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1.
Nat Med ; 28(8): 1662-1671, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35953718

RESUMO

Richter transformation (RT) is a paradigmatic evolution of chronic lymphocytic leukemia (CLL) into a very aggressive large B cell lymphoma conferring a dismal prognosis. The mechanisms driving RT remain largely unknown. We characterized the whole genome, epigenome and transcriptome, combined with single-cell DNA/RNA-sequencing analyses and functional experiments, of 19 cases of CLL developing RT. Studying 54 longitudinal samples covering up to 19 years of disease course, we uncovered minute subclones carrying genomic, immunogenetic and transcriptomic features of RT cells already at CLL diagnosis, which were dormant for up to 19 years before transformation. We also identified new driver alterations, discovered a new mutational signature (SBS-RT), recognized an oxidative phosphorylation (OXPHOS)high-B cell receptor (BCR)low-signaling transcriptional axis in RT and showed that OXPHOS inhibition reduces the proliferation of RT cells. These findings demonstrate the early seeding of subclones driving advanced stages of cancer evolution and uncover potential therapeutic targets for RT.


Assuntos
Leucemia Linfocítica Crônica de Células B , Linfoma Difuso de Grandes Células B , Transformação Celular Neoplásica/genética , Progressão da Doença , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia
2.
Nature ; 608(7924): 724-732, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35948631

RESUMO

The lymphocyte genome is prone to many threats, including programmed mutation during differentiation1, antigen-driven proliferation and residency in diverse microenvironments. Here, after developing protocols for expansion of single-cell lymphocyte cultures, we sequenced whole genomes from 717 normal naive and memory B and T cells and haematopoietic stem cells. All lymphocyte subsets carried more point mutations and structural variants than haematopoietic stem cells, with higher burdens in memory cells than in naive cells, and with T cells accumulating mutations at a higher rate throughout life. Off-target effects of immunological diversification accounted for approximately half of the additional differentiation-associated mutations in lymphocytes. Memory B cells acquired, on average, 18 off-target mutations genome-wide for every on-target IGHV mutation during the germinal centre reaction. Structural variation was 16-fold higher in lymphocytes than in stem cells, with around 15% of deletions being attributable to off-target recombinase-activating gene activity. DNA damage from ultraviolet light exposure and other sporadic mutational processes generated hundreds to thousands of mutations in some memory cells. The mutation burden and signatures of normal B cells were broadly similar to those seen in many B-cell cancers, suggesting that malignant transformation of lymphocytes arises from the same mutational processes that are active across normal ontogeny. The mutational landscape of normal lymphocytes chronicles the off-target effects of programmed genome engineering during immunological diversification and the consequences of differentiation, proliferation and residency in diverse microenvironments.


Assuntos
Linfócitos , Mutação , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Diferenciação Celular , Proliferação de Células , Microambiente Celular , Dano ao DNA/genética , Dano ao DNA/efeitos da radiação , Centro Germinativo/citologia , Centro Germinativo/imunologia , Humanos , Memória Imunológica/genética , Linfócitos/citologia , Linfócitos/imunologia , Linfócitos/metabolismo , Linfócitos/patologia , Neoplasias/genética , Neoplasias/patologia
3.
Nat Commun ; 13(1): 4622, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35941135

RESUMO

Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool.


Assuntos
Leucemia Mieloide Aguda , Análise Citogenética , Citometria de Fluxo/métodos , Humanos , Quimioterapia de Indução/métodos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Neoplasia Residual
4.
Nat Commun ; 13(1): 4272, 2022 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-35953478

RESUMO

Germ cell tumours (GCTs) are a collection of benign and malignant neoplasms derived from primordial germ cells. They are uniquely able to recapitulate embryonic and extraembryonic tissues, which carries prognostic and therapeutic significance. The developmental pathways underpinning GCT initiation and histogenesis are incompletely understood. Here, we study the relationship of histogenesis and clonal diversification in GCTs by analysing the genomes and transcriptomes of 547 microdissected histological units. We find no correlation between genomic and histological heterogeneity. However, we identify unifying features including the retention of fetal developmental transcripts across tissues, expression changes on chromosome 12p, and a conserved somatic evolutionary sequence of whole genome duplication followed by clonal diversification. While this pattern is preserved across all GCTs, the developmental timing of the duplication varies between prepubertal and postpubertal cases. In addition, tumours of younger children exhibit distinct substitution signatures which may lend themselves as potential biomarkers for risk stratification. Our findings portray the extensive diversification of GCT tissues and genetic subclones as randomly distributed, while identifying overarching transcriptional and genomic features.


