1. |
- Nik-Zainal, Serena, et al.
(author)
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Mutational Processes Molding the Genomes of 21 Breast Cancers
- 2012
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In: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 149:5, s. 979-993
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Journal article (peer-reviewed)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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2. |
- Gumz, Michelle L, et al.
(author)
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Toward Precision Medicine : Circadian Rhythm of Blood Pressure and Chronotherapy for Hypertension - 2021 NHLBI Workshop Report
- 2023
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In: Hypertension. - : Wolters Kluwer. - 0194-911X .- 1524-4563. ; 80:3, s. 503-522
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Journal article (peer-reviewed)abstract
- Healthy individuals exhibit blood pressure variation over a 24-hour period with higher blood pressure during wakefulness and lower blood pressure during sleep. Loss or disruption of the blood pressure circadian rhythm has been linked to adverse health outcomes, for example, cardiovascular disease, dementia, and chronic kidney disease. However, the current diagnostic and therapeutic approaches lack sufficient attention to the circadian rhythmicity of blood pressure. Sleep patterns, hormone release, eating habits, digestion, body temperature, renal and cardiovascular function, and other important host functions as well as gut microbiota exhibit circadian rhythms, and influence circadian rhythms of blood pressure. Potential benefits of nonpharmacologic interventions such as meal timing, and pharmacologic chronotherapeutic interventions, such as the bedtime administration of antihypertensive medications, have recently been suggested in some studies. However, the mechanisms underlying circadian rhythm-mediated blood pressure regulation and the efficacy of chronotherapy in hypertension remain unclear. This review summarizes the results of the National Heart, Lung, and Blood Institute workshop convened on October 27 to 29, 2021 to assess knowledge gaps and research opportunities in the study of circadian rhythm of blood pressure and chronotherapy for hypertension.
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4. |
- Howell, Daniel, et al.
(author)
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Report of the Working Group on Multispecies Assessment Methods (WGSAM), 9–13 November 2015, Woods Hole, USA
- 2016
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Reports (other academic/artistic)abstract
- Three meetings were held between 2013 and 2015 (Stockholm, London and Woods Hole), with progress being made on all the Terms of Reference. WGSAM has been making significant contributions required to enable ICES to develop its capability to give advice on the ecosystem impacts of fishing and climate change. This is a priority area identified in the ICES strategic plan and is consistent with scientific needs to support implementation of the Common Fisheries Policy and Marine Strategy Framework Directive. This final report summarises the key progress made against each ToR. A particularly important area established during this period has been the discussions that have led to guidelines on quality assurance of ecosystem models in-tended for advice giving. WGSAM prepared a specific briefing on this issue and con-tinues to work on issues related to model review processes, model validation and developing methods for generating advice from multi-model ensembles. These are all important areas of work in the evolution toward giving integrated, ecosystem-based advice to ICES clients. We recommend that ICES supports continuation of WGSAM new ToRs and considers more specifically how to support WGSAM in developing advice relevant products.
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5. |
- Ju, Young Seok, et al.
(author)
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Somatic mutations reveal asymmetric cellular dynamics in the early human embryo
- 2017
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 543:7647, s. 714-718
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Journal article (peer-reviewed)abstract
- Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.
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6. |
- Malik, Rainer, et al.
(author)
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Low-frequency and common genetic variation in ischemic stroke : The METASTROKE collaboration
- 2016
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In: Neurology. - 1526-632X. ; 86:13, s. 26-1217
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Journal article (peer-reviewed)abstract
- OBJECTIVE: To investigate the influence of common and low-frequency genetic variants on the risk of ischemic stroke (all IS) and etiologic stroke subtypes.METHODS: We meta-analyzed 12 individual genome-wide association studies comprising 10,307 cases and 19,326 controls imputed to the 1000 Genomes (1 KG) phase I reference panel. We selected variants showing the highest degree of association (p < 1E-5) in the discovery phase for replication in Caucasian (13,435 cases and 29,269 controls) and South Asian (2,385 cases and 5,193 controls) samples followed by a transethnic meta-analysis. We further investigated the p value distribution for different bins of allele frequencies for all IS and stroke subtypes.RESULTS: We showed genome-wide significance for 4 loci: ABO for all IS, HDAC9 for large vessel disease (LVD), and both PITX2 and ZFHX3 for cardioembolic stroke (CE). We further refined the association peaks for ABO and PITX2. Analyzing different allele frequency bins, we showed significant enrichment in low-frequency variants (allele frequency <5%) for both LVD and small vessel disease, and an enrichment of higher frequency variants (allele frequency 10% and 30%) for CE (all p < 1E-5).CONCLUSIONS: Our findings suggest that the missing heritability in IS subtypes can in part be attributed to low-frequency and rare variants. Larger sample sizes are needed to identify the variants associated with all IS and stroke subtypes.
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7. |
- Nik-Zainal, Serena, et al.
(author)
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The Life History of 21 Breast Cancers
- 2012
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In: Cell. - : Elsevier BV. - 1097-4172 .- 0092-8674. ; 149:5
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Journal article (peer-reviewed)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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8. |
- Waight, Tod E., et al.
(author)
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Hf isotope evidence for variable slab input and crustal addition in basalts and andesites of the Taupo Volcanic Zone, New Zealand
- 2017
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In: Lithos. - : ELSEVIER SCIENCE BV. - 0024-4937 .- 1872-6143. ; 284-285, s. 222-236
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Journal article (peer-reviewed)abstract
- Crustal contamination complicates the identification of primary mantle-derived magma compositions in continental arcs. However, when crustal processes and components are well characterised, it is possible to extrapolate through continental arc magma compositional arrays towards the Hf and Nd isotope compositions of uncontaminated primary magmas. This is because of the similar behaviour of Hf and Nd during fractional crystallisation and mantle melting, and the subsequent limited variation in Hf/Nd in mantle-derived magmas and in many crustal lithologies, resulting in linear contamination trends for Hf-Nd isotopes. Here we present new Hf isotope data for a selection of volcanic rocks and crustal lithologies from the Taupo Volcanic Zone (TVZ), New Zealand and propose that the scatter in Hf-Nd isotopes indicates heterogeneity in the parental magmas prior to interactions with crustal lithologies. The observed variations likely represent variability in primary magma compositions as a result of different degrees of sediment addition at the slab-wedge interface. Coupled variations in isotopic composition, LILE/HFSE ratios (e.g. Rb/Zr and Ba/La) and SiO2 also clearly indicate that shallower level crustal interactions have occurred. Andesites from Ruapehu Volcano have more consistent parental magma compositions, and require greater amounts of a source sediment contribution. Notably, the compositions of older Ruapehu lavas can be modelled by interactions between mantle-derived magmas and lower crustal granulites, whereas younger lavas have probably interacted more with mid- to shallow crustal meta-sedimentary greywacke-argillite lithologies of the Permian to Cretaceous composite Torlesse Terrane. Hf-Nd isotopic compositions of meta-igneous granulite xenoliths from Mt. Ruapehu are consistent with previous interpretations that they are derived from oceanic crust that underlies the Torlesse meta-sediments. The results indicate that interactions with sediments at both the slab-wedge interface and in the lithosphere must be considered when evaluating trace element and isotopic variations in continental arcs.
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