some Neanderthal ancestry and Melanesian populations additionally possess some Denisovan ancestry. Human populations both within and outside Africa also adapted to diverse aspects of their local environment including altitude, climate, UV exposure, diet and pathogens, in some cases leaving clear signatures of patterns of genetic variation. Notable examples include haemoglobin changes conferring resistance to malaria, other immune changes and the skin adaptations favouring the synthesis of vitamin D. As humans migrated across Eurasia, further major mitochondrial changes occurred with some interbreeding with ancient hominins and the development of alcohol intolerance. More recently, an ability to retain lactase persistence into adulthood has evolved rapidly under the environmental stimulus of pastoralism with the ability to husband lactating ruminants. Increased amylase copy numbers seem to relate to the availability of starchy foods, whereas the capacity to desaturase and elongate monounsaturated fatty acids in different societies seems to be influenced by whether there is a lack of supply of readily available dietary sources of long-chain polyunsaturated fatty acids. The process of human evolution includes genetic drift and adaptation to local environments, in part through changes in mitochondrial and nuclear DNA. These genetic changes may underlie susceptibilities to some modern human pathologies including folate-responsive neural tube defects, diabetes, other age-related pathologies and mental health disorders.
Topics: Animals; Biological Evolution; DNA, Mitochondrial; Emigration and Immigration; Hominidae; Humans; Mutation; Nutritional Physiological Phenomena
PubMed: 30772945
DOI: 10.1111/joim.12878 -
Nature Oct 2023Scientists have been trying to identify every gene in the human genome since the initial draft was published in 2001. In the years since, much progress has been made in... (Review)
Review
Scientists have been trying to identify every gene in the human genome since the initial draft was published in 2001. In the years since, much progress has been made in identifying protein-coding genes, currently estimated to number fewer than 20,000, with an ever-expanding number of distinct protein-coding isoforms. Here we review the status of the human gene catalogue and the efforts to complete it in recent years. Beside the ongoing annotation of protein-coding genes, their isoforms and pseudogenes, the invention of high-throughput RNA sequencing and other technological breakthroughs have led to a rapid growth in the number of reported non-coding RNA genes. For most of these non-coding RNAs, the functional relevance is currently unclear; we look at recent advances that offer paths forward to identifying their functions and towards eventually completing the human gene catalogue. Finally, we examine the need for a universal annotation standard that includes all medically significant genes and maintains their relationships with different reference genomes for the use of the human gene catalogue in clinical settings.
Topics: Humans; Genome, Human; Molecular Sequence Annotation; Protein Isoforms; Human Genome Project; Genes; Pseudogenes; RNA
PubMed: 37794265
DOI: 10.1038/s41586-023-06490-x -
Wellcome Open Research 2018The PubMLST.org website hosts a collection of open-access, curated databases that integrate population sequence data with provenance and phenotype information for over...
The PubMLST.org website hosts a collection of open-access, curated databases that integrate population sequence data with provenance and phenotype information for over 100 different microbial species and genera. Although the PubMLST website was conceived as part of the development of the first multi-locus sequence typing (MLST) scheme in 1998 the software it uses, the Bacterial Isolate Genome Sequence database (BIGSdb, published in 2010), enables PubMLST to include all levels of sequence data, from single gene sequences up to and including complete, finished genomes. Here we describe developments in the BIGSdb software made from publication to June 2018 and show how the platform realises microbial population genomics for a wide range of applications. The system is based on the gene-by-gene analysis of microbial genomes, with each deposited sequence annotated and curated to identify the genes present and systematically catalogue their variation. Originally intended as a means of characterising isolates with typing schemes, the synthesis of sequences and records of genetic variation with provenance and phenotype data permits highly scalable (whole genome sequence data for tens of thousands of isolates) means of addressing a wide range of functional questions, including: the prediction of antimicrobial resistance; likely cross-reactivity with vaccine antigens; and the functional activities of different variants that lead to key phenotypes. There are no limitations to the number of sequences, genetic loci, allelic variants or schemes (combinations of loci) that can be included, enabling each database to represent an expanding catalogue of the genetic variation of the population in question. In addition to providing web-accessible analyses and links to third-party analysis and visualisation tools, the BIGSdb software includes a RESTful application programming interface (API) that enables access to all the underlying data for third-party applications and data analysis pipelines.
PubMed: 30345391
DOI: 10.12688/wellcomeopenres.14826.1 -
Nucleic Acids Research Jan 2019COSMIC, the Catalogue Of Somatic Mutations In Cancer (https://cancer.sanger.ac.uk) is the most detailed and comprehensive resource for exploring the effect of somatic...