Assuntos
Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Criança , Genômica , Humanos , Masculino , Neoplasias Embrionárias de Células Germinativas/genética , Neoplasias Testiculares/genética , Transcriptoma/genética
5.
Nat Commun ; 13(1): 3949, 2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35803914

RESUMO

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.


Assuntos
Polipose Adenomatosa do Colo , Neoplasias Colorretais , DNA Glicosilases/genética , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , DNA Glicosilases/metabolismo , Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Humanos , Mutação , Taxa de Mutação
6.
Nature ; 606(7913): 343-350, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35650442

RESUMO

Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4-6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.


Assuntos
Envelhecimento , Hematopoiese Clonal , Células Clonais , Longevidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Criança , Pré-Escolar , Hematopoiese Clonal/genética , Células Clonais/citologia , Feminino , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/patologia , Células-Tronco Hematopoéticas/citologia , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Células-Tronco Multipotentes/citologia , Adulto Jovem
7.
Nature ; 606(7913): 335-342, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35650444

RESUMO

Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.


Assuntos
Hematopoiese Clonal , Células Clonais , Idoso , Envelhecimento , Hematopoiese Clonal/genética , Células Clonais/citologia , Genoma Humano , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Mutação , Filogenia
8.
Nat Commun ; 13(1): 2710, 2022 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-35581206

RESUMO

Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.


Assuntos
Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo de Erro de Pareamento de DNA/genética , Células Epiteliais/patologia , Mutação em Linhagem Germinativa , Humanos , Mutação , Filogenia
9.
Blood Adv ; 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-35363872

RESUMO

Follicular lymphoma is morphologically and clinically diverse; with mutations in epigenetic regulators alongside t(14;18) identified as disease initiating events. Identification of additional mutational entities confirm this cancer's heterogeneity, but whether mutational data can be resolved into mechanistically distinct subsets remains an open question. Targeted sequencing was applied to an unselected population-based FL cohort (n=548) with full clinical follow-up (n=538), which included 96 DLBCL transformations. We investigated whether molecular subclusters of FL can be identified, and whether mutational data provide predictive information relating to transformation. DNA extracted from FL samples was sequenced with a 293-gene panel representing genes frequently mutated in DLBCL and FL. Three clusters were resolved using mutational data alone, independent of translocation status: FL_aSHM, with high burden of aberrant somatic hypermutation (aSHM) targets; FL_STAT6, with high STAT6 & CREBBP mutation and low aSHM; FL_Com, with absence of features of other subtypes and enriched KMT2D mutation. Analysis of mutation signatures demonstrated differential enrichment of predicted mutation signatures between subgroups, and a dominant preference in the FL_aSHM subgroup for G(C>T)T and G(C>T)C transitions consistent with previously defined aSHM-like patterns. Of transformed cases with paired samples, 17/26 had evidence of branching evolution. Poorer OS in the aSHM group (p=0.04) was associated with older age, however overall tumor genetics provided limited information to predict individual patient risk. Our approach identifies three molecular subclusters of FL linked to differences in underlying mechanistic pathways. These clusters, which may be further resolved by the inclusion of translocation status and wider mutation profiles, have implications for understanding pathogenesis as well as improving treatment strategies in the future.

10.
Commun Biol ; 5(1): 306, 2022 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-35379892

RESUMO

Bayesian networks (BNs) are disciplined, explainable Artificial Intelligence models that can describe structured joint probability spaces. In the context of understanding complex relations between a number of variables in biological settings, they can be constructed from observed data and can provide a guiding, graphical tool in exploring such relations. Here we propose BNs for elucidating the relations between driver events in large cancer genomic datasets. We present a methodology that is specifically tailored to biologists and clinicians as they are the main producers of such datasets. We achieve this by using an optimal BN learning algorithm based on well established likelihood functions and by utilising just two tuning parameters, both of which are easy to set and have intuitive readings. To enhance value to clinicians, we introduce (a) the use of heatmaps for families in each network, and (b) visualising pairwise co-occurrence statistics on the network. For binary data, an optional step of fitting logic gates can be employed. We show how our methodology enhances pairwise testing and how biologists and clinicians can use BNs for discussing the main relations among driver events in large genomic cohorts. We demonstrate the utility of our methodology by applying it to 5 cancer datasets revealing complex genomic landscapes. Our networks identify central patterns in all datasets including a central 4-way mutual exclusivity between HDR, t(4,14), t(11,14) and t(14,16) in myeloma, and a 3-way mutual exclusivity of three major players: CALR, JAK2 and MPL, in myeloproliferative neoplasms. These analyses demonstrate that our methodology can play a central role in the study of large genomic cancer datasets.


