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- Alexandrov, Ludmil B., et al.
(författare)
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Signatures of mutational processes in human cancer
- 2013
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 500:7463, s. 415-421
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Tidskriftsartikel (refereegranskat)abstract
- All cancers are caused by somatic mutations; however, understanding of the biological processes generating these mutations is limited. The catalogue of somatic mutations from a cancer genome bears the signatures of the mutational processes that have been operative. Here we analysed 4,938,362 mutations from 7,042 cancers and extracted more than 20 distinct mutational signatures. Some are present in many cancer types, notably a signature attributed to the APOBEC family of cytidine deaminases, whereas others are confined to a single cancer class. Certain signatures are associated with age of the patient at cancer diagnosis, known mutagenic exposures or defects in DNA maintenance, but many are of cryptic origin. In addition to these genome-wide mutational signatures, hypermutation localized to small genomic regions, 'kataegis', is found in many cancer types. The results reveal the diversity of mutational processes underlying the development of cancer, with potential implications for understanding of cancer aetiology, prevention and therapy.
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- Nik-Zainal, Serena, et al.
(författare)
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Mutational Processes Molding the Genomes of 21 Breast Cancers
- 2012
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 149:5, s. 979-993
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Tidskriftsartikel (refereegranskat)abstract
- All cancers carry somatic mutations. The patterns of mutation in cancer genomes reflect the DNA damage and repair processes to which cancer cells and their precursors have been exposed. To explore these mechanisms further, we generated catalogs of somatic mutation from 21 breast cancers and applied mathematical methods to extract mutational signatures of the underlying processes. Multiple distinct single- and double-nucleotide substitution signatures were discernible. Cancers with BRCA1 or BRCA2 mutations exhibited a characteristic combination of substitution mutation signatures and a distinctive profile of deletions. Complex relationships between somatic mutation prevalence and transcription were detected. A remarkable phenomenon of localized hypermutation, termed "kataegis,'' was observed. Regions of kataegis differed between cancers but usually colocalized with somatic rearrangements. Base substitutions in these regions were almost exclusively of cytosine at TpC dinucleotides. The mechanisms underlying most of these mutational signatures are unknown. However, a role for the APOBEC family of cytidine deaminases is proposed.
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- Nik-Zainal, Serena, et al.
(författare)
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The Life History of 21 Breast Cancers
- 2012
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Ingår i: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 149:5
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Tidskriftsartikel (refereegranskat)abstract
- Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis.
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- Brussaard, Lijbert, et al.
(författare)
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Biodiversity and ecosystem functioning in soil
- 1997
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Ingår i: Ambio: a Journal of Human Environment. - 0044-7447. ; 26:8, s. 563-570
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Tidskriftsartikel (refereegranskat)abstract
- We review the current knowledge on biodiversity in soils, its role in ecosystem processes, its importance for human purposes, and its resilience against stress and disturbance. The number of existing species is vastly higher than the number described, even in the macroscopically visible taxa, and biogeographical syntheses are largely lacking. A major effort in taxonomy and the training of a new generation of systematists is imperative. This effort has to be focussed on the groups of soil organisms that, to the best of our knowledge, play key roles in ecosystem functioning. To identify such groups, spheres of influence (SOI) of soil biota - such as the root biota, the shredders of organic matter and the soil bioturbators - are recognized that presumably control ecosystem processes, for example, through interactions with plants. Within those SOI, functional groups of soil organisms are recognized. Research questions of the highest urgency are the assignment of species to functional groups and determining the redundancy of species within functional groups. These priorities follow from the need to address the extent of any loss of functioning in soils, associated with intensive agriculture, forest disturbance, pollution of the environment, and global environmental change. The soil biota considered at present to be most at risk are species-poor functional groups among macrofaunal shredders of organic matter, bioturbators of soil, specialized bacteria like nitrifiers and nitrogen fixers, and fungiforming mycorrhizas. An experimental approach in addressing these research priorities is needed, using longterm and large-scale field experiments and modern methods of geostatistics and geographic information systems.
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- Curran, S.J., et al.
(författare)
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Redshifted H I and OH absorption in radio galaxies and quasars
- 2011
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 413:2, s. 1165-1173
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Tidskriftsartikel (refereegranskat)abstract
- From a survey for the redshifted H i 21-cm and OH 18-cm absorption in the hosts of a sample of radio galaxies and quasars, we detect H i in three of the 10 and OH in none of the 14 sources for which useful data were obtained. As expected from our recent result, all of the 21-cm detections occur in sources with ultraviolet (UV) continuum luminosities of L(UV) 1023 W Hz-1. Our 21-cm detections in combination with those previously published give a total of eight (associated and intervening) H i-absorbing sources searched and undetected in OH. Using the detected 21-cm line strengths to normalize the limits, we find that only two of these eight sources may have been searched sufficiently deeply in OH, even though these are marginal.
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- Seth-Smith, Helena M. B., et al.
(författare)
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Co-evolution of genomes and plasmids within Chlamydia trachomatis and the emergence in Sweden of a new variant strain
- 2009
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Ingår i: BMC Genomics. - : Springer Science and Business Media LLC. - 1471-2164. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Chlamydia trachomatis is the most common cause of sexually transmitted infections globally and the leading cause of preventable blindness in the developing world. There are two biovariants of C trachomatis: 'trachoma', causing ocular and genital tract infections, and the invasive 'lymphogranuloma venereum' strains. Recently, a new variant of the genital tract C trachomatis emerged in Sweden. This variant escaped routine diagnostic tests because it carries a plasmid with a deletion. Failure to detect this strain has meant it has spread rapidly across the country provoking a worldwide alert. In addition to being a key diagnostic target, the plasmid has been linked to chlamydial virulence. Analysis of chlamydial plasmids and their cognate chromosomes was undertaken to provide insights into the evolutionary relationship between chromosome and plasmid. This is essential knowledge if the plasmid is to be continued to be relied on as a key diagnostic marker, and for an understanding of the evolution of Chlamydia trachomatis. Results: The genomes of two new C trachomatis strains were sequenced, together with plasmids from six C trachomatis isolates, including the new variant strain from Sweden. The plasmid from the new Swedish variant has a 377 bp deletion in the first predicted coding sequence, abolishing the site used for PCR detection, resulting in negative diagnosis. In addition, the variant plasmid has a 44 bp duplication downstream of the deletion. The region containing the second predicted coding sequence is the most highly conserved region of the plasmids investigated. Phylogenetic analysis of the plasmids and chromosomes are fully congruent. Moreover this analysis also shows that ocular and genital strains diverged from a common C trachomatis progenitor. Conclusion: The evolutionary pathways of the chlamydial genome and plasmid imply that inheritance of the plasmid is tightly linked with its cognate chromosome. These data suggest that the plasmid is not a highly mobile genetic element and does not transfer readily between isolates. Comparative analysis of the plasmid sequences has revealed the most conserved regions that should be used to design future plasmid based nucleic acid amplification tests, to avoid diagnostic failures.
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