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1.
Cells ; 10(6)2021 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-34202997

RESUMO

The current SARS-CoV-2 pandemic underscores the importance of understanding the evolution of RNA genomes. While RNA is subject to the formation of similar lesions as DNA, the evolutionary and physiological impacts RNA lesions have on viral genomes are yet to be characterized. Lesions that may drive the evolution of RNA genomes can induce breaks that are repaired by recombination or can cause base substitution mutagenesis, also known as base editing. Over the past decade or so, base editing mutagenesis of DNA genomes has been subject to many studies, revealing that exposure of ssDNA is subject to hypermutation that is involved in the etiology of cancer. However, base editing of RNA genomes has not been studied to the same extent. Recently hypermutation of single-stranded RNA viral genomes have also been documented though its role in evolution and population dynamics. Here, we will summarize the current knowledge of key mechanisms and causes of RNA genome instability covering areas from the RNA world theory to the SARS-CoV-2 pandemic of today. We will also highlight the key questions that remain as it pertains to RNA genome instability, mutations accumulation, and experimental strategies for addressing these questions.


Assuntos
Evolução Molecular , RNA Viral/genética , SARS-CoV-2/genética , COVID-19/epidemiologia , COVID-19/virologia , Genoma Viral/genética , Humanos , Mutação , Pandemias , Edição de RNA/fisiologia , Estabilidade de RNA/fisiologia
2.
Am J Epidemiol ; 190(6): 962-976, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-33712835

RESUMO

Epidemiologic studies often rely on questionnaire data, exposure measurement tools, and/or biomarkers to identify risk factors and the underlying carcinogenic processes. An emerging and promising complementary approach to investigate cancer etiology is the study of somatic "mutational signatures" that endogenous and exogenous processes imprint on the cellular genome. These signatures can be identified from a complex web of somatic mutations thanks to advances in DNA sequencing technology and analytical algorithms. This approach is at the core of the Sherlock-Lung study (2018-ongoing), a retrospective case-only study of over 2,000 lung cancers in never-smokers (LCINS), using different patterns of mutations observed within LCINS tumors to trace back possible exposures or endogenous processes. Whole genome and transcriptome sequencing, genome-wide methylation, microbiome, and other analyses are integrated with data from histological and radiological imaging, lifestyle, demographic characteristics, environmental and occupational exposures, and medical records to classify LCINS into subtypes that could reveal distinct risk factors. To date, we have received samples and data from 1,370 LCINS cases from 17 study sites worldwide and whole-genome sequencing has been completed on 1,257 samples. Here, we present the Sherlock-Lung study design and analytical strategy, also illustrating some empirical challenges and the potential for this approach in future epidemiologic studies.


Assuntos
Análise Mutacional de DNA/métodos , Predisposição Genética para Doença/epidemiologia , Neoplasias Pulmonares/genética , Medição de Risco/métodos , Sequenciamento Completo do Genoma/métodos , Causalidade , Humanos , Estudos Retrospectivos , Fatores de Risco
3.
PLoS Genet ; 17(1): e1009302, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33444353

RESUMO

Human skin is continuously exposed to environmental DNA damage leading to the accumulation of somatic mutations over the lifetime of an individual. Mutagenesis in human skin cells can be also caused by endogenous DNA damage and by DNA replication errors. The contributions of these processes to the somatic mutation load in the skin of healthy humans has so far not been accurately assessed because the low numbers of mutations from current sequencing methodologies preclude the distinction between sequencing errors and true somatic genome changes. In this work, we sequenced genomes of single cell-derived clonal lineages obtained from primary skin cells of a large cohort of healthy individuals across a wide range of ages. We report here the range of mutation load and a comprehensive view of the various somatic genome changes that accumulate in skin cells. We demonstrate that UV-induced base substitutions, insertions and deletions are prominent even in sun-shielded skin. In addition, we detect accumulation of mutations due to spontaneous deamination of methylated cytosines as well as insertions and deletions characteristic of DNA replication errors in these cells. The endogenously induced somatic mutations and indels also demonstrate a linear increase with age, while UV-induced mutation load is age-independent. Finally, we show that DNA replication stalling at common fragile sites are potent sources of gross chromosomal rearrangements in human cells. Thus, somatic mutations in skin of healthy individuals reflect the interplay of environmental and endogenous factors in facilitating genome instability and carcinogenesis.