Assuntos
Inteligência Artificial , Neoplasias , Algoritmos , Teorema de Bayes , Genômica , Humanos , Neoplasias/genética
11.
Nature ; 604(7906): 517-524, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35418684

RESUMO

The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans1-7. Comparative analyses can shed light on the diversity of mutagenesis across species, and on long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans8, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.


Assuntos
Longevidade , Taxa de Mutação , Animais , Humanos , Longevidade/genética , Mamíferos/genética , Mutagênese/genética , Mutação
13.
Nature ; 602(7895): 162-168, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35058638

RESUMO

Mutations in cancer-associated genes drive tumour outgrowth, but our knowledge of the timing of driver mutations and subsequent clonal dynamics is limited1-3. Here, using whole-genome sequencing of 1,013 clonal haematopoietic colonies from 12 patients with myeloproliferative neoplasms, we identified 580,133 somatic mutations to reconstruct haematopoietic phylogenies and determine clonal histories. Driver mutations were estimated to occur early in life, including the in utero period. JAK2V617F was estimated to have been acquired by 33 weeks of gestation to 10.8 years of age in 5 patients in whom JAK2V617F was the first event. DNMT3A mutations were acquired by 8 weeks of gestation to 7.6 years of age in 4 patients, and a PPM1D mutation was acquired by 5.8 years of age. Additional genomic events occurred before or following JAK2V617F acquisition and as independent clonal expansions. Sequential driver mutation acquisition was separated by decades across life, often outcompeting ancestral clones. The mean latency between JAK2V617F acquisition and diagnosis was 30 years (range 11-54 years). Estimated historical rates of clonal expansion varied substantially (3% to 190% per year), increased with additional driver mutations, and predicted latency to diagnosis. Our study suggests that early driver mutation acquisition and life-long growth and evolution underlie adult myeloproliferative neoplasms, raising opportunities for earlier intervention and a new model for cancer development.


Assuntos
Mutação , Transtornos Mieloproliferativos , Neoplasias , Adulto , Pré-Escolar , Células Clonais/patologia , Humanos , Janus Quinase 2/genética , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Filogenia , Proteína Fosfatase 2C , Sequenciamento Completo do Genoma
14.
Nat Commun ; 12(1): 6910, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34824211

RESUMO

Most cancers are characterized by the somatic acquisition of genomic rearrangements during tumour evolution that eventually drive the oncogenesis. Here, using multiplatform sequencing technologies, we identify and characterize a remarkable mutational mechanism in human hepatocellular carcinoma caused by Hepatitis B virus, by which DNA molecules from the virus are inserted into the tumour genome causing dramatic changes in its configuration, including non-homologous chromosomal fusions, dicentric chromosomes and megabase-size telomeric deletions. This aberrant mutational mechanism, present in at least 8% of all HCC tumours, can provide the driver rearrangements that a cancer clone requires to survive and grow, including loss of relevant tumour suppressor genes. Most of these events are clonal and occur early during liver cancer evolution. Real-time timing estimation reveals some HBV-mediated rearrangements occur as early as two decades before cancer diagnosis. Overall, these data underscore the importance of characterising liver cancer genomes for patterns of HBV integration.


Assuntos
Carcinoma Hepatocelular/genética , DNA Viral , Genoma Humano , Vírus da Hepatite B/genética , Neoplasias Hepáticas/genética , Carcinoma Hepatocelular/virologia , Regulação Neoplásica da Expressão Gênica , Humanos , Integração Viral , Sequenciamento Completo do Genoma
15.
Nature ; 598(7881): 473-478, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34646017

RESUMO

The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes1-8. Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease9-13 than in normal liver13-16, which enables positive selection to shape the genomic landscape9-13. Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes17-19, and GPAM, which produces storage triacylglycerol from free fatty acids20,21, also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease.


Assuntos
Hepatopatias/genética , Hepatopatias/metabolismo , Fígado/metabolismo , Mutação/genética , Transporte Ativo do Núcleo Celular/genética , Proteínas Reguladoras de Apoptose/genética , Linhagem Celular Tumoral , Doença Crônica , Estudos de Coortes , Ácidos Graxos não Esterificados/metabolismo , Feminino , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Resistência à Insulina , Hepatopatias Alcoólicas/genética , Hepatopatias Alcoólicas/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Triglicerídeos/metabolismo
16.
PLoS One ; 16(10): e0258269, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34614038