COSMIC, the Catalogue Of Somatic Mutations In Cancer (https://cancer.sanger.ac.uk) is the most detailed and comprehensive resource for exploring the effect of somatic mutations in human cancer. The latest release, COSMIC v86 (August 2018), includes almost 6 million coding mutations across 1.4 million tumour samples, curated from over 26 000 publications. In addition to coding mutations, COSMIC covers all the genetic mechanisms by which somatic mutations promote cancer, including non-coding mutations, gene fusions, copy-number variants and drug-resistance mutations. COSMIC is primarily hand-curated, ensuring quality, accuracy and descriptive data capture. Building on our manual curation processes, we are introducing new initiatives that allow us to prioritize key genes and diseases, and to react more quickly and comprehensively to new findings in the literature. Alongside improvements to the public website and data-download systems, new functionality in COSMIC-3D allows exploration of mutations within three-dimensional protein structures, their protein structural and functional impacts, and implications for druggability. In parallel with COSMIC's deep and broad variant coverage, the Cancer Gene Census (CGC) describes a curated catalogue of genes driving every form of human cancer. Currently describing 719 genes, the CGC has recently introduced functional descriptions of how each gene drives disease, summarized into the 10 cancer Hallmarks.
Topics: Databases, Nucleic Acid; Genes; Humans; Mutation; Neoplasms; Protein Conformation
PubMed: 30371878
DOI: 10.1093/nar/gky1015 -
Free Neuropathology Jan 2023This paper reviews ten highly impactful studies published in the previous year selected by the author from the neurodegenerative neuropathology literature. As in...
This paper reviews ten highly impactful studies published in the previous year selected by the author from the neurodegenerative neuropathology literature. As in previous years, the focus is to highlight human tissue-based experimentation most relevant to neuropathologists. A concerted effort was made to balance the selected studies across disease categories, approaches, and methodologies to capture the breadth of the research landscape. Studies include an integrated proteomic and transcriptomic study of Alzheimer disease (AD) and new consensus diagnostic neuropathological criteria for progressive supranuclear palsy. A number of studies looking at TAR DNA-binding protein 43 (TDP-43) are highlighted. One examined interaction between AD and limbic age-related TDP-43 encephalopathy (LATE) and yet another demonstrated how TDP-43 represses cryptic exon inclusion in , suggesting a novel pathogenic mechanism. Most surprisingly, three cryogenic electron microscopy (cryo-EM) studies showed that filaments form the core of TDP-43-positive inclusions. Cryo-EM revealed a prion protein amyloid structure from aggregates in Gerstmann-Sträussler-Scheinker disease. There was an elegant functional genomic study cataloging microglial gene expression in the human brain. A study shed light on how influences chronic traumatic encephalopathy. A pathoanatomical study tested the dual hit hypothesis of Lewy body progression throughout the nervous system. And finally, deep learning continues to show its promise with application of a weakly supervised multiple instance learning paradigm to assess aging post-mortem brains.
PubMed: 37694160
DOI: 10.17879/freeneuropathology-2023-4899 -
Breast Cancer Research : BCR 2009Next-generation sequencing (also known as massively parallel sequencing) technologies are revolutionising our ability to characterise cancers at the genomic,...
Next-generation sequencing (also known as massively parallel sequencing) technologies are revolutionising our ability to characterise cancers at the genomic, transcriptomic and epigenetic levels. Cataloguing all mutations, copy number aberrations and somatic rearrangements in an entire cancer genome at base pair resolution can now be performed in a matter of weeks. Furthermore, massively parallel sequencing can be used as a means for unbiased transcriptomic analysis of mRNAs, small RNAs and noncoding RNAs, genome-wide methylation assays and high-throughput chromatin immunoprecipitation assays. Here, I discuss the potential impact of this technology on breast cancer research and the challenges that come with this technological breakthrough.