Assuntos
Dano ao DNA/efeitos da radiação , Metilação de DNA/genética , Replicação do DNA/genética , Pele/efeitos da radiação , Metilação de DNA/efeitos da radiação , Reparo do DNA/efeitos da radiação , Replicação do DNA/efeitos da radiação , Fibroblastos/efeitos da radiação , Genoma Humano/genética , Genoma Humano/efeitos da radiação , Instabilidade Genômica/efeitos da radiação , Genômica/métodos , Humanos , Mutação INDEL/efeitos da radiação , Melanócitos/efeitos da radiação , Mutagênese/genética , Mutagênese/efeitos da radiação , Pele/metabolismo , Raios Ultravioleta/efeitos adversos
4.
Nat Genet ; 52(11): 1178-1188, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33020667

RESUMO

Somatic mutations in driver genes may ultimately lead to the development of cancer. Understanding how somatic mutations accumulate in cancer genomes and the underlying factors that generate somatic mutations is therefore crucial for developing novel therapeutic strategies. To understand the interplay between spatial genome organization and specific mutational processes, we studied 3,000 tumor-normal-pair whole-genome datasets from 42 different human cancer types. Our analyses reveal that the change in somatic mutational load in cancer genomes is co-localized with topologically-associating-domain boundaries. Domain boundaries constitute a better proxy to track mutational load change than replication timing measurements. We show that different mutational processes lead to distinct somatic mutation distributions where certain processes generate mutations in active domains, and others generate mutations in inactive domains. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation-rate variations observed in human cancers.


Assuntos
Cromatina/química , Genoma Humano , Mutação , Neoplasias/genética , Linhagem Celular Tumoral , Cromossomos Humanos X/genética , Reparo de Erro de Pareamento de DNA , Análise Mutacional de DNA , DNA de Neoplasias , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Conformação Proteica , Domínios Proteicos , Dobramento de Proteína , Inativação do Cromossomo X
5.
PLoS One ; 15(10): e0237689, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33006981

RESUMO

Genomes of tens of thousands of SARS-CoV2 isolates have been sequenced across the world and the total number of changes (predominantly single base substitutions) in these isolates exceeds ten thousand. We compared the mutational spectrum in the new SARS-CoV-2 mutation dataset with the previously published mutation spectrum in hypermutated genomes of rubella-another positive single stranded (ss) RNA virus. Each of the rubella virus isolates arose by accumulation of hundreds of mutations during propagation in a single subject, while SARS-CoV-2 mutation spectrum represents a collection events in multiple virus isolates from individuals across the world. We found a clear similarity between the spectra of single base substitutions in rubella and in SARS-CoV-2, with C to U as well as A to G and U to C being the most prominent in plus strand genomic RNA of each virus. Of those, U to C changes universally showed preference for loops versus stems in predicted RNA secondary structure. Similarly, to what was previously reported for rubella virus, C to U changes showed enrichment in the uCn motif, which suggested a subclass of APOBEC cytidine deaminase being a source of these substitutions. We also found enrichment of several other trinucleotide-centered mutation motifs only in SARS-CoV-2-likely indicative of a mutation process characteristic to this virus. Altogether, the results of this analysis suggest that the mutation mechanisms that lead to hypermutation of the rubella vaccine virus in a rare pathological condition may also operate in the background of the SARS-CoV-2 viruses currently propagating in the human population.