RESUMO

Ionizing radiation (IR) is widely used in cancer therapy and accidental or environmental exposure is a major concern. However, little is known about the genome-wide effects IR exerts on germ cells and the relative contribution of DNA repair pathways for mending IR-induced lesions. Here, using C. elegans as a model system and using primary sequencing data from our recent high-level overview of the mutagenic consequences of 11 genotoxic agents, we investigate in detail the genome-wide mutagenic consequences of exposing wild-type and 43 DNA repair and damage response defective C. elegans strains to a Caesium (Cs-137) source, emitting γ-rays. Cs-137 radiation induced single nucleotide variants (SNVs) at a rate of ~1 base substitution per 3 Gy, affecting all nucleotides equally. In nucleotide excision repair mutants, this frequency increased 2-fold concurrently with increased dinucleotide substitutions. As observed for DNA damage induced by bulky DNA adducts, small deletions were increased in translesion polymerase mutants, while base changes decreased. Structural variants (SVs) were augmented with dose, but did not arise with significantly higher frequency in any DNA repair mutants tested. Moreover, 6% of all mutations occurred in clusters, but clustering was not significantly altered in any DNA repair mutant background. Our data is relevant for better understanding how DNA repair pathways modulate IR-induced lesions.


Assuntos
Caenorhabditis elegans/genética , Caenorhabditis elegans/efeitos da radiação , Reparo do DNA/genética , Reparo do DNA/efeitos da radiação , Genoma Helmíntico , Radiação Ionizante , Animais , Caenorhabditis elegans/efeitos dos fármacos , Cisplatino/farmacologia , Reparo do DNA/efeitos dos fármacos , Humanos , Mutação/genética , Neoplasias/genética , Polimorfismo de Nucleotídeo Único/genética , Raios Ultravioleta
17.
Nat Genet ; 53(10): 1434-1442, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34594041

RESUMO

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


Assuntos
DNA Polimerase III/genética , DNA Polimerase II/genética , Mutação em Linhagem Germinativa/genética , Adolescente , Adulto , Idoso , Desenvolvimento Embrionário/genética , Genoma Humano/genética , Humanos , Neoplasias Intestinais/patologia , Intestinos/patologia , Pessoa de Meia-Idade , Mutagênese/genética , Filogenia , Células-Tronco/patologia , Adulto Jovem
18.
Nature ; 597(7876): 381-386, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34433962

RESUMO

Over the course of an individual's lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.


Assuntos
Células Germinativas/metabolismo , Mutação em Linhagem Germinativa , Taxa de Mutação , Especificidade de Órgãos/genética , Idoso , Células Clonais/metabolismo , Feminino , Saúde , Humanos , Masculino , Microdissecção , Pessoa de Meia-Idade , Estresse Oxidativo , Espermatogônias/metabolismo
19.
Nature ; 597(7876): 387-392, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34433963

RESUMO

Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.


Assuntos
Linhagem da Célula/genética , Embrião de Mamíferos/citologia , Embrião de Mamíferos/metabolismo , Desenvolvimento Embrionário/genética , Mutação , Encéfalo/metabolismo , Cromossomos Humanos Y/genética , Células Clonais/metabolismo , Mutação em Linhagem Germinativa/genética , Humanos , Masculino , Mosaicismo , Especificidade de Órgãos/genética , Polimorfismo de Nucleotídeo Único/genética
20.
Nature ; 595(7865): 85-90, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33981037

RESUMO

The ontogeny of the human haematopoietic system during fetal development has previously been characterized mainly through careful microscopic observations1. Here we reconstruct a phylogenetic tree of blood development using whole-genome sequencing of 511 single-cell-derived haematopoietic colonies from healthy human fetuses at 8 and 18 weeks after conception, coupled with deep targeted sequencing of tissues of known embryonic origin. We found that, in healthy fetuses, individual haematopoietic progenitors acquire tens of somatic mutations by 18 weeks after conception. We used these mutations as barcodes and timed the divergence of embryonic and extra-embryonic tissues during development, and estimated the number of blood antecedents at different stages of embryonic development. Our data support a hypoblast origin of the extra-embryonic mesoderm and primitive blood in humans.


Assuntos
Linhagem da Célula/genética , Desenvolvimento Embrionário/genética , Sistema Hematopoético/embriologia , Sistema Hematopoético/metabolismo , Mutação , Células Sanguíneas/citologia , Células Sanguíneas/metabolismo , Células Clonais/citologia , Células Clonais/metabolismo , Análise Mutacional de DNA , Feto/citologia , Feto/embriologia , Feto/metabolismo , Camadas Germinativas/citologia , Camadas Germinativas/metabolismo , Saúde , Sistema Hematopoético/citologia , Humanos , Cariotipagem , Masculino , Mesoderma/citologia , Mesoderma/embriologia , Mesoderma/metabolismo , Taxa de Mutação , Especificidade de Órgãos/genética , Fatores de Tempo , Sequenciamento Completo do Genoma , Fluxo de Trabalho
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