Topics: Breast Neoplasms; Female; Genetic Predisposition to Disease; Genome, Human; Humans; Mutation; Sequence Analysis, DNA
PubMed: 20030863
DOI: 10.1186/bcr2431 -
Bone Sep 2017Osteosarcoma is the predominant form of bone cancer, affecting mostly adolescents. Recent progress made in molecular genetic studies of osteosarcoma has changed our view... (Review)
Review
Osteosarcoma is the predominant form of bone cancer, affecting mostly adolescents. Recent progress made in molecular genetic studies of osteosarcoma has changed our view on the cause of the disease and ongoing therapeutic approaches for patients. As we draw closer to gaining more complete catalogs of candidate cancer driver genes in common forms of cancer, the landscape of somatic mutations in osteosarcoma is emerging from its first phase. In this review, we summarize recent whole genome and/or whole exome genomic studies, and then put these findings in the context of genetic hallmarks of somatic mutations and mutational processes in human osteosarcoma. One of the lessons learned here is that the extent of somatic mutations and complexity of the osteosarcoma genome are similar to that of common forms of adult cancer. Thus, a much higher number of samples than those currently obtained are needed to complete the catalog of driver mutations in human osteosarcoma. In parallel, genetic studies in other species have revealed candidate driver genes and their roles in the genesis of osteosarcoma. This review also summarizes newly identified drivers in genetically engineered mouse models (GEMMs) and discusses our understanding of the impact of nature and number of drivers on tumor latency, subtypes, and metastatic potentials of osteosarcoma. It is becoming apparent that a synergistic team composed of three drivers (one 'first driver' and two 'synergistic drivers') may be required to generate an animal model that recapitulates aggressive osteosarcoma with a short latency. Finally, new cancer therapies are urgently needed to improve survival rate and quality of life for osteosarcoma patients. Several vulnerabilities in osteosarcoma are illustrated in this review to exemplify the opportunities for next generation molecularly targeted therapies. However, much work remains in order to complete our understanding of the somatic mutation basis of osteosarcoma, to develop reliable animal models of human disease, and to apply this information to guide new therapeutic approaches for reducing morbidity and mortality of this rare disease.
Topics: Animals; Genomics; High-Throughput Nucleotide Sequencing; Humans; Inheritance Patterns; Models, Biological; Mutation; Osteosarcoma
PubMed: 27760307
DOI: 10.1016/j.bone.2016.10.017 -
The Journal of Histochemistry and... May 2012The widespread use of whole genome analysis based on array comparative genomic hybridization in diagnostics and research has led to a continuously growing number of... (Review)
Review
The widespread use of whole genome analysis based on array comparative genomic hybridization in diagnostics and research has led to a continuously growing number of microdeletion and microduplication syndromes (MMSs) connected to certain phenotypes. These MMSs also include increasing instances in which the critical region can be reciprocally deleted or duplicated. This review catalogues the currently known MMSs and the corresponding critical regions including phenotypic consequences. Besides the pathogenic pathways leading to such rearrangements, the different detection methods and their limitations are discussed. Finally, the databases available for distinguishing between reported benign or pathogenic copy number alterations are highlighted. Overall, a review of MMSs that previously were also denoted "genomic disorders" or "contiguous gene syndromes" is given.
Topics: Chromosome Aberrations; Databases, Factual; Gene Deletion; Gene Duplication; Genome, Human; Humans; In Situ Hybridization, Fluorescence; Intellectual Disability; Nucleic Acid Amplification Techniques; Oligonucleotide Array Sequence Analysis; Syndrome
PubMed: 22396478
DOI: 10.1369/0022155412440001 -
Urologie (Heidelberg, Germany) Aug 2022Over the past 30 years, outpatient surgery has developed into an indispensable pillar of patient care in Germany, without its full potential coming to light. (Review)
Review
BACKGROUND
Over the past 30 years, outpatient surgery has developed into an indispensable pillar of patient care in Germany, without its full potential coming to light.
QUESTION
What are the reasons for the stagnation of further development of outpatient surgery and its suboptimal status quo?
MATERIALS AND METHODS
Presentation and comparison of outpatient surgery numbers from clinics and practices, and a critical analysis of their development.
RESULTS
After reaching a maximum number of outpatient operations in practices and clinics in 2015, there has been a location-independent decrease and stagnation due to underfunding of outpatient surgical structures and a shortage of resources.
CONCLUSION
Outpatient surgery represents a patient-friendly and cost-effective alternative to inpatient interventions, provided that that medical and social indications rule out an increased risk. The expansion of outpatient surgery has so far provided relieve to the cost-intensive hospital sector and-in view of the shortage of nurses and physicians-will do so to an even greater extent as soon as politicians and payers commit to remuneration that is performance-related and actually covers the costs. Furthermore, the future of the healthcare system also depends on the future of outpatient surgery, which is to be assessed as positive.
Topics: Ambulatory Surgical Procedures; Cost-Benefit Analysis; Germany; Hospital Costs; Humans; Outpatients
PubMed: 35925293
DOI: 10.1007/s00120-022-01878-5