Assuntos
Betacoronavirus/genética , Genoma Viral , RNA Viral/genética , Vírus da Rubéola/genética , COVID-19 , Infecções por Coronavirus/virologia , Citidina Desaminase/genética , Bases de Dados Genéticas , Evolução Molecular , Humanos , Mutação , Pandemias , Pneumonia Viral/virologia , SARS-CoV-2
6.
bioRxiv ; 2020 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-32793907

RESUMO

Genomes of tens of thousands of SARS-CoV2 isolates have been sequenced across the world and the total number of changes (predominantly single base substitutions) in these isolates exceeds ten thousand. We compared the mutational spectrum in the new SARS-CoV-2 mutation dataset with the previously published mutation spectrum in hypermutated genomes of rubella - another positive single stranded (ss) RNA virus. Each of the rubella isolates arose by accumulation of hundreds of mutations during propagation in a single subject, while SARS-CoV-2 mutation spectrum represents a collection events in multiple virus isolates from individuals across the world. We found a clear similarity between the spectra of single base substitutions in rubella and in SARS-CoV-2, with C to U as well as A to G and U to C being the most prominent in plus strand genomic RNA of each virus. Of those, U to C changes universally showed preference for loops versus stems in predicted RNA secondary structure. Similarly, to what was previously reported for rubella, C to U changes showed enrichment in the uCn motif, which suggested a subclass of APOBEC cytidine deaminase being a source of these substitutions. We also found enrichment of several other trinucleotide-centered mutation motifs only in SARS-CoV-2 - likely indicative of a mutation process characteristic to this virus. Altogether, the results of this analysis suggest that the mutation mechanisms that lead to hypermutation of the rubella vaccine virus in a rare pathological condition may also operate in the background of the SARS-CoV-2 viruses currently propagating in the human population.

7.
Nat Genet ; 52(9): 884-890, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32719516

RESUMO

Chromothripsis and kataegis are frequently observed in cancer and may arise from telomere crisis, a period of genome instability during tumorigenesis when depletion of the telomere reserve generates unstable dicentric chromosomes1-5. Here we examine the mechanism underlying chromothripsis and kataegis by using an in vitro telomere crisis model. We show that the cytoplasmic exonuclease TREX1, which promotes the resolution of dicentric chromosomes4, plays a prominent role in chromothriptic fragmentation. In the absence of TREX1, the genome alterations induced by telomere crisis primarily involve breakage-fusion-bridge cycles and simple genome rearrangements rather than chromothripsis. Furthermore, we show that the kataegis observed at chromothriptic breakpoints is the consequence of cytosine deamination by APOBEC3B. These data reveal that chromothripsis and kataegis arise from a combination of nucleolytic processing by TREX1 and cytosine editing by APOBEC3B.


Assuntos
Citidina Desaminase/genética , Exodesoxirribonucleases/genética , Fosfoproteínas/genética , Telômero/genética , Linhagem Celular Tumoral , Cromotripsia , Citosina Desaminase/genética , Instabilidade Genômica/genética , Humanos , Mutação/genética , Neoplasias/genética , Células U937
8.
DNA Repair (Amst) ; 91-92: 102868, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32438271

RESUMO

Regions of genomic DNA can become single-stranded in the course of normal replication and transcription as well as during DNA repair. Abnormal repair and replication intermediates can contain large stretches of persistent single-stranded DNA, which is extremely vulnerable to DNA damaging agents and hypermutation. Since such single-stranded DNA spans only a fraction of the genome at a given instance, hypermutation in these regions leads to tightly-spaced mutation clusters. This phenomenon of hypermutation in single-stranded DNA has been documented in several experimental models as well as in cancer genomes. Recently, hypermutated single-stranded RNA viral genomes also have been documented. Moreover, indications of hypermutation in single-stranded DNA may also be found in the human germline. This review will summarize key current knowledge and the recent developments in understanding the diverse mechanisms and sources of ssDNA hypermutation.


