Somatic mutation rates scale with lifespan across mammals

Nature, Journal Year: 2022, Volume and Issue: 604(7906), P. 517 - 524

Published: April 13, 2022

Abstract The rates and patterns of somatic mutation in normal tissues are largely unknown outside humans 1–7 . Comparative analyses can shed light on the diversity mutagenesis across species, long-standing hypotheses about evolution their role cancer ageing. Here we performed whole-genome sequencing 208 intestinal crypts from 56 individuals to study landscape 16 mammalian species. We found that was dominated by seemingly endogenous mutational processes all including 5-methylcytosine deamination oxidative damage. With some differences, signatures other species resembled those described 8 , although relative contribution each signature varied Notably, rate per year greatly exhibited a strong inverse relationship with lifespan, no life-history trait studied showing comparable association. Despite widely different life histories among examined—including variation around 30-fold lifespan 40,000-fold body mass—the burden at end only factor 3. These data unveil common mammals, suggest evolutionarily constrained may be contributing

Language: Английский

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The mutational landscape of human somatic and germline cells

Nature, Journal Year: 2021, Volume and Issue: 597(7876), P. 381 - 386

Published: Aug. 25, 2021

Language: Английский

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The longitudinal dynamics and natural history of clonal haematopoiesis

Nature, Journal Year: 2022, Volume and Issue: 606(7913), P. 335 - 342

Published: June 1, 2022

Abstract Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where phenomenon is termed clonal haematopoiesis 1–4 . The understanding of how and when develops, factors that govern its behaviour, it interacts ageing these variables relate to malignant progression remains limited 5,6 Here we track 697 clones from 385 individuals 55 years age or older over a median 13 years. We find 92.4% expanded at stable exponential rate study period, different driving substantially growth rates, ranging 5% ( DNMT3A TP53 ) more than 50% per year SRSF2 P95H ). Growth rates same mutation differed approximately ±5% year, proportionately affecting slow drivers substantially. By combining our time-series data phylogenetic analysis 1,731 whole-genome sequences colonies 7 an group, reveal distinct patterns lifelong behaviour. -mutant preferentially early life displayed slower old context increasingly competitive oligoclonal landscape. contrast, splicing gene drove expansion only later life, whereas TET2 emerged all ages. Finally, show faster carry higher risk progression. Our findings characterize natural history give fundamental insights into interactions between mutation, selection.

Language: Английский

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Life histories of myeloproliferative neoplasms inferred from phylogenies

Nature, Journal Year: 2022, Volume and Issue: 602(7895), P. 162 - 168

Published: Jan. 20, 2022

Language: Английский

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Limitations and opportunities of technologies for the analysis of cell-free DNA in cancer diagnostics

Nature Biomedical Engineering, Journal Year: 2022, Volume and Issue: 6(3), P. 232 - 245

Published: Jan. 31, 2022

Language: Английский

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Pan-cancer whole-genome comparison of primary and metastatic solid tumours

Nature, Journal Year: 2023, Volume and Issue: 618(7964), P. 333 - 341

Published: May 10, 2023

Metastatic cancer remains an almost inevitably lethal disease1-3. A better understanding of disease progression and response to therapies therefore utmost importance. Here we characterize the genomic differences between early-stage untreated primary tumours late-stage treated metastatic using a harmonized pan-cancer analysis (or reanalysis) two unpaired primary4 metastatic5 cohorts 7,108 whole-genome-sequenced tumours. in general have lower intratumour heterogeneity conserved karyotype, displaying only modest increase mutations, although frequencies structural variants are elevated overall. Furthermore, highly variable tumour-specific contributions mutational footprints endogenous (for example, SBS1 APOBEC) exogenous processes platinum treatment) present. The majority types had either moderate lung adenocarcinoma) or consistent portraits ovarian serous carcinoma) when comparing disease. Breast, prostate, thyroid kidney renal clear cell carcinomas pancreatic neuroendocrine exceptions rule, extensive transformation their landscape advanced stages. Exposure treatment further scars tumour genome introduces evolutionary bottleneck that selects for known therapy-resistant drivers approximately half patients. Our data showcase potential whole-genome identify distinctive features provide valuable resource investigate biological basis resistance therapies.

Language: Английский

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Somatic genomic changes in single Alzheimer’s disease neurons

Nature, Journal Year: 2022, Volume and Issue: 604(7907), P. 714 - 722

Published: April 20, 2022

Language: Английский

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A body map of somatic mutagenesis in morphologically normal human tissues

Nature, Journal Year: 2021, Volume and Issue: 597(7876), P. 398 - 403

Published: Aug. 25, 2021

Language: Английский

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Increased somatic mutation burdens in normal human cells due to defective DNA polymerases

Nature Genetics, Journal Year: 2021, Volume and Issue: 53(10), P. 1434 - 1442

Published: Sept. 30, 2021

Abstract Mutation accumulation in somatic cells contributes to cancer development and is proposed as a cause of aging. DNA polymerases Pol ε δ replicate during cell division. However, some cancers, defective proofreading due acquired POLE / POLD1 exonuclease domain mutations causes markedly elevated mutation burdens with distinctive mutational signatures. Germline familial predisposition. Here, we sequenced normal tissue tumor from individuals germline mutations. Increased characteristic signatures were found adult types, early embryogenesis sperm. Thus human physiology can tolerate ubiquitously burdens. Except for increased risk, do not exhibit overt features premature These results support model which all aging are attributable widespread malfunction directly resulting accrued life.

Language: Английский

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Genetics of human telomere biology disorders

Nature Reviews Genetics, Journal Year: 2022, Volume and Issue: 24(2), P. 86 - 108

Published: Sept. 23, 2022

Language: Английский

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