Assuntos
DNA de Cadeia Simples , Mutação , Animais , Bactérias/genética , Eucariotos/genética , Humanos , Mutagênese , Neoplasias/genética , Telômero , Vírus/genética
9.
Proc Natl Acad Sci U S A ; 117(17): 9440-9450, 2020 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-32277034

RESUMO

Yeast strains with low levels of the replicative DNA polymerases (alpha, delta, and epsilon) have high levels of chromosome deletions, duplications, and translocations. By examining the patterns of mutations induced in strains with low levels of DNA polymerase by the human protein APOBEC3B (a protein that deaminates cytosine in single-stranded DNA), we show dramatically elevated amounts of single-stranded DNA relative to a wild-type strain. During DNA replication, one strand (defined as the leading strand) is replicated processively by DNA polymerase epsilon and the other (the lagging strand) is replicated as short fragments initiated by DNA polymerase alpha and extended by DNA polymerase delta. In the low DNA polymerase alpha and delta strains, the APOBEC-induced mutations are concentrated on the lagging-strand template, whereas in the low DNA polymerase epsilon strain, mutations occur on the leading- and lagging-strand templates with similar frequencies. In addition, for most genes, the transcribed strand is mutagenized more frequently than the nontranscribed strand. Lastly, some of the APOBEC-induced clusters in strains with low levels of DNA polymerase alpha or delta are greater than 10 kb in length.


Assuntos
Citidina Desaminase/farmacologia , DNA Polimerase Dirigida por DNA/metabolismo , Proteínas Fúngicas/metabolismo , Antígenos de Histocompatibilidade Menor/farmacologia , Saccharomyces cerevisiae/genética , Cromossomos Fúngicos , Replicação do DNA , DNA Fúngico , DNA Polimerase Dirigida por DNA/genética , Proteínas Fúngicas/genética , Regulação Fúngica da Expressão Gênica/fisiologia , Estudo de Associação Genômica Ampla , Humanos , Mutação , Análise de Sequência de DNA/métodos
10.
Nucleic Acids Res ; 48(7): 3692-3707, 2020 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-32133535

RESUMO

Alkylation is one of the most ubiquitous forms of DNA lesions. However, the motif preferences and substrates for the activity of the major types of alkylating agents defined by their nucleophilic substitution reactions (SN1 and SN2) are still unclear. Utilizing yeast strains engineered for large-scale production of single-stranded DNA (ssDNA), we probed the substrate specificity, mutation spectra and signatures associated with DNA alkylating agents. We determined that SN1-type agents preferably mutagenize double-stranded DNA (dsDNA), and the mutation signature characteristic of the activity of SN1-type agents was conserved across yeast, mice and human cancers. Conversely, SN2-type agents preferably mutagenize ssDNA in yeast. Moreover, the spectra and signatures derived from yeast were detectable in lung cancers, head and neck cancers and tumors from patients exposed to SN2-type alkylating chemicals. The estimates of mutation loads associated with the SN2-type alkylation signature were higher in lung tumors from smokers than never-smokers, pointing toward the mutagenic activity of the SN2-type alkylating carcinogens in cigarettes. In summary, our analysis of mutations in yeast strains treated with alkylating agents, as well as in whole-exome and whole-genome-sequenced tumors identified signatures highly specific to alkylation mutagenesis and indicate the pervasive nature of alkylation-induced mutagenesis in cancers.


Assuntos
Alquilantes/toxicidade , Mutagênese , Mutação , Neoplasias/genética , Adenina/química , Animais , DNA Glicosilases/metabolismo , DNA Fúngico/química , DNA de Cadeia Simples/química , Humanos , Camundongos , Leveduras/efeitos dos fármacos , Leveduras/genética , Leveduras/metabolismo
12.
Nature ; 578(7793): 94-101, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32025018

RESUMO

Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature1. Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses3-15, enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated-but distinct-DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.


Assuntos
Mutação/genética , Neoplasias/genética , Fatores Etários , Sequência de Bases , Exoma/genética , Genoma Humano/genética , Humanos , Análise de Sequência de DNA
13.
PLoS Pathog ; 15(10): e1008080, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658304

RESUMO

Rubella viruses (RV) have been found in an association with granulomas in children with primary immune deficiencies (PID). Here, we report the recovery and characterization of infectious immunodeficiency-related vaccine-derived rubella viruses (iVDRV) from diagnostic skin biopsies of four patients. Sequence evolution within PID hosts was studied by comparison of the complete genomic sequences of the iVDRVs with the genome of the vaccine virus RA27/3. The degree of divergence of each iVDRV correlated with the duration of persistence indicating continuous intrahost evolution. The evolution rates for synonymous and nonsynonymous substitutions were estimated to be 5.7 x 10-3 subs/site/year and 8.9 x 10-4 subs/site/year, respectively. Mutational spectra and signatures indicated a major role for APOBEC cytidine deaminases and a secondary role for ADAR adenosine deaminases in generating diversity of iVDRVs. The distributions of mutations across the genes and 3D hotspots for amino acid substitutions in the E1 glycoprotein identified regions that may be under positive selective pressure. Quasispecies diversity was higher in granulomas than in recovered infectious iVDRVs. Growth properties of iVDRVs were assessed in WI-38 fibroblast cultures. None of the iVDRV isolates showed complete reversion to wild type phenotype but the replicative and persistence characteristics of iVDRVs were different from those of the RA27/3 vaccine strain, making predictions of iVDRV transmissibility and teratogenicity difficult. However, detection of iVDRV RNA in nasopharyngeal specimen and poor neutralization of some iVDRV strains by sera from vaccinated persons suggests possible public health risks associated with iVDRV carriers. Detection of IgM antibody to RV in sera of two out of three patients may be a marker of virus persistence, potentially useful for identifying patients with iVDRV before development of lesions. Studies of the evolutionary dynamics of iVDRV during persistence will contribute to development of infection control strategies and antiviral therapies.


Assuntos
Granuloma/virologia , Vacina contra Sarampo-Caxumba-Rubéola/efeitos adversos , Doenças da Imunodeficiência Primária/imunologia , Vírus da Rubéola/genética , Vírus da Rubéola/isolamento & purificação , Desaminases APOBEC/metabolismo , Adenosina Desaminase/metabolismo , Adolescente , Animais , Anticorpos Antivirais/sangue , Biópsia , Linhagem Celular , Criança , Chlorocebus aethiops , Genoma Viral/genética , Humanos , Imunoglobulina M/sangue , Vacina contra Sarampo-Caxumba-Rubéola/imunologia , Proteínas de Ligação a RNA/metabolismo , Pele/virologia , Células Vero , Proteínas do Envelope Viral/genética , Eliminação de Partículas Virais/genética
14.
PLoS Biol ; 17(9): e3000464, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31568516

RESUMO

A single cancer genome can harbor thousands of clustered mutations. Mutation signature analyses have revealed that the origin of clusters are lesions in long tracts of single-stranded (ss) DNA damaged by apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases, raising questions about molecular mechanisms that generate long ssDNA vulnerable to hypermutation. Here, we show that ssDNA intermediates formed during the repair of gamma-induced bursts of double-strand breaks (DSBs) in the presence of APOBEC3A in yeast lead to multiple APOBEC-induced clusters similar to cancer. We identified three independent pathways enabling cluster formation associated with repairing bursts of DSBs: 5' to 3' bidirectional resection, unidirectional resection, and break-induced replication (BIR). Analysis of millions of mutations in APOBEC-hypermutated cancer genomes revealed that cancer tolerance to formation of hypermutable ssDNA is similar to yeast and that the predominant pattern of clustered mutagenesis is the same as in resection-defective yeast, suggesting that cluster formation in cancers is driven by a BIR-like mechanism. The phenomenon of genome-wide burst of clustered mutagenesis revealed by our study can play an important role in generating somatic hypermutation in cancers as well as in noncancerous cells.


Assuntos
Quebras de DNA de Cadeia Dupla , Genoma Fúngico/efeitos da radiação , Mutagênese , Neoplasias/genética , Desaminases APOBEC/metabolismo , Raios gama , Humanos , Neoplasias/enzimologia , Saccharomyces cerevisiae
16.
PLoS Biol ; 17(5): e3000263, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31067233

RESUMO

Redox stress is a major hallmark of cancer. Analysis of thousands of sequenced cancer exomes and whole genomes revealed distinct mutational signatures that can be attributed to specific sources of DNA lesions. Clustered mutations discovered in several cancer genomes were linked to single-strand DNA (ssDNA) intermediates in various processes of DNA metabolism. Previously, only one clustered mutational signature had been clearly associated with a subclass of ssDNA-specific apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) cytidine deaminases. Others remain to be elucidated. We report here deciphering of the mutational spectra and mutational signature of redox stress in ssDNA of budding yeast and the signature of aging in human mitochondrial DNA. We found that the predominance of C to T substitutions is a common feature of both signatures. Measurements of the frequencies of hydrogen peroxide-induced mutations in proofreading-defective yeast mutants supported the conclusion that hydrogen peroxide-induced mutagenesis is not the result of increased DNA polymerase misincorporation errors but rather is caused by direct damage to DNA. Proteins involved in modulation of chromatin status play a significant role in prevention of redox stress-induced mutagenesis, possibly by facilitating protection through modification of chromatin structure. These findings provide an opportunity for the search and identification of the mutational signature of redox stress in cancers and in other pathological conditions and could potentially be used for informing therapeutic decisions. In addition, the discovery of such signatures that may be present in related organisms should also advance our understanding of evolution.


Assuntos
Envelhecimento/genética , DNA Mitocondrial/genética , DNA de Cadeia Simples/genética , Mutação/genética , Saccharomyces cerevisiae/genética , Estresse Fisiológico/genética , Sequência de Bases , Dano ao DNA/genética , DNA Polimerase Dirigida por DNA/metabolismo , Humanos , Peróxido de Hidrogênio/toxicidade , Mutagênese/genética , Taxa de Mutação , Neoplasias/genética , Oxirredução , Paraquat/toxicidade
17.
Microb Cell ; 6(1): 1-64, 2019 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-30652105

RESUMO

Understanding the plasticity of genomes has been greatly aided by assays for recombination, repair and mutagenesis. These assays have been developed in microbial systems that provide the advantages of genetic and molecular reporters that can readily be manipulated. Cellular assays comprise genetic, molecular, and cytological reporters. The assays are powerful tools but each comes with its particular advantages and limitations. Here the most commonly used assays are reviewed, discussed, and presented as the guidelines for future studies.

18.
Prion ; 13(1): 33-36, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30582399

RESUMO

This commentary is a tribute to the late colleague, Prof. Michael D. Ter-Avanesyan - prominent contributor into knowledge about prion maintenance and function. The commentary describes his early steps in genetics which brought him into prion research.


Assuntos
Saccharomyces cerevisiae/genética , História do Século XX , História do Século XXI , Mutação/genética , Poliploidia
20.
Environ Mol Mutagen ; 59(8): 672-686, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30152078

RESUMO

Somatic genome instability is a hallmark of cancer genomes and has been linked to aging and a variety of other pathologies. Large-scale cancer genome and exome sequencing have revealed that mutation load and spectra in cancers can be influenced by environmental exposures, the anatomical site of exposures, and tissue type. There is now an abundance of data favoring the hypothesis that a substantial portion of the mutations in cancers originate prior to carcinogenesis in stem cells of the healthy individual. Rapid advances in sequencing of noncancer cells from healthy humans have shown that their mutation loads and spectra resemble cancer data. Similar to cancer genomes, mutation profiles of healthy cells show marked intra-individual variation, thus providing a metric of the various factors-environmental and endogenous-involved in mutagenesis in these individuals. This review focuses on the current methodologies to measure mutation loads and to determine mutation signatures for evaluating the environmental and endogenous sources of DNA damage in human somatic cells. We anticipate that in future, such large-scale studies aimed at exploring the landscapes of somatic mutations across different cell types in healthy people would provide a valuable resource for designing personalized preventative strategies against diseases associated with somatic genome instability. Environ. Mol. Mutagen. 59:672-686, 2018. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.


Assuntos
Dano ao DNA/genética , Reparo do DNA/genética , Instabilidade Genômica/genética , Neoplasias/genética , Envelhecimento/genética , Genoma Humano/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Mutação/genética
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